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  • 1. Aahlin, Kristofer
    et al.
    Arvidsson, Per I.
    Huerta, Fernando
    Yngve, Ulrika.
    Preparation of 1-(4-(5-amino-6-(oxazolo[4,5-c]pyridin-2-yl)pyrazin-2-yl)benzoyl)piperazine derivatives as glycogen synthase kinase 3 inhibitors.2011Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    Title compds. I [R1 = H or Me], and their pharmaceutically acceptable salts, are prepd. and disclosed as glycogen synthase kinase 3 (GSK3) inhibitors. Thus, e.g., II was prepd. by cyclization of 3-amino-N-(4-hydroxypyridin-3-yl)pyrazine-2-carboxamide (prepn. given) to get intermediate 3-(oxazolo[4,5-c]pyridin-2-yl)pyrazin-2-amine, which underwent bromination followed by Suzuki reaction with (4-methylpiperazin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone. Compds. of the invention were tested for their selective inhibitory activity of GSK3β, e.g., II exhibited Ki value of 2.3 nM. The invention compds. are useful for the treatment of cognitive disorders, diabetes, cancer, etc. [on SciFinder(R)]

  • 2.
    Abass, Ahmed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Syntes av MPro-inhibitor2020Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    December 2019 the new pandemic Covid-19 sweeps the world and impose unmatched challenges on modern humanity, the virus started from Wuhan China and in just a few months the virus had spread to other countries and WHO (World Health Organization) called the disease a pandemic, Covid-19 is caused by the virus SARS-CoV -2 (severe acute respiratory syndrome-Coronavirus2), the virus is largely spread through human-to-human transmission, today more than 263 million people have been infected with the virus while more than 5 million have died.

    SARS-CoV-2 is closely related to other viruses of the genus Betacoronavirus such as bat coronavirus BatCoV RaTG13 (~ 96% sequence identity) and SARS-CoV (~ 80% sequence identity), Coronavirus such as SARS-CoV and SARS-CoV -2 need main protease MPro (3CLPro), MPro is interesting as there are no similar proteases in humans, and it is vital for virus survival as it has essential role in processing and replicating polyproteins of viral RNA.

    ML188 is a SARS-CoV MPro inhibitor, SARS-CoV and SARS-CoV -2 have 80% sequence identity, ML188 can be used as a starting point to analyze and improve MPro inhibitors that can be used against SARS-CoV -2.

    In this study with the use of UGI reaction to synthesized and modified analog to ML188 by exchanging 3-pyridialkarboxaldehyd which is one of the 4 starting material the compound with 4-pyridilkarboxaldehyd. By changing the nitrogen position in the aromatic ring, we want to see if this change can increase or decrease the compound effectiveness and if it has deferent effect on SARS-CoV2.  

    TLC and LC-MS are analysis method that is used to monitor the reaction and determine the purity of the reaction, column chromatography is used to purify the reaction mixture, NMR analysis both proton and carbon NMR is used to confirm the structure of our synthesized product. Result from the LCMS-Analyze showed a clear high peak with the exact mass of our Sought product but it also showed that the purification of the mixture didn’t happen fully thus we still had some impurities in the mixture. both the proton and carbon NMR results data were consistent with our compound structure. Now we need to test if this new compound can result to better inhibition in SARS-CoV2.

  • 3.
    Abd El-Wahed, Aida
    et al.
    Agr Res Ctr, Plant Protect Res Inst, Dept Bee Res, Giza 12627, Egypt.;Menoufia Univ, Dept Chem, Fac Sci, Shibin Al Kawm 32512, Egypt..
    Yosri, Nermeen
    Menoufia Univ, Dept Chem, Fac Sci, Shibin Al Kawm 32512, Egypt.;Jiangsu Univ, Sch Food & Biol Engn, Zhenjiang 212013, Jiangsu, Peoples R China..
    Sakr, Hanem H.
    Menoufia Univ, Dept Zool, Fac Sci, Shibin Al Kawm 32512, Egypt..
    Du, Ming
    Dalian Polytech Univ, Sch Food Sci & Technol, Natl Engn Res Ctr Seafood, Dalian 116034, Peoples R China..
    Algethami, Ahmed F. M.
    Alnahalaljwal Fdn Saudi Arabia, POB 617, Al Jumum 21926, Makkah, Saudi Arabia..
    Zhao, Chao
    Fujian Agr & Forestry Univ, Coll Food Sci, Fuzhou 350002, Peoples R China.;Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Control Chinese Med, Taipa, Macao, Peoples R China..
    Abdelazeem, Ahmed H.
    Beni Suef Univ, Dept Med Chem, Fac Pharm, Bani Suwayf 62514, Egypt.;Riyadh Elm Univ, Dept Pharmaceut Sci, Coll Pharm, Riyadh 11681, Saudi Arabia..
    Tahir, Haroon Elrasheid
    Jiangsu Univ, Sch Food & Biol Engn, Zhenjiang 212013, Jiangsu, Peoples R China..
    Masry, Saad H. D.
    Abu Dhabi Food Control Author, Al Ain 52150, U Arab Emirates.;City Sci Res & Technol Applicat, Arid Lands Cultivat Res Inst ALCRI, Dept Plant Protect & Biomol Diag, Alexandria 21934, Egypt..
    Abdel-Daim, Mohamed M.
    Suez Canal Univ, Dept Pharmacol, Fac Vet Med, Ismailia 41522, Egypt..
    Musharraf, Syed Ghulam
    Univ Karachi, HEJ Res Inst Chem, Int Ctr Chem & Biol Sci, Karachi 75270, Pakistan..
    El-Garawani, Islam
    Menoufia Univ, Dept Zool, Fac Sci, Shibin Al Kawm 32512, Egypt..
    Kai, Guoyin
    Zhejiang Chinese Med Univ, Coll Pharm, Lab Med Plant Biotechnol, Hangzhou 310053, Peoples R China..
    Al Naggar, Yahya
    Martin Luther Univ Halle Wittenberg, Inst Biol, Gen Zool, Hoher Weg 8, D-06120 Halle, Saale, Germany.;Tanta Univ, Fac Sci, Zool Dept, Tanta 31527, Egypt..
    Khalifa, Shaden A. M.
    Stockholm Univ, Dept Mol Biosci, Wenner Gren Inst, SE-10691 Stockholm, Sweden..
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi. Menoufia Univ, Dept Chem, Fac Sci, Shibin Al Kawm 32512, Egypt.;Stockholm Univ, Dept Mol Biosci, Wenner Gren Inst, SE-10691 Stockholm, Sweden.;Jiangsu Univ, Int Res Ctr Food Nutr & Safety, Zhenjiang 212013, Jiangsu, Peoples R China..
    Wasp Venom Biochemical Components and Their Potential in Biological Applications and Nanotechnological Interventions2021In: Toxins, ISSN 2072-6651, E-ISSN 2072-6651, Vol. 13, no 3, article id 206Article, review/survey (Refereed)
    Abstract [en]

    Wasps, members of the order Hymenoptera, are distributed in different parts of the world, including Brazil, Thailand, Japan, Korea, and Argentina. The lifestyles of the wasps are solitary and social. Social wasps use venom as a defensive measure to protect their colonies, whereas solitary wasps use their venom to capture prey. Chemically, wasp venom possesses a wide variety of enzymes, proteins, peptides, volatile compounds, and bioactive constituents, which include phospholipase A2, antigen 5, mastoparan, and decoralin. The bioactive constituents have anticancer, antimicrobial, and anti-inflammatory effects. However, the limited quantities of wasp venom and the scarcity of advanced strategies for the synthesis of wasp venom's bioactive compounds remain a challenge facing the effective usage of wasp venom. Solid-phase peptide synthesis is currently used to prepare wasp venom peptides and their analogs such as mastoparan, anoplin, decoralin, polybia-CP, and polydim-I. The goal of the current review is to highlight the medicinal value of the wasp venom compounds, as well as limitations and possibilities. Wasp venom could be a potential and novel natural source to develop innovative pharmaceuticals and new agents for drug discovery.

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  • 4.
    Abouzayed, Ayman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Theranostic Targeting of GRPR and PSMA in Prostate Cancer2023Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is based on five original articles that investigated the theranostics of prostate cancer by gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) targeting. GRPR and PSMA are two extensively evaluated prostate cancer cell markers due to their overexpression in the majority of prostate cancer samples. Theranostic targeting of GRPR and PSMA is an attractive strategy to improve the management of prostate cancer patients.

    Papers I and II focused on the dual targeting of GRPR and PSMA. The effect of linker modification on the affinity for GRPR and PSMA and the pharmacokinetic profile was evaluated. In Paper III, the effect of the GRPR antagonist RM26 conjugation to an albumin-binding domain on the pharmacokinetic profile and its potential use in therapy was investigated. Paper IV focused on developing a GRPR antagonist that was suitable for single-photon emission computed tomography (SPECT) using technetium-99m. In Paper V, the GRPR antagonist developed in Paper IV was translated into a phase I clinical trial to assess safety and dosimetry.

    Modifying the linkers in GRPR and PSMA heterodimers can largely impact the affinity for both targets. This modification influenced the in vivo targeting specificity and biodistribution, with [125I]I-BO530 in Paper I and [111In]In-BQ7812 in Paper II outperforming other analogues. Our findings in Paper III indicated that the conjugation of an albumin-binding domain to RM26 increased the blood concentration of the radiotracer. This increase led to elevated and stable tumour uptake of [111In]In-DOTA-ABD-RM26 after several days of injection. However, [111In]In-DOTA-ABD-RM26 was also increasingly taken up by various healthy organs. The GRPR antagonist [99mTc]Tc-maSSS-PEG2-RM26, studied in Paper IV, showed high specificity and affinity for GRPR. This resulted in elevated GRPR-mediated uptake. Additionally, maSSS-PEG2-RM26 could be radiolabelled via a straightforward radiolabelling protocol. Clinical evaluation of [99mTc]Tc-maSSS-PEG2-RM26 in prostate and breast cancer patients (Paper V) demonstrated the safety and tolerability of the radiotracer, with favourable dosimetry and no side effects.

    In conclusion, this thesis evaluated different tools for the theranostic targeting of GRPR and PSMA. The findings warrant further investigation to optimise the reported radiotracers.

    List of papers
    1. Synthesis and Preclinical Evaluation of Radio-Iodinated GRPR/PSMA Bispecific Heterodimers for the Theranostics Application in Prostate Cancer
    Open this publication in new window or tab >>Synthesis and Preclinical Evaluation of Radio-Iodinated GRPR/PSMA Bispecific Heterodimers for the Theranostics Application in Prostate Cancer
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    2019 (English)In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 11, no 7, article id 358Article in journal (Refereed) Published
    Abstract [en]

    Gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) are overexpressed in most prostate cancers. GRPR expression is higher in early stages while PSMA expression increases with progression. The possibility of targeting both markers with a single theranostics radiotracer could improve patient management. Three GRPR/PSMA-targeting bispecific heterodimers (urea derivative PSMA-617 and bombesin-based antagonist RM26 linked via X-triazolyl-Tyr-PEG2, X = PEG2 (BO530), (CH2)(8) (BO535), none (BO536)) were synthesized by solid-phase peptide synthesis. Peptides were radio-iodinated and evaluated in vitro for binding specificity, cellular retention, and affinity. In vivo specificity for all heterodimers was studied in PC-3 (GRPR-positive) and LNCaP (PSMA-positive) xenografts. [I-125]I-BO530 was evaluated in PC-3pip (GRPR/PSMA-positive) xenografts. Micro single-photon emission computed tomography/computed tomography (microSPECT/CT) scans were acquired. The heterodimers were radiolabeled with high radiochemical yields, bound specifically to both targets, and demonstrated high degree of activity retention in PC-3pip cells. Only [I-125]I-BO530 demonstrated in vivo specificity to both targets. A biodistribution study of [I-125]I-BO530 in PC-3pip xenografted mice showed high tumor activity uptake (30%-35%ID/g at 3 h post injection (pi)). Activity uptake in tumors was stable and exceeded all other organs 24 h pi. Activity uptake decreased only two-fold 72 h pi. The GRPR/PSMA-targeting heterodimer [I-125]I-BO530 is a promising agent for theranostics application in prostate cancer.

    Keywords
    prostate cancer, GRPR, PSMA, bispecific heterodimers, theranostics, radio-iodine
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-393138 (URN)10.3390/pharmaceutics11070358 (DOI)000478995100060 ()31340483 (PubMedID)
    Funder
    Swedish Research Council, 2015-02509Swedish Research Council, 2015-02353Swedish Cancer Society, CAN 2017/425Swedish Cancer Society, CAN2015/350Swedish Cancer Society, CAN 2018/436
    Available from: 2019-09-23 Created: 2019-09-23 Last updated: 2023-05-06Bibliographically approved
    2. Heterodimeric Radiotracer Targeting PSMA and GRPR for Imaging of Prostate Cancer-Optimization of the Affinity towards PSMA by Linker Modification in Murine Model
    Open this publication in new window or tab >>Heterodimeric Radiotracer Targeting PSMA and GRPR for Imaging of Prostate Cancer-Optimization of the Affinity towards PSMA by Linker Modification in Murine Model
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    2020 (English)In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 12, no 7, article id 614Article in journal (Refereed) Published
    Abstract [en]

    Prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) are promising targets for molecular imaging of prostate cancer (PCa) lesions. Due to the heterogenic overexpression of PSMA and GRPR in PCa, a heterodimeric radiotracer with the ability to bind to both targets could be beneficial. Recently, our group reported the novel heterodimer BQ7800 consisting of a urea-based PSMA inhibitor, the peptide-based GRPR antagonist RM26 and NOTA chelator. The study reported herein, aimed to improve the affinity of BQ7800 towards PSMA by changing the composition of the two linkers connecting the PSMA- and GRPR-targeting motifs. Three novel heterodimeric analogues were synthesized by incorporation of phenylalanine in the functional linker of the PSMA-binding motif and/or shortening the PEG-linker coupled to RM26. The heterodimers were labeled with indium-111 and evaluated in vitro. In the competitive binding assay, BQ7812, featuring phenylalanine and shorter PEG-linker, demonstrated a nine-fold improved affinity towards PSMA. In the in vivo biodistribution study of [In-111]In-BQ7812 in PC3-pip tumor-bearing mice (PSMA and GRPR positive), the activity uptake was two-fold higher in the tumor and three-fold higher in kidneys than for [In-111]In-BQ7800. Herein, we showed that the affinity of a bispecific PSMA/GRPR heterodimer towards PSMA could be improved by linker modification.

    Place, publisher, year, edition, pages
    MDPI, 2020
    Keywords
    prostate cancer, PSMA, GRPR, heterodimer, molecular imaging, SPPS
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-420766 (URN)10.3390/pharmaceutics12070614 (DOI)000556488600001 ()32630176 (PubMedID)
    Funder
    Swedish Research Council, 2019-00986Swedish Cancer Society, 2017/425
    Available from: 2020-10-06 Created: 2020-10-06 Last updated: 2023-05-06Bibliographically approved
    3. Preclinical Evaluation of the GRPR-Targeting Antagonist RM26 Conjugated to the Albumin-Binding Domain for GRPR-Targeting Therapy of Cancer
    Open this publication in new window or tab >>Preclinical Evaluation of the GRPR-Targeting Antagonist RM26 Conjugated to the Albumin-Binding Domain for GRPR-Targeting Therapy of Cancer
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    2020 (English)In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 12, no 10, article id 977Article in journal (Refereed) Published
    Abstract [en]

    The targeting of gastrin-releasing peptide receptors (GRPR) was recently proposed for targeted therapy, e.g., radiotherapy. Multiple and frequent injections of peptide-based therapeutic agents would be required due to rapid blood clearance. By conjugation of the GRPR antagonist RM26 (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) to an ABD (albumin-binding domain), we aimed to extend the blood circulation of peptides. The synthesized conjugate DOTA-ABD-RM26 was labelled with indium-111 and evaluated in vitro and in vivo. The labelled conjugate was stable in PBS and retained specificity and its antagonistic function against GRPR. The half-maximal inhibitory concentration (IC50) of In-nat-DOTA-ABD-RM26 in the presence of human serum albumin was 49 +/- 5 nM. [In-111]In-DOTA-ABD-RM26 had a significantly longer residence time in blood and in tumors (without a significant decrease of up to 144 h pi) than the parental RM26 peptide. We conclude that the ABD-RM26 conjugate can be used for GRPR-targeted therapy and delivery of cytotoxic drugs. However, the undesirable elevated activity uptake in kidneys abolishes its use for radionuclide therapy. This proof-of-principle study justified further optimization of the molecular design of the ABD-RM26 conjugate.

    Place, publisher, year, edition, pages
    MDPI, 2020
    Keywords
    prostate cancer, gastrin-releasing peptide receptor, RM26, albumin-binding domain, targeted therapy, gastrin-releasing peptide receptors (GRPR) antagonist
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-425851 (URN)10.3390/pharmaceutics12100977 (DOI)000585297400001 ()33081166 (PubMedID)
    Funder
    Vinnova, 2019/00104Swedish Cancer Society, CAN 2017/425Swedish Cancer Society, 2018/436Swedish Cancer Society, 19 0212 Pj 01HSwedish Research Council, 2019-00986Swedish Research Council, 2015-02353Swedish Research Council, 2016-05207
    Note

    De två första författarna delar förstaförfattarskapet.

    De två sista författarna delar sistaförfattarskapet.

    Available from: 2020-11-23 Created: 2020-11-23 Last updated: 2023-05-06Bibliographically approved
    4. Preclinical Evaluation of 99mTc-Labeled GRPR Antagonists maSSS/SES-PEG2-RM26 for Imaging of Prostate Cancer
    Open this publication in new window or tab >>Preclinical Evaluation of 99mTc-Labeled GRPR Antagonists maSSS/SES-PEG2-RM26 for Imaging of Prostate Cancer
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    2021 (English)In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 13, no 2, article id 182Article in journal (Refereed) Published
    Abstract [en]

    Background: Gastrin-releasing peptide receptor (GRPR) is an important target for imaging of prostate cancer. The wide availability of single-photon emission computed tomography/computed tomography (SPECT/CT) and the generator-produced 99mTc can be utilized to facilitate the use of GRPR-targeting radiotracers for diagnostics of prostate cancers.

    Methods: Synthetically produced mercaptoacetyl-Ser-Ser-Ser (maSSS)-PEG2-RM26 and mercaptoacetyl-Ser-Glu-Ser (maSES)-PEG2-RM26 (RM26 = d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) were radiolabeled with 99mTc and characterized in vitro using PC-3 cells and in vivo, using NMRI or PC-3 tumor bearing mice. SPECT/CT imaging and dosimetry calculations were performed for [99mTc]Tc-maSSS-PEG2-RM26.

    Results: Peptides were radiolabeled with high yields (>98%), demonstrating GRPR specific binding and slow internalization in PC-3 cells. [99mTc]Tc-maSSS-PEG2-RM26 outperformed [99mTc]Tc-maSES-PEG2-RM26 in terms of GRPR affinity, with a lower dissociation constant (61 pM vs 849 pM) and demonstrating higher tumor uptake. [99mTc]Tc-maSSS-PEG2-RM26 had tumor-to-blood, tumor-to-muscle, and tumor-to-bone ratios of 97 ± 56, 188 ± 32, and 177 ± 79, respectively. SPECT/CT images of [99mTc]Tc-maSSS-PEG2-RM26 clearly visualized the GRPR-overexpressing tumors. The dosimetry estimated for [99mTc]Tc-maSSS-PEG2-RM26 showed the highest absorbed dose in the small intestine (1.65 × 10−3 mGy/MBq), and the effective dose is 3.49 × 10−3 mSv/MBq.

    Conclusion: The GRPR antagonist maSSS-PEG2-RM26 is a promising GRPR-targeting agent that can be radiolabeled through a single-step with the generator-produced 99mTc and used for imaging of GRPR-expressing prostate cancer.

    Place, publisher, year, edition, pages
    MDPI, 2021
    Keywords
    prostate cancer, gastrin-releasing peptide receptor antagonist, technetium-99m, single-photon emission computed tomography, RM26
    National Category
    Radiology, Nuclear Medicine and Medical Imaging Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-438735 (URN)10.3390/pharmaceutics13020182 (DOI)000622994100001 ()33573232 (PubMedID)
    Funder
    Swedish Research Council, 2019-00986Swedish Cancer Society, 2017/425Swedish Cancer Society, 20 0815 PjFSwedish Cancer Society, 20 0814 UsF
    Available from: 2021-03-29 Created: 2021-03-29 Last updated: 2024-01-15Bibliographically approved
    5. Phase I Trial of [Tc-99m]Tc-maSSS-PEG(2)-RM26, a Bombesin Analogue Antagonistic to Gastrin-Releasing Peptide Receptors (GRPRs), for SPECT Imaging of GRPR Expression in Malignant Tumors
    Open this publication in new window or tab >>Phase I Trial of [Tc-99m]Tc-maSSS-PEG(2)-RM26, a Bombesin Analogue Antagonistic to Gastrin-Releasing Peptide Receptors (GRPRs), for SPECT Imaging of GRPR Expression in Malignant Tumors
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    2023 (English)In: Cancers, ISSN 2072-6694, Vol. 15, no 6, article id 1631Article in journal (Refereed) Published
    Abstract [en]

    The gastrin-releasing peptide receptor (GRPR) is overexpressed in prostate cancer (PCa) and in hormone-driven breast cancer (BCa). The aim of this phase I clinical trial was to evaluate safety, biodistribution, and dosimetry after the administration of the recently developed GRPR-targeting antagonistic bombesin analogue [Tc-99m]Tc-maSSS-PEG(2)-RM26 in PCa and BCa patients. Planar and whole-body SPECT/CT imaging was performed in six PCa patients and seven BCa patients 2, 4, 6, and 24 h post the intravenous administration of 40 mu g of [Tc-99m]Tc-maSSS-PEG(2)-RM26 (600-700 MBq). No adverse events or pathological changes were observed. The rapid blood clearance of [Tc-99m]Tc-maSSS-PEG(2)-RM26 was observed with predominantly hepatobiliary excretion. The effective doses were 0.0053 +/- 0.0007 for male patients and 0.008 +/- 0.003 mSv/MBq for female patients. The accumulation of [Tc-99m]Tc-maSSS-PEG(2)-RM26 in tumors was observed in four out of six PCa and in seven out of seven BCa patients. In four BCa patients, a high uptake of the agent into the axillary lymph nodes was detected. Immunohistochemistry revealed positive GRPR expression in 60% of primary PCa, 71.4% of BCa tumors, and 50% of examined BCa lymph nodes. In conclusion, a single administration of [Tc-99m]Tc-maSSS-PEG(2)-RM26 was safe and well tolerated. [Tc-99m]Tc-maSSS-PEG(2)-RM26 SPECT may be useful for tumor detection in PCa and BCa patients, pending further studies.

    Place, publisher, year, edition, pages
    MDPI, 2023
    Keywords
    GRPR, antagonist, 99mTc, phase I trial
    National Category
    Cancer and Oncology Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-500596 (URN)10.3390/cancers15061631 (DOI)000957432700001 ()36980517 (PubMedID)
    Funder
    Swedish Cancer Society, 20-0815 PjFSwedish Cancer Society, 20 0814 UsFSwedish Research Council, 2019-00986Swedish Research Council, 2022-00556
    Available from: 2023-04-21 Created: 2023-04-21 Last updated: 2023-05-06Bibliographically approved
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  • 5.
    Adeyemi, Ahmed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Palladium(0)-Catalyzed Synthesis of Spirocycles and Supercritical Chemistry using a Resistively Heated Flow Reactor2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This doctoral thesis focusses on an effective and selective approach to the synthesis of spirocycles using palladium(0)-catalyzed Mizoroki-Heck reactions. In addition, selective and efficient chemistry was highlighted by the design and evaluation of a novel resistively heated system for continuous flow (CF) synthesis for high-temperature and high-pressure applications.

    Paper I described the design and evaluation of a novel resistively heated CF system. The design of a low-cost, simple, robust, and effective CF system involving a resistively heated steel reactor capable of delivering 400 °C and 200 bar was reported. The reactor was evaluated with esterification, transesterification and direct carboxylic acid to nitrile conversions using supercritical ethanol, methanol and acetonitrile respectively. Diels-Alder reactions under neat conditions were also carried out at high temperature and pressure.

    Paper II reported the synthesis of spirooxindoles by a selective application of the palladium(0)-catalyzed Mizoroki-Heck spirocyclization. The precursors for the reaction were synthesized by coupling 2-iodoanilines with esters derived from enantiomerically pure (+)-Vince lactam decorated with the bulky, directing 2,5-dimethylpyrrole protecting group. Ten different spirooxindoles were reported with good yields and high regio- and stereoselectivity. Functionalization of a synthesized spirooxindole was done by a palladium(0)-catalyzed alkoxycarbonylation, followed by selective deprotections.

    In Paper III, ether precursors were synthesized from (+)-Vince lactam, via a Mitsunobu reaction with the corresponding iodophenols. The precursors were later subjected to conditions for intramolecular Mizoroki-Heck reaction. Overall, 12 spiroethers were synthesized in useable yields, regioselectivity up to 98% and with excellent diastereoselectivity (d.e.>98%). Further functionalization to mono-protected rigidified amino acids was also demonstrated.

    List of papers
    1. Continuous Flow Synthesis under High-Temperature/High-Pressure Conditions Using a Resistively Heated Flow Reactor
    Open this publication in new window or tab >>Continuous Flow Synthesis under High-Temperature/High-Pressure Conditions Using a Resistively Heated Flow Reactor
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    2017 (English)In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 21, no 7, p. 947-955Article in journal (Refereed) Published
    Abstract [en]

    A cheap, easy-to-build, and effective resistively heated reactor for continuous flow synthesis at high temperature and pressure is herein presented. The reactor is rapidly heated directly using, an electric current and is capable of rapidly delivering temperatures and pressures up to 400 degrees C and 200 bar, respectively. High-temperature and high-pressure applications of this reactor were safely performed and demonstrated by selected transformations such as esterifications, transesterifications, and direct carboxylic acid to nitrile reactions using supercritical ethanol, methanol, and acetonitrile. Reaction temperatures were between 300 and 400 degrees C with excellent conversions and good to excellent isolated product yields. Examples of Diels-Alder reactions were also carried out at temperatures up to 300 degrees C in high yield. No additives or catalysts were used in the reactions.

    Place, publisher, year, edition, pages
    AMER CHEMICAL SOC, 2017
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-333407 (URN)10.1021/acs.oprd.7b00063 (DOI)000406356200003 ()
    Funder
    EU, FP7, Seventh Framework Programme, 607517
    Available from: 2017-11-15 Created: 2017-11-15 Last updated: 2020-01-16Bibliographically approved
    2. Regio- and Stereoselective Synthesis of Spirooxindoles via Mizoroki-Heck Coupling of Aryl Iodides
    Open this publication in new window or tab >>Regio- and Stereoselective Synthesis of Spirooxindoles via Mizoroki-Heck Coupling of Aryl Iodides
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    2019 (English)In: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, Vol. 30, no 1, p. 82-88Article in journal, Letter (Refereed) Published
    Abstract [en]

    A method for highly regio- and stereoselective intramolecular Mizoroki-Heck 5- exo cyclization of aryl iodides to the corresponding spirooxindoles has been developed. Electron-rich and electron-deficient aryl iodide precursors were selectively ring-closed with high stereoselectivity and good yields. The double-bond position in the cyclopentene ring was controlled by careful choice of reaction conditions. These rare spiro compounds were further functionalized to rigidified unnatural amino acid derivatives by a subsequent gas-free Pd(0)-catalyzed alkoxycarbonylation, followed by selective O - and N -deprotections.

    Place, publisher, year, edition, pages
    GEORG THIEME VERLAG KG, 2019
    Keywords
    spirooxindoles, Mizoroki-Heck, cyclization, carbonylation
    National Category
    Medicinal Chemistry Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-372880 (URN)10.1055/s-0037-1611360 (DOI)000453250700013 ()
    Funder
    EU, FP7, Seventh Framework Programme, 607517
    Available from: 2019-01-09 Created: 2019-01-09 Last updated: 2020-01-16Bibliographically approved
    3. Regio- and Stereo-Selective Synthesis of Allylic Spiroethers (Spirobenzofuranes) via Intramolecular Mizoroki-Heck Reaction
    Open this publication in new window or tab >>Regio- and Stereo-Selective Synthesis of Allylic Spiroethers (Spirobenzofuranes) via Intramolecular Mizoroki-Heck Reaction
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Palladium(0)-catalyzed intramolecular annulation of twelve 1,3-disubstituted cyclopentenes, derived from (+)-vince lactam, resulted in 5-exo cyclizations, furnishing a series of 2,5-dimethyl-1-((3R,4'S)-2H-spiro[benzofuran-3,1'-cyclopentan]-2'-en-4'-yl)-1H-pyrroles in excellent diastereoselectivities and useful isolated yields. The double bond migration process, following the arylpalladium insertion, was controlled by fine-tuning of the reaction system, providing regioselectivities of up to 98:2. The selective Mizoroki-Heck reaction was used as the key transformation for preparing two new spirocyclic monoprotected amino acids as single diastereoisomers.

    National Category
    Organic Chemistry Pharmaceutical Sciences
    Research subject
    Chemistry with specialization in Organic Chemistry; Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-402335 (URN)
    Available from: 2020-01-16 Created: 2020-01-16 Last updated: 2020-01-24
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  • 6.
    Adeyemi, Ahmed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Wetzel, Alexander
    AstraZeneca, Dept Med Chem, Cardiovasc Renal & Metab IMED Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden.
    Bergman, Joakim
    AstraZeneca, Dept Med Chem, Cardiovasc Renal & Metab IMED Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden.
    Brånalt, Jonas
    AstraZeneca, Dept Med Chem, Cardiovasc Renal & Metab IMED Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Regio- and Stereoselective Synthesis of Spirooxindoles via Mizoroki-Heck Coupling of Aryl Iodides2019In: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, Vol. 30, no 1, p. 82-88Article in journal (Refereed)
    Abstract [en]

    A method for highly regio- and stereoselective intramolecular Mizoroki-Heck 5- exo cyclization of aryl iodides to the corresponding spirooxindoles has been developed. Electron-rich and electron-deficient aryl iodide precursors were selectively ring-closed with high stereoselectivity and good yields. The double-bond position in the cyclopentene ring was controlled by careful choice of reaction conditions. These rare spiro compounds were further functionalized to rigidified unnatural amino acid derivatives by a subsequent gas-free Pd(0)-catalyzed alkoxycarbonylation, followed by selective O - and N -deprotections.

  • 7.
    Adler, Camille
    et al.
    Univ Appl Sci & Arts Northwestern Switzerland, Inst Pharmaceut Technol, Grundenstr 40, CH-4132 Muttenz, Switzerland.;Univ Basel, Inst Pharmaceut Technol, Klingelbergstr 50, CH-4056 Basel, Switzerland..
    Schoenenberger, Monica
    Swiss Nanosci Inst, Nanotech Serv Lab, Klingelbergstr 82, CH-4056 Basel, Switzerland..
    Teleki, Alexandra
    DSM Nutr Prod Ltd, R&D Ctr Formulat & Applicat, POB 2676, CH-4002 Basel, Switzerland..
    Kuentz, Martin
    Univ Appl Sci & Arts Northwestern Switzerland, Inst Pharmaceut Technol, Grundenstr 40, CH-4132 Muttenz, Switzerland..
    Molecularly designed lipid microdomains for solid dispersions using a polymer/inorganic carrier matrix produced by hot-melt extrusion2016In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 499, no 1-2, p. 90-100Article in journal (Refereed)
    Abstract [en]

    Amorphous solid dispersions have for many years been a focus in oral formulations, especially in combination with a hot-melt extrusion process. The present work targets a novel approach with a system based on a fatty acid, a polymer and an inorganic carrier. It was intended to adsorb the acidic lipid by specific molecular interactions onto the solid carrier to design disorder in the alkyl chains of the lipid. Such designed lipid microdomains (DLM) were created as a new microstructure to accommodate a compound in a solid dispersion. Vibrational spectroscopy, X-ray powder diffraction, atomic force microscopy as well as electron microscopic imaging were employed to study a system of stearic acid, hydroxypropylcellulose and aluminum magnesium silicate. beta-carotene was used as a poorly water-soluble model substance that is difficult to formulate with conventional solid dispersion formulations. The results indicated that the targeted molecular excipient interactions indeed led to DLMs for specific compositions. The different methods provided complementary aspects and important insights into the created microstructure. The novel delivery system appeared to be especially promising for the formulation of oral compounds that exhibit both high crystal energy and lipophilicity. (C) 2015 Elsevier B.V. All rights reserved.

  • 8.
    Adler, Camille
    et al.
    Univ Appl Sci & Arts Northwestern Switzerland, Inst Pharmaceut Technol, CH-4132 Muttenz, Switzerland.;Univ Basel, Inst Pharmaceut Technol, CH-4056 Basel, Switzerland..
    Schoenenberger, Monica
    Swiss Nanosci Inst, Nanotech Serv Lab, CH-4056 Basel, Switzerland..
    Teleki, Alexandra
    DSM Nutr Prod Ltd, Res Ctr Formulat & Applicat, CH-4002 Basel, Switzerland..
    Leuenberger, Bruno
    DSM Nutr Prod Ltd, Res Ctr Formulat & Applicat, CH-4002 Basel, Switzerland..
    Kuentz, Martin
    Univ Appl Sci & Arts Northwestern Switzerland, Inst Pharmaceut Technol, CH-4132 Muttenz, Switzerland..
    Flow-through cross-polarized imaging as a new tool to overcome the analytical sensitivity challenges of a low-dose crystalline compound in a lipid matrix2015In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 115, p. 20-30Article in journal (Refereed)
    Abstract [en]

    Assessing the physical state of a low-dose active compound in a solid lipid or polymer matrix is analytically challenging, especially if the matrix exhibits some crystallinity. The aim of this study was first to compare the ability of current methods to detect the presence of a crystalline model compound in lipid matrices. Subsequently, a new technique was introduced and evaluated because of sensitivity issues that were encountered with current methods. The new technique is a flow-through version of cross-polarized imaging in transmission mode. The tested lipid-based solid dispersions (SDs) consisted of beta-carotene (BC) as a model compound, and of Gelucire 50/13 or Geleol mono- and diglycerides as lipid matrices. The solid dispersions were analyzed by (hyper) differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and microscopic techniques including atomic force microscopy (AFM). DSC and XRPD could analyze crystalline BC at concentrations as low as 3% (w/w) in the formulations. However, with microscopic techniques crystalline particles were detected at significantly lower concentrations of even 0.5% (w/w) BC. A flow-through cross-polarized imaging technique was introduced that combines the advantage of analyzing a larger sample size with high sensitivity of microscopy. Crystals were detected easily in samples containing even less than 0.2% (w/w) BC. Moreover, the new tool enabled approximation of the kinetic BC solubility in the crystalline lipid matrices. As a conclusion, the flow-through cross-polarized imaging technique has the potential to become an indispensable tool for characterizing low-dose crystalline compounds in a lipid or polymer matrix of solid dispersions. (C) 2015 Elsevier B.V. All rights reserved.

  • 9. Adler, Camille
    et al.
    Teleki, Alexandra
    DSM Nutritional Products Ltd., R&D Center Formulation & Application, P. O. Box 2676, 4002 Basel, Switzerland.
    Kuentz, Martin
    Multifractal and mechanical analysis of amorphous solid dispersions2017In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 523, no 1, p. 91-101, article id S0378-5173(17)30191-6Article in journal (Refereed)
    Abstract [en]

    The formulation of lipophilic and hydrophobic compounds is a challenge for the pharmaceutical industry and it requires the development of complex formulations. Our first aim was to investigate hot-melt extrudate microstructures by means of multifractal analysis using scanning electron microscopy imaging. Since the microstructure can affect solid dosage form performance such as mechanical properties, a second objective was to study the influence of the type of adsorbent and of the presence of an amorphous compound on extrudate hardness. β-Carotene (BC) was chosen as poorly water-soluble model compound. Formulations containing a polymer, a lipid and two different silica based inorganic carriers were produced by hot-melt extrusion. Based on scanning electron microscopy/energy dispersive X-ray spectroscopy, the obtained images were analyzed using multifractal formalism. The breaking force of the strands was assessed by a three point bending test. Multifractal analysis and three point bending results showed that the nature of interparticle interactions in the inorganic carrier as well as the presence of amorphous BC had an influence on the microstructure and thus on the mechanical performance. The use of multifractal analysis and the study of the mechanical properties were complementary to better characterize and understand complex formulations obtained by hot-melt extrusion.

  • 10. Adler, Camille
    et al.
    Teleki, Alexandra
    Kuentz, Martin
    Multifractal Characterization of Pharmaceutical Hot-Melt Extrudates.2017In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 34, no 2, p. 321-332Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Multifractal geometry has become a powerful tool to describe complex structures in many fields. Our first aim was to combine imaging and multifractal analysis to better understand the microstructure of pharmaceutical extrudates. A second objective was to study erosion/dispersion behavior of the formulations because it would condition release of any drug.

    METHODS: Different formulations containing a lipid, a polymer and different silica based inorganic carriers were produced by hot-melt extrusion at various screw speeds. Multifractal analysis was based on scanning electron microscopy/energy dispersive X-Ray spectroscopy images. This microstructural analysis was complemented with dynamic optical imaging of formulation erosion/dispersion behavior.

    RESULTS: Multifractal analysis indicated that inorganic carrier type and concentration as well as the screw speed affected the microstructure of the extrudates. The aqueous erosion/dispersion study showed that only the type and concentration of inorganic carrier were important.

    CONCLUSIONS: The use of microstructural and dispersion analysis appeared to be complementary to better characterize and understand complex formulations obtained by hot-melt extrusion.

  • 11.
    Afzelius, Lovisa
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Computational Modelling of Structures and Ligands of CYP2C92004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    CYP2C9 is one of our major drug metabolising enzymes and belongs to the cytochrome P450 (CYP) super family. The aim of this thesis was to gain an understanding of the quantitative structure–activity relationships (QSAR) of CYP2C9 substrates and inhibitors. This information will be useful in predicting drug metabolism and the potential for drug–drug interactions. To achieve this, a well characterised data set of structurally diverse, competitive CYP2C9 inhibitors was identified in our laboratory. Several computational methodologies, many based on GRID molecular interaction fields, were applied or developed in order to handle issues such as compound alignment and bioactive conformer selection. First, a traditional 3D QSAR was carried out in GOLPE, generating a predictive model. In this model the selection of a bioactive conformer and alignment was based on docking in a homology model of CYP2C9. Secondly, we introduced the concept of alignment independent descriptors from ALMOND. These descriptors were used to generate quantitatively and qualitatively predictive models. We subsequently derived conformation independent descriptors from molecular interaction fields calculated in FlexGRID. This enabled the derivation of 3D QSAR models without taking into account the selection of an alignment or a bioactive conformer. A subsequent programming effort enabled the conversion of this model back to 3D aligned pharmacophores. Similar alignment independent descriptors were also used in the development of the software MetaSite® that predicts the site of metabolism for CYP2C9 ligands. Finally, as crystal information on this isoform emerged, the performance of molecular dynamics simulations and homology models and the flexibility of the protein were evaluated using statistical analyses.

    These modelling efforts have resulted in detailed knowledge of the structural characteristics in ligand interactions with the cytochrome P450 2C9 isoform.

    List of papers
    1. Competitive CYP2C9 Inhibitors: Enzyme inhibition Studies, Protein Homology Modelling, and Three-Dimensional Quantitative Structure Activity Relationship Analysis
    Open this publication in new window or tab >>Competitive CYP2C9 Inhibitors: Enzyme inhibition Studies, Protein Homology Modelling, and Three-Dimensional Quantitative Structure Activity Relationship Analysis
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    2001 In: Molecular Pharmacology, ISSN 0026-895, Vol. 59, p. 909 - 919Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91425 (URN)
    Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
    2. Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors.
    Open this publication in new window or tab >>Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors.
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    2002 In: Journal of Computer-Aided Molecular Design, ISSN 0920-654, Vol. 16, p. 443 - 458Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91426 (URN)
    Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
    3. Predicting Drug Metabolism: A Site of Metabolism Tool Applied to the Cytochrome P450 CYP2C9.
    Open this publication in new window or tab >>Predicting Drug Metabolism: A Site of Metabolism Tool Applied to the Cytochrome P450 CYP2C9.
    2003 In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 46, no 12, p. 2313-2324Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91427 (URN)
    Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
    4. A Conformer and Alignment independent model to predict structurally diverse competitive CYP2C9 inhibitors.
    Open this publication in new window or tab >>A Conformer and Alignment independent model to predict structurally diverse competitive CYP2C9 inhibitors.
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    2004 In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. Web Release Date: 13-JanArticle in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91428 (URN)
    Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
    5. Structural analysis of CYP2C9 and CYP2C5 and critical assessment of molecular modelling techniques.
    Open this publication in new window or tab >>Structural analysis of CYP2C9 and CYP2C5 and critical assessment of molecular modelling techniques.
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    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91429 (URN)
    Available from: 2004-02-27 Created: 2004-02-27 Last updated: 2010-01-13Bibliographically approved
    6. Virtual receptor site (VRS) derivation for competitive CYP2C9 inhibitors: - a novel approach for structurally diverse compounds.
    Open this publication in new window or tab >>Virtual receptor site (VRS) derivation for competitive CYP2C9 inhibitors: - a novel approach for structurally diverse compounds.
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    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91430 (URN)
    Available from: 2004-02-27 Created: 2004-02-27 Last updated: 2010-01-13Bibliographically approved
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  • 12.
    Akaberi, Dario
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Chinthakindi, Praveen K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Båhlström, Amanda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Palanisamy, Navaneethan
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lennerstrand, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Identification of a C2-symmetric diol based human immunodeficiency virus protease inhibitor targeting Zika virus NS2B-NS3 protease2020In: Journal of Biomolecular Structure and Dynamics, ISSN 0739-1102, E-ISSN 1538-0254, Vol. 38, no 18, p. 5526-5536Article in journal (Refereed)
    Abstract [en]

    Zika virus (ZIKV) is an emerging mosquito-borne flavivirus and infection by ZIKV Asian lineage is known to cause fetal brain anomalies and Guillain-Barrés syndrome. The WHO declared ZIKV a global public health emergency in 2016. However, currently neither vaccines nor antiviral prophylaxis/treatments are available. In this study, we report the identification of a C2-symmetric diol-based Human immunodeficiency virus type-1 (HIV) protease inhibitor active against ZIKV NS2B-NS3 protease. The compound, referred to as 9b, was identified by in silico screening of a library of 6265 protease inhibitors. Molecular dynamics (MD) simulation studies revealed that compound 9b formed a stable complex with ZIKV protease. Interaction analysis of compound 9b's binding pose from the cluster analysis of MD simulations trajectories predicted that 9b mostly interacted with ZIKV NS3. Although designed as an aspartyl protease inhibitor, compound 9b was found to inhibit ZIKV serine protease in vitro with IC50 = 143.25 ± 5.45 µM, in line with the in silico results. Additionally, linear interaction energy method (LIE) was used to estimate binding affinities of compounds 9b and 86 (a known panflavivirus peptide hybrid with IC50 = 1.64 ± 0.015 µM against ZIKV protease). The LIE method correctly predicted the binding affinity of compound 86 to be lower than that of 9b, proving to be superior to the molecular docking methods in scoring and ranking compounds. Since most of the reported ZIKV protease inhibitors are positively charged peptide-hybrids, with our without electrophilic warheads, compound 9b represents a less polar and more drug-like non-peptide hit compound useful for further optimization.Communicated by Ramaswamy Sarma.

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  • 13.
    Akaberi, Dario
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pourghasemi Lati, Monireh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Krambrich, Janina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berger, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Turunen, Pauliina
    Science for Life Laboratory, Human Antibody Therapeutics, Drug Discovery and Development Platform, Solna, Sweden.
    Gullberg, Hjalmar
    Science for Life Laboratory, Biochemical and Cellular Assay Facility, Drug Discovery and Development Platform, Department of Biochemistry and Biophysics, Stockholm University, Solna, Stockholm, Sweden.
    Moche, Martin
    Department of Medical Biochemistry and Biophysics, Protein Science Facility, Karolinska Institutet, Stockholm, Sweden.
    Chinthakindi, Praveen Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Nyman, Tomas
    Department of Medical Biochemistry and Biophysics, Protein Science Facility, Karolinska Institutet, Stockholm, Sweden..
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Sandberg, Kristian
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Verho, Oscar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Lennerstrand, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Identification of unique and potent inhibitors of SARS-CoV-2 main protease from DNA-encoded chemical librariesManuscript (preprint) (Other academic)
  • 14.
    Alhalaweh, Amjad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Alzghoul, Ahmad
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computing Science.
    Mahlin, Denny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Physical stability of drugs after storage above and below the glass transition temperature: Relationship to glass-forming ability2015In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 495, no 1, p. 312-317Article in journal (Refereed)
    Abstract [en]

    Amorphous materials are inherently unstable and tend to crystallize upon storage. In this study, we investigated the extent to which the physical stability and inherent crystallization tendency of drugs are related to their glass-forming ability (GFA), the glass transition temperature (T-g) and thermodynamic factors. Differential scanning calorimetry was used to produce the amorphous state of 52 drugs [ 18 compounds crystallized upon heating (Class II) and 34 remained in the amorphous state (Class III)] and to perform in situ storage for the amorphous material for 12 h at temperatures 20 degrees C above or below the T-g. A computational model based on the support vector machine (SVM) algorithm was developed to predict the structure-property relationships. All drugs maintained their Class when stored at 20 degrees C below the T-g. Fourteen of the Class II compounds crystallized when stored above the T-g whereas all except one of the Class III compounds remained amorphous. These results were only related to the glass-forming ability and no relationship to e. g. thermodynamic factors was found. The experimental data were used for computational modeling and a classification model was developed that correctly predicted the physical stability above the T-g. The use of a large dataset revealed that molecular features related to aromaticity and pi-pi interactions reduce the inherent physical stability of amorphous drugs.

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  • 15. Al-Henhena, Nawal
    et al.
    Khalifa, Shaden A. M.
    Ying, Rozaida Poh Yuen
    Hassandarvish, Pouya
    Rouhollahi, Elham
    Al-Wajeeh, Nahla Saeed
    Ali, Habibah Mohd
    Abdulla, Mahmood Ameen
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Chemopreventive effects of Strobilanthes crispus leaf extract on azoxymethane-induced aberrant crypt foci in rat colon2015In: Scientific Reports, E-ISSN 2045-2322, Vol. 5, article id 13312Article in journal (Refereed)
    Abstract [en]

    In this work, microscopic and histological studies suggest that Strobilanthes crispus ethanol extract reduce azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in rats. S. crispus is considered a traditional medicine and used as an antioxidant. Its leaf contains a large amount of phenolic compounds to which its radical scavenging role is attributed and enhance its ability to eradicate oxidative stress reactions. The study was designed to determine the chemopreventive effect of S. crispus ethanol extract in vivo and in vitro by elucidating the effect of the extract on intermediate biomarkers which can be used as effective predictors of colon cancer. S. crispus was analyzed for DPPH free radical scavenging, nitric oxide (NO) and ferric acid reduction. The results indicated that S. crispus oral administration significantly inhibited colorectal carcinogenesis induced by AOM as revealed by the reduction in the number of ACF. S. crispus down-regulated the expression of PCNA, Bcl2 and beta-catenin. Additionally, it exerted a pronounced inhibitory effect on MDA and NO levels and stimulatory effect on CAT and GPx activities. These results demonstrate that S. crispus is a chemopreventive agent for colorectal cancer through the suppression of early and intermediate carcinogenic phases that may be related to its flavonoid content.

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  • 16.
    Al-Henhena, Nawal
    et al.
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia.;Sanaa Univ, Fac Med, Dept Biochem, Sanaa, Yemen..
    Khalifa, Shaden A. M.
    Karolinska Univ Hosp, Dept Expt Hematol, SE-14186 Stockholm, Sweden..
    Ying, Rozaida Poh Yuen
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Ismail, Salmah
    Univ Malaya, Fac Sci, Inst Biol Sci, Kuala Lumpur 50603, Malaysia..
    Hamadi, Riad
    Sanaa Univ, Fac Med, Dept Biochem, Sanaa, Yemen..
    Shawter, Abdrabu N.
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Idris, Azila Mohd
    Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Azizan, Ainnul
    Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Al-Wajeeh, Nahla Saeed
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Abdulla, Mahmood Ameen
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Evaluation of chemopreventive potential of Strobilanthes crispus against colon cancer formation in vitro and in vivo2015In: BMC Complementary and Alternative Medicine, E-ISSN 1472-6882, Vol. 15, article id 419Article in journal (Refereed)
    Abstract [en]

    Background: With cancer being one of the major causes of death around the world, studies are ongoing to find new chemotherapeutic leads. There are common mechanisms for colorectal cancer (CRC) formation. Several are connected with oxidative stress-induced cell apoptosis and others are related to imbalanced homeostasis or intake of drugs/toxins. Plants that have been used for decades in folk and traditional medicine have been accepted as one of the commonest sources of discovered natural agents of cancer chemotherapy and chemoprevention. The aim was to study the antioxidant and chemopreventive effects of Strobilanthes crispus on colorectal cancer formation. Methods: Five groups of rats were injected subcutaneously with AOM, 15 mg/kg body weight, each once weekly for 2 weeks. The cancer group was continued on 10 % Tween-20 feeding for 8 weeks. The standard drug group was continued on 35 mg/kg 5-fluorouracil intraperitoneal injection twice a week for 8 weeks, and the experimental groups were continued on 250 and 500 mg/kg S. crispus extract oral feeding for 8 weeks, respectively. The normal group was injected subcutaneously with normal saline once a week for 2 weeks, followed by oral administration of 10 % Tween-20 for 8 weeks. All the rats were sacrificed after 10 weeks. The colons were evaluated grossly and histopathologically for aberrant crypt foci (ACF). Gene expression was performed for Bax, Bcl2, Defa24, Slc24a3, and APC genes by real-time PCR. S. crispus and its fractions were evaluated for their chemopreventive effects against human colorectal adenocarcinoma cell line HT29 and cytotoxicity for normal human colon epithelial cell line CCD 841, and the active fraction was assessed for its components. Results: We observed significant decrease in total colonic ACF formation, malonaldehyde (MDA) and lactate dehydrogenase (LDH), increase in superoxide dismutase (SOD), up-regulation of APC, Bax and Slc24a3, and down-regulation of Defa24 and Bcl-2 in rats treated with Strobilanthes crispus. Conclusion: Our results support the in vivo protection of S. crispus against CRC formation (azoxymethane-induced aberrant crypt foci) and suggest that the mechanism is highly specific to protect from oxidative insults and the following apoptotic cascade.

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  • 17. Al-Henhena, Nawal
    et al.
    Ying, Rozaida Poh Yuen
    Ismail, Salmah
    Najm, Wala
    Khalifa, Shaden A. M.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Abdulla, Mahmood Ameen
    Chemopreventive Efficacy of Andrographis paniculata on Azoxymethane-Induced Aberrant Colon Crypt Foci In Vivo2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 11, article id e111118Article in journal (Refereed)
    Abstract [en]

    Andrographis paniculata is a grass-shaped medicinal herb, traditionally used in Southeast Asia. The aim of this study was to evaluate the chemoprotective effects of A. paniculata on colorectal cancer. A. paniculata ethanol extract was tested on azoxymethane (AOM)-induced aberrant crypt foci (ACF) in vivo and in vitro. A. paniculata treated groups showed a significant reduction in the number of ACF of the treated rats. Microscopically, ACF showed remarkably elongated and stratified cells, and depletion of the submucosal glands of AOM group compared to the treated groups. Histologically, staining showed slightly elevated masses above the surrounding mucosa with oval or slit-like orifices. Immunohistochemically, expression of proliferating cell nuclear antigen (PCNA) and beta-catenin protein were down-regulated in the A. paniculata treated groups compared to the AOM group. When colon tissue was homogenized, malondialdehyde (MDA) and nitric oxide (NO) levels were significantly decreased, whereas superoxide dismutase (SOD) activity was increased in the treated groups compared to the AOM group. A. paniculata ethanol extract showed antioxidant and free radical scavenging activity, as elucidated by the measure of oxidative stress markers. Further, the active fractions were assessed against cell lines of CCD841 and HT29 colon cancer cells.

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  • 18.
    Al-ikabi, Mohammed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Developing Inhibitors Against the SARS-CoV-2 Main Protease (MPro)2022Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    COVID-19, the disease caused by the SARS-CoV-2 virus, was first identified in 2019 and spread rapidly, leading to a global pandemic. Over 528,7 million cases have been reported worldwide, alongside 6.2 million deaths. There have been two earlier coronavirus outbreaks; SARS in 2002, and MERS in 2012, but treatment for these diseases remains limited. This shows a clear need for the development of treatments, not only for the current, but also possible future coronavirus outbreaks. While vaccines exist for the current coronavirus, many individuals cannot take them, so the preparation of antiviral agents remains important.

    Small molecule drugs are an attractive alternative for when vaccines are not available or feasible. An appealing target is the coronavirus main protease (MPro). MPro’s biological role is to cleave the viruses two non-functional polyproteins and is therefore important for viral proliferation. Furthermore, it has different selectivity than any known human protease enzymes making it a promising drug target. It was discovered that the Mpro of SARS-CoV and SARS-CoV-2 share 96% sequence identity, making previously explored SARS-CoV Mpro inhibitors a good starting point for drug development.

    ML188 is an Mpro inhibitor that can be synthesized by the Ugi reaction, and a range of analogues have been evaluated in the Moodie group by changing the P1’, P1, P2, and P3 positions. While there were improvements to ML188, there became a problem with the molecules becoming too lipophilic. At the P3 position, there was a plan to include heterocycles to increase polarity and potency, but the corresponding isocyanides needed for the Ugi reaction proved difficult to synthesize. The strategy in this project was to use a dummy isocyanide, which could be removed after the Ugi reaction to unveil a carboxylic acid group at P3. Then standard amide couplings could be used to explore previously inaccessible P3 analogues. Due to the unexplored nature of the chemistry of the synthesis, an optimization process was used at every step. Different conditions, including solvents, temperature, reagent, work up conditions, and reaction durations were investigated. Inividual reactions were evaluated and compared by documenting yields and comparing purity in NMR and LC-MS.

    The first main target for the optimization was the cleavable ugi product. The required dummy 6-bromo-2-isocyanopyridine was made in two steps. First by N-formylation, and then dehydration with POCl3 to create the isocyanide group. The Ugi reaction was then conducted to make an analogue with the same P1, P1l and P2 groups as ML188. During the optimization of this reaction, it was found that using the solvent 2,2,2-trifluoroethanol resulted in a productof increased purity. Cleavage of the dummy group was performed with different reaction durations and temperatures, and a range of purification conditions were explored. This method provides high purity carboxylic acid that will be used for amide coupling to create new P3 analogues. Developing methodology to alter the largely unexplored P3 group of ML188 is a crucial step to synthesize new ML188 analogues. This work could potentially lead to drugs with stronger inhibitory effects on Mpro and therefore coronavirus viralproliferation. Because of the similarities between coronavirus Mpro’s, these compounds may also be effective against future coronaviruses.

  • 19.
    AL-Jabiry, Ekram
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Syntetisering av en ny MALDI-MS matris med användning av Suzukikopplingsreaktion2021Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
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  • 20.
    Al-kaisy, Muhammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Matthias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Persson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Petterson Bergstrand, Madeleine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sterby, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Vall, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wang, Pin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    En förstudie för framtagning av HIV-proteashämmare: Me-too läkemedel till indinavir2012Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    The purpose of this report was to develop theoretical analogues of indinavir that ispredicted to bind well to HIV-I protease, wild type and mutants. These analogues aremeant for experimental testing by enzyme assay and cell-based β-galactosidase activityassay to see if they have potential to be new protease inhibitors for HIV. 80 analoguesprovided by the company Syntesdesign AB were analyzed with the software Glide.This was done to find out the binding affinities to HIV-I protease and some of its mostcommon mutations. The results were analyzed to see how different structuralelements contributed to high affinity. 48 new analogues were suggested and alsoanalyzed based on the results of the computer simulations. The 30 analogues with thepredicted highest affinity to the wild type protease and the mutations were selectedand ranked. All but one of these analogues were predicted to have better binding tothe protease than Indinavir.

  • 21.
    Alniss, Hasan Y.
    et al.
    Univ Sharjah, Coll Pharm, POB 27272, Sharjah, U Arab Emirates;Univ Sharjah, Sharjah Inst Med Res, POB 27272, Sharjah, U Arab Emirates.
    Witzel, Ini-Isabee
    New York Univ Abu Dhabi, Core Technol Platform, POB 129188, Abu Dhabi, U Arab Emirates.
    Semreen, Mohammad H.
    Univ Sharjah, Coll Pharm, POB 27272, Sharjah, U Arab Emirates;Univ Sharjah, Sharjah Inst Med Res, POB 27272, Sharjah, U Arab Emirates.
    Panda, Pritam Kumar
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Mishra, Yogendra Kumar
    Univ Kiel, Inst Mat Sci, Funct Nanomat, Kaiserstr 2, D-24143 Kiel, Germany;Univ Southern Denmark, NanoSYD, Mads Clausen Inst, Alsion 2, DK-6400 Sonderborg, Denmark.
    Ahuja, Rajeev
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory. Royal Inst Technol KTH, Dept Mat & Engn, SE-10044 Stockholm, Sweden.
    Parkinson, John A.
    Univ Strathclyde, Dept Pure & Appl Chem, WestCHEM, 295 Cathedral St, Glasgow G1 1XL, Lanark, Scotland.
    Investigation of the Factors That Dictate the Preferred Orientation of Lexitropsins in the Minor Groove of DNA2019In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 62, no 22, p. 10423-10440Article in journal (Refereed)
    Abstract [en]

    Lexitropsins are small molecules that bind to the minor groove of DNA as antiparallel dimers in a specific orientation. These molecules have shown therapeutic potential in the treatment of several diseases; however, the development of these molecules to target particular genes requires revealing the factors that dictate their preferred orientation in the minor grooves, which to date have not been investigated. In this study, a distinct structure (thzC) was carefully designed as an analog of a well-characterized lexitropsin (thzA) to reveal the factors that dictate the preferred binding orientation. Comparative evaluations of the biophysical and molecular modeling results of both compounds showed that the position of the dimethylaminopropyl group and the orientation of the amide links of the ligand with respect to the 5'-3'-ends; dictate the preferred orientation of lexitropsins in the minor grooves. These findings could be useful in the design of novel lexitropsins to selectively target specific genes.

  • 22. Alogheli, Hiba
    A study of conformational energy penalties of protein-bound macrocyclesIn: Article in journal (Refereed)
  • 23.
    Alogheli, Hiba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Computational Studies of Macrocycles and Molecular Modeling of Hepatitis C Virus NS3 Protease Inhibitors2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Computational tools are utilized in the drug discovery process to discover, design, and optimize new therapeutics. One important approach is structure-based drug design which relies on knowledge about the 3D structure of the biological target. The first part of this work focuses on applying structure-based drug design for binding mode prediction of HCV NS3 protease inhibitors. The NS3 protease is a challenging target from a computational perspective as it contains an extended binding site. Binding mode predictions were performed for various classes of new acyclic and macrocyclic HCV NS3 protease inhibitors and was used in the design of new inhibitors. None of the synthetized inhibitors have been co-crystallized yet, which has made the evaluation of the suggested binding mode predictions challenging.

    Macrocycles are an interesting compound class in drug discovery due to their unique structural architecture, which can enable access to new chemical space. Macrocycles can successfully modulate difficult therapeutic targets, as exemplified in the development of protease inhibitors. Furthermore they can improve drug-like properties, such as cell permeability and bioavailability. The second part of this thesis focuses on macrocycles from a computational point of view. A data set of 47 clinically relevant macrocycles was compiled and used in these studies. First, two different docking protocols rigid docking of pre-generated conformers and flexible docking in Glide were evaluated and compared. The results showed that flexible docking in Glide was sufficient for docking of macrocycles with respect to accuracy and speed.

    The aim of the second study was to evaluate and compare the performance of the more general conformational analysis tools, MCMM and MTLMOD, with the recently developed macrocycle-specialized conformational sampling tools, Prime-MCS and MMBS. In most cases, the general conformational analysis tools (with enhanced parameter settings) performed equally well as compared to the macrocycle-specialized conformational sampling techniques. However, MMBS was superior at locating the global energy minimum conformation.

    Finally, calculation of the conformational energy penalty of protein-bound macrocycles was performed. The macrocycle data set was complemented with linear analogues that are similar either with respect to physicochemical properties or 2D fingerprints. The conformational energy penalties of these linear analogues were calculated and compared to the conformational energy penalties of the macrocycles. The complete data set of macrocycles and non-macrocycles in this study differ from previously published work addressing conformational energy penalties, since it covers a more extended area of chemical space. Furthermore, there was a weak correlation between the calculated conformational energy penalties and the flexibility of the structures.

    List of papers
    1. Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold
    Open this publication in new window or tab >>Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold
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    2018 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 148, p. 453-464Article in journal (Refereed) Published
    Abstract [en]

    Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors and show that elongated R-3 urea substituents were associated with increased inhibitory potencies over several NS3 protein variants. The inhibitors are believed to rely on beta-sheet mimicking hydrogen bonds which are similar over different genotypes and current drug resistant variants and correspond to the beta-sheet interactions of the natural peptide substrate. Inhibitor 36, for example, with a urea substituent including a cyclic imide showed balanced nanomolar inhibitory potencies against genotype la, both wild-type (K-i=30 nM) and R155K (K-i=2 nM), and genotype 3a (K-i=5 nM).

    Place, publisher, year, edition, pages
    Elsevier, 2018
    Keywords
    Hepatitis C, NS3, Genotype 3, Resistance, Pyrazinone
    National Category
    Medicinal Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-340862 (URN)10.1016/j.ejmech.2018.02.032 (DOI)000428824700036 ()
    Funder
    Swedish Research Council, D0571301
    Available from: 2018-02-04 Created: 2018-02-04 Last updated: 2018-05-31Bibliographically approved
    2. A study of conformational energy penalties of protein-bound macrocycles
    Open this publication in new window or tab >>A study of conformational energy penalties of protein-bound macrocycles
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-340863 (URN)
    Available from: 2018-02-04 Created: 2018-02-04 Last updated: 2018-02-04
    3. Conformational Analysis of Macrocycles: Comparing General and Specialized Methods
    Open this publication in new window or tab >>Conformational Analysis of Macrocycles: Comparing General and Specialized Methods
    2020 (English)In: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 34, p. 231-252Article in journal (Refereed) Published
    Abstract [en]

    Macrocycles represent an important class of medicinally relevant small molecules due to their interesting biological properties. Therefore, a firm understanding of their conformational preferences is important for drug design. Given the importance of macrocycle-protein modelling in drug discovery, we envisaged that a systematic study of both classical and recent specialized methods would provide guidance for other practitioners within the field. In this study we compare the performance of the general, well established conformational analysis methods Monte Carlo Multiple Minimum (MCMM) and Mixed Torsional/Low-Mode sampling (MTLMOD) with two more recent and specialized macrocycle sampling techniques: MacroModel macrocycle Baseline Search (MD/LLMOD) and Prime macrocycle conformational sampling (PRIME-MCS). Using macrocycles extracted from 44 macrocycle-protein X-ray crystallography complexes, we evaluated each method based on their ability to (i) generate unique conformers, (ii) generate unique macrocycle ring conformations, (iii) identify the global energy minimum, (iv) identify conformers similar to the X-ray ligand conformation after Protein Preparation Wizard treatment (X-ray(ppw)), and (v) to the X-ray(ppw) ring conformation. Computational speed was also considered. In addition, conformational coverage, as defined by the number of conformations identified, was studied. In order to study the relative energies of the bioactive conformations, the energy differences between the global energy minima and the energy minimized X-ray(ppw) structures and, the global energy minima and the MCMM-Exhaustive (1,000,000 search steps) generated conformers closest to the X-ray(ppw) structure, were calculated and analysed. All searches were performed using relatively short run times (10,000 steps for MCMM, MTLMOD and MD/LLMOD). To assess the performance of the methods, they were compared to an exhaustive MCMM search using 1,000,000 search steps for each of the 44 macrocycles (requiring ca 200 times more CPU time). Prior to our analysis, we also investigated if the general search methods MCMM and MTLMOD could also be optimized for macrocycle conformational sampling. Taken together, our work concludes that the more general methods can be optimized for macrocycle modelling by slightly adjusting the settings around the ring closure bond. In most cases, MCMM and MTLMOD with either standard or enhanced settings performed well in comparison to the more specialized macrocycle sampling methods MD/LLMOD and PRIME-MCS. When using enhanced settings for MCMM and MTLMOD, the X-ray(ppw) conformation was regenerated with the greatest accuracy. The, MD/LLMOD emerged as the most efficient method for generating the global energy minima. Graphic abstract

    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-340864 (URN)10.1007/s10822-020-00277-2 (DOI)000515183900002 ()31965404 (PubMedID)
    Funder
    Swedish Research Council, 521-2014-6711
    Available from: 2018-02-04 Created: 2018-02-04 Last updated: 2021-06-16Bibliographically approved
    4. Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide
    Open this publication in new window or tab >>Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide
    Show others...
    2017 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 57, no 2, p. 190-202Article in journal (Refereed) Published
    Abstract [en]

    In recent years, there has been an increased interest in using macrocyclic compounds for drug discovery and development. For docking of these commonly large and flexible compounds to be addressed, a screening and a validation set were assembled from the PDB consisting of 16 and 31 macrocycle-containing protein complexes, respectively. The macrocycles were docked in Glide by rigid docking of pregenerated conformational ensembles produced by the macrocycle conformational sampling method (MCS) in Schrödinger Release 2015-3 or by direct Glide flexible docking after performing ring-templating. The two protocols were compared to rigid docking of pregenerated conformational ensembles produced by an exhaustive Monte Carlo multiple minimum (MCMM) conformational search and a shorter MCMM conformational search (MCMM-short). The docking accuracy was evaluated and expressed as the RMSD between the heavy atoms of the ligand as found in the X-ray structure after refinement and the poses obtained by the docking protocols. The median RMSD values for top-scored poses of the screening set were 0.83, 0.80, 0.88, and 0.58 Å for MCMM, MCMM-short, MCS, and Glide flexible docking, respectively. There was no statistically significant difference in the performance between rigid docking of pregenerated conformations produced by the MCS and direct docking using Glide flexible docking. However, the flexible docking protocol was 2-times faster in docking the screening set compared to that of the MCS protocol. In a final study, the new Prime-MCS method was evaluated in Schrödinger Release 2016-3. This method is faster compared that of to MCS; however, the conformations generated were found to be suboptimal for rigid docking. Therefore, on the basis of timing, accuracy, and ease of set up, standard Glide flexible docking with prior ring-templating is recommended over current gold standard protocols using rigid docking of pregenerated conformational ensembles.

    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-318050 (URN)10.1021/acs.jcim.6b00443 (DOI)000395226100010 ()28079375 (PubMedID)
    Funder
    Swedish Research Council, 521-2014-6711
    Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2021-06-16Bibliographically approved
    5. Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles
    Open this publication in new window or tab >>Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles
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    2014 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 22, no 23, p. 6595-6615Article in journal (Refereed) Published
    Abstract [en]

    With three recent market approvals and several inhibitors in advanced stages of development, the hepatitis C virus (HCV) NS3/4A protease represents a successful target for antiviral therapy against hepatitis C. As a consequence of dealing with viral diseases in general, there are concerns related to the emergence of drug resistant strains which calls for development of inhibitors with an alternative binding-mode than the existing highly optimized ones. We have previously reported on the use of phenylglycine as an alternative P2 residue in HCV NS3/4A protease inhibitors. Herein, we present the synthesis, structure-activity relationships and in vitro pharmacokinetic characterization of a diverse series of linear and macrocyclic P2 pyrimidinyloxyphenylglycine based inhibitors. With access to vinyl substituents in P3, P2 and P1' positions an initial probing of macrocyclization between different positions, using ring-closing metathesis (RCM) could be performed, after addressing some synthetic challenges. Biochemical results from the wild type enzyme and drug resistant variants (e.g., R155 K) indicate that P3-P1' macrocyclization, leaving the P2 substituent in a flexible mode, is a promising approach. Additionally, the study demonstrates that phenylglycine based inhibitors benefit from p-phenylpyrimidinyloxy and m-vinyl groups as well as from the combination with an aromatic P1 motif with alkenylic P1' elongations. In fact, linear P2-P1' spanning intermediate compounds based on these fragments were found to display promising inhibitory potencies and drug like properties.

    Keywords
    HCV, NS3, Protease inhibitors, Macrocyclization, Phenylglycine, Metathesis
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-239738 (URN)10.1016/j.bmc.2014.10.010 (DOI)000345287300007 ()
    Available from: 2014-12-31 Created: 2014-12-30 Last updated: 2022-01-28Bibliographically approved
    6. Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2–P1′ Region
    Open this publication in new window or tab >>Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2–P1′ Region
    Show others...
    2014 (English)In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 5, no 3, p. 249-254Article in journal, Letter (Refereed) Published
    Abstract [en]

    Herein, novel hepatitis C virus NS3/4A protease inhibitors based on a P2 pyrimidinyloxyphenylglycine in combination with various regioisomers of an aryl acyl sulfonamide functionality in P1 are presented. The P1′ 4-(trifluoromethyl)phenyl side chain was shown to be particularly beneficial in terms of inhibitory potency. Several inhibitors with Ki-values in the nanomolar range were developed and included identification of promising P3-truncated inhibitors spanning from P2–P1′. Of several different P2 capping groups that were evaluated, a preference for the sterically congested Boc group was revealed. The inhibitors were found to retain inhibitory potencies for A156T, D168V, and R155K variants of the protease. Furthermore, in vitro pharmacokinetic profiling showed several beneficial effects on metabolic stability as well as on apparent intestinal permeability from both P3 truncation and the use of the P1′ 4-(trifluoromethyl)phenyl side chain.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-221229 (URN)10.1021/ml400217r (DOI)000333006200005 ()
    Available from: 2014-03-26 Created: 2014-03-26 Last updated: 2022-01-28Bibliographically approved
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  • 24.
    Alogheli, Hiba
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Olanders, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Brandt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Anders, Karlén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide2017In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 57, no 2, p. 190-202Article in journal (Refereed)
    Abstract [en]

    In recent years, there has been an increased interest in using macrocyclic compounds for drug discovery and development. For docking of these commonly large and flexible compounds to be addressed, a screening and a validation set were assembled from the PDB consisting of 16 and 31 macrocycle-containing protein complexes, respectively. The macrocycles were docked in Glide by rigid docking of pregenerated conformational ensembles produced by the macrocycle conformational sampling method (MCS) in Schrödinger Release 2015-3 or by direct Glide flexible docking after performing ring-templating. The two protocols were compared to rigid docking of pregenerated conformational ensembles produced by an exhaustive Monte Carlo multiple minimum (MCMM) conformational search and a shorter MCMM conformational search (MCMM-short). The docking accuracy was evaluated and expressed as the RMSD between the heavy atoms of the ligand as found in the X-ray structure after refinement and the poses obtained by the docking protocols. The median RMSD values for top-scored poses of the screening set were 0.83, 0.80, 0.88, and 0.58 Å for MCMM, MCMM-short, MCS, and Glide flexible docking, respectively. There was no statistically significant difference in the performance between rigid docking of pregenerated conformations produced by the MCS and direct docking using Glide flexible docking. However, the flexible docking protocol was 2-times faster in docking the screening set compared to that of the MCS protocol. In a final study, the new Prime-MCS method was evaluated in Schrödinger Release 2016-3. This method is faster compared that of to MCS; however, the conformations generated were found to be suboptimal for rigid docking. Therefore, on the basis of timing, accuracy, and ease of set up, standard Glide flexible docking with prior ring-templating is recommended over current gold standard protocols using rigid docking of pregenerated conformational ensembles.

  • 25.
    Alsaleem, Hind
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Syntes av 2-tert-butyl imidazol- ett intermediat i syntesen av en Lol-CDE-inhibitor2023Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Bakterier, encelliga organismer som finns överallt omkring oss, kan vara vänligt sinnade, som de som hjälper till med matsmältning och stärker immunförsvaret. De kan också vara farliga, och detta arbete fokuserar på de farliga gramnegativa bakterierna och deras skyddande yttre membran.

    Historien om antibiotika börjar med upptäckten av penicillin av Alexander Fleming 1928 och revolutionerade medicin. Dock har bakterier med tiden utvecklat antibiotikaresistens, vilket skapar ett globalt problem. Därför behövs nya antibiotika och innovativ forskning, som kan inleda till nya måltavlor där Lol-proteiner och deras roll i gramnegativa bakteriers överlevnad kan möjligtvis leda till en ny måltavla.

    I detta arbete utforskas syntesen av 2-tert-butylimidazol, en nyckelkomponent i utvecklingen av en Lol-CDE-hämmare. Syftet är att undersöka dess struktur och funktion i jämförelse med andra föreningar och dess roll i inhibitorns framställning. Framgångsrik syntes av 2-tert-butylimidazol skulle vara ett stort steg mot önskad hämning av Lol-CDE-proteinet.

    I detta arbete framställdes 2-tert-butylimidazol omfattar en Debus-Radzszewski-reaktion enligt en tidigare metod där en blandning av ammoniaklösning (25%), tert-butyl-aldehyd och glyoxallösning (40%) användes. För att övervaka reaktionens framsteg användes tunnskiktskromatografi (TLC), och när reaktionen var avslutad filtrerades blandningen genom vakuumsug. Produktens struktur och renhet analyserades med hjälp av gaskromatografi-masspektrometri (GC-MS), vätskekromatografi-masspektrometri (LC-MS) och kärnmagnetisk resonansspektroskopi (NMR). Kolonnkromatografi användes sedan för att rena produkten. Nästan 2 gram 2-tert-butyl imidazol framställdes, och produktens struktur och renhet bekräftades genom olika metoder som analyserade molekylens massa och atommiljö. Denna molekyl kommer att användas i framtiden för att skapa en ny inhibitor för Lol-CDE, och dess struktur-aktivitetsförhållande kommer att utforskas närmare. 

    Sammanfattningsvis representerar den framgångsrika syntesen av 2-tert-butylimidazol ett viktigt steg mot utvecklingen av en Lol-CDE-hämmare. Arbetet belyser de utmaningar som är förknippade med syntes av komplexa molekyler och betonar vikten av analytiska tekniker för validering av produkten. Denna forskning bidrar till ansträngningarna att bekämpa antibiotikaresistens och upptäcka nya strategier för behandling av bakteriella infektioner.

  • 26.
    Alterman, Mathias
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Chemistry.
    Design and synthesis of HIV-1 protease inhibitors2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immune Deficiency Syndrome (AIDS). The C2-symmetric HIV-1 protease is one of the prime targets for chemotherapy in the treatment of the HIV infection. Inhibition of HIV-1 protease leads to immature and non-infectious viral particles. Design and synthesis of a number of C2-symmetrical C-terminal duplicated HIV-1 protease inhibitors and subsequent biological evaluation is presented in this thesis.

    A versatile three step synthetic route has been developed using a carbohydrate as an inexpensive chiral starting material thus allowing inhibitors with the desired stereochemistry to be obtained. By this efficient method a series of tailor-made P2/P2' modified inhibitors were synthesized, and these were evaluated on purified HIV-1 protease and in HIV-1 infected cell assays. Highly active HIV-1 protease inhibitors were identified among the tested compounds. Analyses of the X-ray crystal structures of two of the most active compounds, as complexes with the protease, guided the further design of P1/P1' elongated inhibitors. Substitutions in the para-position of the P1/P1' benzyl groups were promoted efficiently by microwave-irradiated of palladium-catalyzed reactions. Particular modifications in the P1/P1' region of the inhibitors resulted in a 40-fold increase of the anti-viral activity on HIV-1 infected cells. Furthermore, a fast, efficient, and general one-pot microwave enhanced synthesis protocol for transformations of organo-bromides to tetrazoles was developed and applied on the inhibitor scaffold. Attachment of linker molecules to the P1/P1' benzyl groups of one inhibitor was used to develop of sensitivity enhancer tools in surface plasmon resonance biosensor assays. These new assays enable the evaluation of low-molecular weight compounds as HIV-1 protease inhibitors.

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  • 27.
    Al-Wendawi, Amena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Synthesis of matrices for MALDI spectrometry2021Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Parkinson's disease (PD) is a neurodegenerative disease characterized by a disorder in the cells that produce dopamine. It mostly affects people older than 60 years old and more common for men than women. Disturbances in these signal transmissions lead to progressive motor impairment such as reduced mobility, dyskinesia, and tremors. 

    Matrix-assisted laser desorption ionization (MALDI) has become one of the most important "soft" mass spectrometry methods to analyze macromolecules such as proteins, polymers, lipids, and peptides in tissue. MALDI is a suitable method for label-free mapping of molecules in tissue samples found in the brain and lung slices. Several research questions can be explored in Parkinson's diseases using MALDI MS to analyze the localization of new PD drugs in the brain. 

    In MALDI MS, the choice of the matrix has a major role in the detection of the analyte. The matrix has the function of absorbing the laser UV light, which protects the integrity of the analysis and helps ionization. Important matrix properties include the ability to absorb the specific wavelength from the laser, maintain stability under vacuum conditions, analyte ionization, and prevent the formation of cluster ions. There are two types of matrices, regular and reactive matrices and recent development has a strong focus on reactive matrices because of their advantages in small molecule detection. 

     

    The purpose of this work to increase sensitivity in MALDI MS by synthesizing three matrices that can either react with carbonyl, aldehyde, or alkene. The matrices were synthesized by using Suzuki coupling reaction, Wittig reaction and methylation. The purpose of this work was achieved, and the three matrices have been synthesized and purified for testing in MALDI MS. 

     The result from MALDI MS will show if these matrices have resolved the problem of low sensitivity. And another possible future work is to test the Wittig reaction on the ketone product to compare this one to aldehyde.

     

     

     

  • 28.
    Amini, Ahmad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Analysis of Caffeine in Dietary Products by Multiple Injection Capillary Electrophoresis2012In: Caffeine: Chemistry, Analysis, Function and Effects / [ed] Victor R Preedy, London: Royal Society of Chemistry, 2012, p. 154-178Chapter in book (Refereed)
  • 29.
    Amini, Ahmad
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Chemistry.
    Enantiomeric separation by capillary electrophoresis: With special emphasis on the partial filling technique1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Capillary electrophoresis as a powerful separation technique was employed for resolution of racemic drugs. Taurodeoxycholate (TDC), different cyclodextrins and α1- acid glycoprotein (AGP) were dissolved in the background electrolyte at low pH (3.0 to 4.0 ) as chiral selectors.

    Enantioresolutions were based on the principle of micellar electrokinetic chromatography, inclusion complexation and affinity interactions between the enantiomers and TDC, cyclodextrins and AGP, respectively.

    The influence of chiral selector concentration and type, temperature and addition of organic modifiers on enantioselectivity were studied. The temperature was found to be an important factor for regulation of the enantioresolution.

    In order to avoid UV-absorbance interferences between AGP as a UV-absorbing chiral selector as well as to reduce consumption of chiral selector solution, the partial filling technique (PFT) was employed. The technique was developed and equations describing the feature of the technique as an efficient separation mode in CE was presented. Parameters such as applied plug length (PLapp) and effective plug length (PLeff) were determined. Equations expressing the relation between the PLeff and selectivity and resolution factors were developed.

    The PFT was used for determination of association constants between AGP as chiral selector and the enantiomers of disopyramide and remoxipride. The association was strongly temperature dependent, and a maximum in binding was observed at 25°C. The PFT was found to be a very convenient approach for measurement of association constants.

    To verity the above mentioned technique for evaluation of binding constants, the association constants between methyl-β-cyclodextrin and the enantiomers of orciprenaline at different chiral selector concentrations were measured and compared with the data obtained by the conventional technique. The results illustrate the reliability of the system based on the PFT.

  • 30.
    Amini, Ahmad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Lodén, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Principles for different modes of multiple-injection CZE2008In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 29, no 19, p. 3952-3958Article in journal (Refereed)
    Abstract [en]

    This paper introduces four different modes of multiple-injection CZE (MICZE). The validity of these MICZE models was evaluated by the experimental data. Prior to the application of MICZE, the electrophoretic conditions are developed in the single-injection mode by adjusting different experimental parameters such as pH, type and concentration of buffer additives and temperature. Based on the migration time difference (tmig) between the analyte and the internal standard or injection marker, one or more MICZE modes can be employed. The injection marker is added to the sample to compensate for injection-volume fluctuations. The inter-plug distance is regulated by applying an electrical field over the capillary for a short period of time between each injection. After the final injection, the separation is completed by electrophoresis for a time period corresponding to that in the single-injection mode

  • 31.
    An, Junxue
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Forchheimer, Daniel
    KTH Royal Inst Technol, Dept Appl Phys, Stockholm, Sweden..
    Savmarker, Jonas
    Orexo AB, Pharmaceut Dev, Uppsala, Sweden..
    Brulls, Mikael
    AstraZeneca, Early Prod Dev & Mfg Pharmaceut Sci, R&D, Gothenburg, Sweden..
    Frenning, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Nanoscale characterization of PEGylated phospholipid coatings formed by spray drying on silica microparticles2020In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 577, p. 92-100Article in journal (Refereed)
    Abstract [en]

    Phospholipids constitute biocompatible and safe excipients for pulmonary drug delivery. They can retard the drug release and, when PEGylated, also prolong the residence time in the lung. The aim of this work was to assess the structure and coherence of phospholipid coatings formed by spray drying on hydrophilic surfaces (silica microparticles) on the nanoscale and, in particular, the effect of addition of PEGylated lipids thereon. Scanning electron microscopy showed the presence of nanoparticles of varying sizes on the microparticles with different PEGylated lipid concentrations. Atomic force microscopy confirmed the presence of a lipid coating on the spray-dried microparticles. It also revealed that the lipid-coated microparticles without PEGylated lipids had a rather homogenous coating whereas those with PEGylated lipids had a very heterogeneous coating with defects, which was corroborated by confocal laser scanning microscopy. All coated microparticles had good dispersibility without agglomerate formation, as indicated by particle size measurements. This study has demonstrated that coherent coatings of phospholipids on hydrophilic surfaces can be obtained by spray drying. However, the incorporation of PEGylated lipids in a one-step spray-drying process to prepare lipid coated microparticles with both controlled-release and stealth properties is very challenging. (C) 2020 The Authors. Published by Elsevier Inc.

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    fulltext
  • 32. Andersen, Thomas L.
    et al.
    Friis, Stig D.
    Audrain, Helene
    Nordeman, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Skrydstrup, Troels
    Efficient C-11-Carbonylation of Isolated Aryl Palladium Complexes for PET: Application to Challenging Radiopharmaceutical Synthesis2015In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 137, no 4, p. 1548-1555Article in journal (Refereed)
    Abstract [en]

    We describe the successful implementation of palladium-aryl oxidative addition complexes as stoichiometric reagents in carbonylation reactions with (CO)-C-11 to produce structurally challenging, pharmaceutically relevant compounds. This method enables the first C-11-carbonyl labeling of an approved PET tracer, [C-11]raclopride, for the dopamine D2/D3 receptor by carbonylation with excellent radiochemical purity and yield. Two other molecules, [C-11]olaparib and [C-11]JNJ 31020028, were efficiently labeled in this manner. The technique distinguishes itself from existing methods by the markedly improved purity profiles of the tracer molecules produced and provides access to complex structures in synthetically useful yields, hereby offering a viable alternative to other C-11-labeling strategies.

  • 33.
    Andersson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Design and Synthesis of Angiotensin IV Peptidomimetics Targeting the Insulin-Regulated Aminopeptidase (IRAP)2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Peptidomimetics derived from the bioactive hexapeptide angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) have been designed and synthesized. These peptidomimetics are aimed at inhibiting the insulin-regulated amino peptidase (IRAP), also known as the AT4 receptor. This membrane-bound zinc-metallopeptidase is currently under investigation regarding its potential as a target for cognitive enhancers. The work presented herein was based on stepwise replacement of the amino acid residues in Ang IV by natural and unnatural amino acids, non-peptidic building blocks, and also on the introduction of conformational constraints. Initially, we focused on the introduction of secondary structure mimetics and backbone mimetics. The C-terminal tripeptide His-Pro-Phe was successfully replaced by a γ-turn mimetic scaffold, 2-(aminomethyl)phenylacetic acid (AMPA), which was coupled via an amide bond to the carboxyl terminus of Val-Tyr-Ile. Substitution of Val-Tyr-Ile, Val-Tyr, Tyr-Ile and Tyr, respectively, by 4-hydroxydiphenylmethane scaffolds comprising a 1,3,5-substituted benzene ring as a central moiety unfortunately rendered peptidomimetics that were less potent than Ang IV. The subsequent approach involved the introduction of conformational constraints into Val-Tyr-Ile-AMPA by replacing Val and Ile by amino acid residues appropriate for disulfide cyclization or ring-closing metathesis. Chemically diverse structures encompassing an N-terminal 13- or 14-membered macrocyclic tripeptide and a C-terminal non-peptidic moiety were developed. Tyr2 and AMPA were modified to acquire further knowledge about the structure-activity relationships and, in addition, to improve the metabolic stability and reduce the polarity. Several of the compounds displayed a high capacity to inhibit IRAP and exhibited Ki values in the low nanomolar range. Hence, the new compounds were more than ten times more potent than the parent peptide Ang IV. Enhanced selectivity over the closely related aminopeptidase N (AP-N) was achieved, as well as improved stability against proteolysis by metallopeptidases present in the assays. However, additional investigations are required to elucidate the bioactive conformation(s) of the relatively flexible N-terminal macrocycles. The compounds presented in this thesis have provided important information on structure-activity relationships regarding the interaction of Ang IV-related pseudopeptides and peptidomimetics with IRAP. The best compounds in the series constitute important starting points for further discovery of Ang IV peptidomimetics suitable as tools in the investigation of IRAP and other potential targets for Ang IV. The literature presents strong support for the hypothesis that drug-like IRAP inhibitors would serve as a new type of future cognitive enhancers with potential use in the treatment of cognitive disorders, e.g. Alzheimer’s disease.

    List of papers
    1. Small potent ligands to the insulin-regulated aminopeptidase (IRAP)/AT(4) receptor
    Open this publication in new window or tab >>Small potent ligands to the insulin-regulated aminopeptidase (IRAP)/AT(4) receptor
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    2007 (English)In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 13, no 7, p. 434-444Article in journal (Refereed) Published
    Abstract [en]

    Angiotensin IV analogs encompassing aromatic scaffolds replacing parts of the backbone of angiotensin IV have been synthesized and evaluated in biological assays. Several of the ligands displayed high affinities to the insulin-regulated aminopeptidase (IRAP)/AT4 receptor. Displacement of the C-terminal of angiotensin IV with an o-substituted aryl acetic acid derivative delivered the ligand 4, which exhibited the highest binding affinity (Ki = 1.9 nM). The high affinity of this ligand provides support to the hypothesis that angiotensin IV adopts a -turn in the C-terminal of its bioactive conformation.Ligand (4) inhibits both human IRAP and aminopeptidase N-activity and induces proliferation of adult neural stem cells at low concentrations. Furthermore, ligand 4 is degraded considerably more slowly in membrane preparations than angiotensin IV. Hence, it might constitute a suitable research tool for biological studies of the (IRAP)/AT4 receptor.

    Keywords
    Adult neural stem cells, Angiotensin IV, Bioactive conformation, Insulin-regulated aminopeptidase, IRAP, Peptide synthesis, Peptidemimetic, Structure-activity relationship, Turn mimetic
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-16622 (URN)10.1002/psc.859 (DOI)000248164400002 ()17559064 (PubMedID)
    Available from: 2008-05-29 Created: 2008-05-29 Last updated: 2018-03-20Bibliographically approved
    2. Ligands to the (IRAP)/AT4 receptor encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr2
    Open this publication in new window or tab >>Ligands to the (IRAP)/AT4 receptor encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr2
    Show others...
    2008 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 16, no 14, p. 6924-6935Article in journal (Refereed) Published
    Abstract [en]

    Analogues of the hexapeptide angiotensin IV (Ang IV, Val(1)-Tyr(2)-Ile(3)-His(4)-Pro(5)-Phe(6)) encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr(2) and a phenylacetic or benzoic acid moiety replacing His(4)-Pro(5)-Phe(6) have been synthesized and evaluated in biological assays. The analogues inhibited the proteolytic activity of cystinyl aminopeptidase (CAP), frequently referred to as the insulin-regulated aminopeptidase (IRAP), and were found less efficient as inhibitors of aminopeptidase N (AP-N). The best Ang IV mimetics in the series were approximately 20 times less potent than Ang IV as IRAP inhibitors. Furthermore, it was found that the ligands at best exhibited a 140 times lower binding affinity to the membrane-bound IRAP/AT4 receptor than Ang IV. Although the best compounds still exert lower activities than Ang IV, it is notable that these compounds comprise only two amino acid residues and are considerably less peptidic in character than the majority of the Ang IV analogues previously reported as IRAP inhibitors in the literature.

    Keywords
    Angiotensin IV, Insulin-regulated aminopeptidase (IRAP), Cystinyl aminopeptidase (CAP), Aminopeptidase N (AP-N), Structure–activity relationship, Peptide synthesis, Peptide mimetic, 4-Hydroxydiphenylmethane, Tyrosine mimetic
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-102954 (URN)10.1016/j.bmc.2008.05.046 (DOI)000257829600031 ()18556208 (PubMedID)
    Available from: 2009-05-13 Created: 2009-05-13 Last updated: 2018-03-20Bibliographically approved
    3. Disulfide cyclized tripeptide analogues of angiotensin IV as potent and selective inhibitors of insulin-regulated aminopeptidase (IRAP)
    Open this publication in new window or tab >>Disulfide cyclized tripeptide analogues of angiotensin IV as potent and selective inhibitors of insulin-regulated aminopeptidase (IRAP)
    Show others...
    2010 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 22, p. 8059-8071Article in journal (Refereed) Published
    Abstract [en]

    The insulin-regulated aminopeptidase (IRAP) localized in areas of the brain associated with memory and learning is emerging as a new promising therapeutic target for the treatment of memory dysfunctions. The angiotensin II metabolite angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) binds with high affinity to IRAP and inhibits this aminopeptidase (Ki = 62.4 nM). Furthermore, Ang IV has been demonstrated to enhance cognition in animal models and seems to play an important role in cognitive processes. It is herein reported that displacement of the C-terminal tripeptide His4-Pro5-Phe6 with a phenylacetic acid functionality combined with a constrained macrocyclic system in the N-terminal affords potent IRAP inhibitors that are less peptidic in character than the hexapeptide Ang IV. The best inhibitors in the series, compound 8 and 12, incorporating a 13- and 14-membered disulfide ring system, respectively, and both with a β3-homotyrosine residue (β3hTyr) replacing Tyr2, exhibit Ki values of 3.3 nM and 5.2 nM, respectively.

    Keywords
    angiotensin IV, insulin-regulated aminopeptidase, inhibitor, disulfide, NAMFIS
    National Category
    Medicinal Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-122213 (URN)10.1021/jm100793t (DOI)000284287200016 ()21047126 (PubMedID)
    Available from: 2010-04-07 Created: 2010-04-07 Last updated: 2018-03-20Bibliographically approved
    4. Potent Macrocyclic Inhibitors of Insulin-Regulated Aminopeptidase (IRAP) by Olefin Ring-Closing Metathesis
    Open this publication in new window or tab >>Potent Macrocyclic Inhibitors of Insulin-Regulated Aminopeptidase (IRAP) by Olefin Ring-Closing Metathesis
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    2011 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, no 11, p. 3779-3792Article in journal (Refereed) Published
    Abstract [en]

    Macrocyclic analogues of angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) targeting the insulin-regulated aminopeptidase (IRAP) have been designed, synthesized, and evaluated biologically. Replacement of His4-Pro5-Phe6 by a 2-(aminomethyl)phenylacetic acid (AMPAA) moiety and of Val1 and Ile3 by amino acids bearing olefinic side chains followed by macrocyclization provided potent IRAP inhibitors. The impact of the ring size and the type (saturated versus unsaturated), configuration, and position of the carbon–carbon bridge was assessed. The ring size generally affects the potency more than the carbon–carbon bond characteristics. Replacing Tyr2 by β3hTyr or Phe is accepted, while N-methylation of Tyr2 is deleterious for activity. Removal of the carboxyl group in the C-terminal slightly reduced the potency. Inhibitors 7 (Ki = 4.1 nM) and 19 (Ki = 1.8 nM), both encompassing 14-membered ring systems connected to AMPAA, are 10-fold more potent than Ang IV and are also more selective over aminopeptidase N (AP-N). Both compounds displayed high stability against proteolysis by metallopeptidases.

    Keywords
    angiotensin IV, insulin-regulated aminopeptidase, inhibitor, macrocyclic, ring-closing metathesis
    National Category
    Medicinal Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-122208 (URN)10.1021/jm200036n (DOI)000291082500008 ()21476495 (PubMedID)
    Available from: 2010-04-07 Created: 2010-04-07 Last updated: 2018-05-29Bibliographically approved
    Download full text (pdf)
    FULLTEXT01
  • 34.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Demaegdt, Heidi
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussels.
    Johnsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Vauquelin, Georges
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussels.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Erdélyi, Máté
    Department of Chemistry, University of Gothenburg.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Potent Macrocyclic Inhibitors of Insulin-Regulated Aminopeptidase (IRAP) by Olefin Ring-Closing Metathesis2011In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, no 11, p. 3779-3792Article in journal (Refereed)
    Abstract [en]

    Macrocyclic analogues of angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) targeting the insulin-regulated aminopeptidase (IRAP) have been designed, synthesized, and evaluated biologically. Replacement of His4-Pro5-Phe6 by a 2-(aminomethyl)phenylacetic acid (AMPAA) moiety and of Val1 and Ile3 by amino acids bearing olefinic side chains followed by macrocyclization provided potent IRAP inhibitors. The impact of the ring size and the type (saturated versus unsaturated), configuration, and position of the carbon–carbon bridge was assessed. The ring size generally affects the potency more than the carbon–carbon bond characteristics. Replacing Tyr2 by β3hTyr or Phe is accepted, while N-methylation of Tyr2 is deleterious for activity. Removal of the carboxyl group in the C-terminal slightly reduced the potency. Inhibitors 7 (Ki = 4.1 nM) and 19 (Ki = 1.8 nM), both encompassing 14-membered ring systems connected to AMPAA, are 10-fold more potent than Ang IV and are also more selective over aminopeptidase N (AP-N). Both compounds displayed high stability against proteolysis by metallopeptidases.

  • 35.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Demaegdt, Heidi
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel.
    Vauquelin, Georges
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Erdélyi, Máté
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Disulfide cyclized tripeptide analogues of angiotensin IV as potent and selective inhibitors of insulin-regulated aminopeptidase (IRAP)2010In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 22, p. 8059-8071Article in journal (Refereed)
    Abstract [en]

    The insulin-regulated aminopeptidase (IRAP) localized in areas of the brain associated with memory and learning is emerging as a new promising therapeutic target for the treatment of memory dysfunctions. The angiotensin II metabolite angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) binds with high affinity to IRAP and inhibits this aminopeptidase (Ki = 62.4 nM). Furthermore, Ang IV has been demonstrated to enhance cognition in animal models and seems to play an important role in cognitive processes. It is herein reported that displacement of the C-terminal tripeptide His4-Pro5-Phe6 with a phenylacetic acid functionality combined with a constrained macrocyclic system in the N-terminal affords potent IRAP inhibitors that are less peptidic in character than the hexapeptide Ang IV. The best inhibitors in the series, compound 8 and 12, incorporating a 13- and 14-membered disulfide ring system, respectively, and both with a β3-homotyrosine residue (β3hTyr) replacing Tyr2, exhibit Ki values of 3.3 nM and 5.2 nM, respectively.

  • 36.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Development of carbon-11 labelled PET tracers-radiochemical and technological challenges in a historic perspective2015In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 58, no 3, p. 65-72Article in journal (Refereed)
    Abstract [en]

    The development of positron emission tomography (PET) from being an exclusive and expensive research tool at major research institutes to a clinically useful modality found at most major hospitals around the world is largely dependent on radiochemistry and synthesis technology achievements by a few pioneer researchers starting their PET careers 40 to 50years ago. Especially, the introduction of [C-11]methyl iodide resulted in a quantum jump in the history of PET tracer development enabling the smooth labelling of a multitude of useful tracers. A more recent and still challenging methodological improvement is transition metal mediated C-11-carbonylations, having a large synthetic potential that has, however, not yet been realized in the clinical setting. This mini-review focuses on the history of carbon-11 radiochemistry and related technology developments and the role this played in PET tracer developments, especially emphasizing radiolabelling of endogenous compounds. A few examples will be presented of how the use of radiolabelled endogenous substances have provided fundamental information of in vivo biochemistry using the concept of position-specific labelling in different positions in the same molecule.

  • 37.
    Antoni, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Trevorrow, Paul
    Wiley, Chichester, England.
    Meet the advisors: An interview with Gunnar Antoni2021In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 64, no 14, p. 517-519Article in journal (Other academic)
  • 38. Antonov, D
    et al.
    Ayesa Alvarez, S
    Belfrage,, Anna Karin G. L.
    Jönsson, C.E.D.
    Mcgowan, D.C.
    Nilsson, K. M.
    Raboisson, P. J
    Rosenquist,, Å. A. K.
    Samuelsson,, B.B.
    HCV inhibiting macrocyclic phenylcarbamates2008Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    Compounds of the formula I: including a stereoisomer thereof, or an N-oxide, a pharmaceutically acceptable addition salt, or a pharmaceutically acceptable addition solvate thereof; useful as HCV inhibitors; processes for preparing these compounds as well as pharmaceutical compositions comprising these compounds as active ingredient.

  • 39.
    Artursson, Madeleine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Excipients selection in multidrugformulations development: Solution behavior of structurally relatedcalcium channel blockers combined with indapamide2019Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The increased demand of formulations containing more than one drugrequire improved understanding of the solution evolving from suchsystems and the effect of included excipients on their solubilityand dissolution behaviors.

    In this study, the solution behavior of structurally related drugs(dihydropyridines) combined with indapamide was explored. Inaddition, the origin of solubility differences between the drugswas investigated by determining their solubility and thermalproperties. The concentration of the drugs from supersaturatedsolutions generated by antisolvent addition was measured in bufferand excipients.

    There were distinct differences between the physiochemicalproperties and solubility values of the dihydropyridines, explainedby the additive effect of their hydrophobicity and strength ofcrystal lattice. Indapamide’s solubility was decreased by the sameextent when combined with either of the dihydropyridines. Thedihydropyridines varied in their behavior. Nifedipine maintainedsame supersaturation level until the amount of indapamide addedexceeded 400 mikrogram/ml and then its solubility increased by 2-folds and was maintained. There was no change in the concentrationof felodipine until the amount of added indapamide exceeded itsamorphous solubility, where a decrease was seen in felodipine’ssolubility.

    There was a clear differential solubilization effect of felodipineand indapamide by the excipients. The cyclodextrins was used inindapamide and felodipine combination because the relativesolubility improvement of indapamide.

    The study demonstrates the complexity of the solution behavior ofmultidrug combinations. This doesn’t only involve drugs formulatedtogether in one formulation but could involve medicine formulatedwith various excipients and administrated at the same time.

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  • 40.
    Arvela, Riina K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Palladium-Catalysed Carbon–Carbon Coupling Reactions: Focusing on Microwave Heating, Low Catalyst Concentrations, Aqueous Conditions, Regioselectivity and Medicinal Chemistry Applications2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    It is widely accepted that palladium is one of the most useful catalysts in organic chemistry, and many palladium(0)-catalysed carbon–carbon bond-forming reactions have been developed over the years. In addition, the ever-growing need for more environmentally benign processes in the chemical industry has driven scientists to look for greener options while developing new methodologies for organic synthesis. This thesis describes a series of studies on Suzuki and Heck coupling reactions in water and the application of palladium(0) catalysis to the development of new HIV-1 integrase inhibitors.

    The previously described 'transition-metal-free Suzuki-type coupling' reaction was shown to take place due to sub-ppm levels of palladium contaminants present in the commercially available sodium carbonate base. Based on this finding, a new, microwave-assisted Suzuki protocol utilizing ppb/ppm levels of palladium in water was developed. This methodology was adapted to terminal Heck coupling, although the scope of the protocol was found to be rather limited. Finally, both Suzuki and Heck reaction processes were successfully scaled up to 100 mmol using an automated batch stop-flow microwave apparatus.

    As the methodologies utilizing ultralow palladium concentrations were not applicable to aryl chlorides, attention was shifted towards palladium on carbon. This simple catalyst, together with microwave heating employing simultaneous cooling, was found to be beneficial in the Suzuki coupling of aryl chlorides with phenylboronic acid in water.

    Ligand-controlled internal arylation of ethylene glycol vinyl ether with aryl halides was shown to be possible in water alone without any additives. Reactions were run under air, using conventional heating and the products formed were isolated as aryl methyl ketones in good to excellent yields. The electron-rich (dippp)2Pd complex was shown to be beneficial for the microwave-assisted internal arylation of some aryl chlorides. Furthermore, the active role of the hydroxyl group of ethylene glycol vinyl ether in the formation of a cationic intermediate leading to internal Heck coupling product was elucidated.

    Finally, to demonstrate the usefulness of palladium(0) catalysis in the development of new pharmaceutical entities, a series of HIV-1 integrase inhibitors was synthesised and evaluated in strand transfer assays and in vitro. Based on the results and docking studies performed, valuable information related to the structure–activity relationship was obtained.

    List of papers
    1. A reassessment of the transition-metal free suzuki-type coupling methodology.
    Open this publication in new window or tab >>A reassessment of the transition-metal free suzuki-type coupling methodology.
    Show others...
    2005 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 70, no 1, p. 161-168Article in journal (Refereed) Published
    Abstract [en]

    We present here a reassessment of our transition-metal free Suzuki-type coupling protocol. We believe that, although the reaction can be run without the need for addition of a metal catalyst, palladium contaminants down to a level of 50 ppb found in commercially available sodium carbonate are responsible for the generation of the biaryl rather than, as previously suggested, an alternative non-palladium-mediated pathway. We present a revised methodology for Suzuki couplings using ultralow palladium concentrations for use with aryl and vinyl boronic acids and discuss the effects of the purity of the boronic acid on the reaction.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-99771 (URN)10.1021/jo048531j (DOI)000226508600019 ()15624918 (PubMedID)
    Available from: 2009-03-19 Created: 2009-03-19 Last updated: 2017-12-13Bibliographically approved
    2. Microwave-promoted Heck coupling using ultralow metal catalyst concentrations.
    Open this publication in new window or tab >>Microwave-promoted Heck coupling using ultralow metal catalyst concentrations.
    2005 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 70, no 5, p. 1786-1790Article in journal (Refereed) Published
    Abstract [en]

    We show that Heck couplings can be performed in water using microwave heating and Pd catalyst concentrations as low as 500 ppb. The methodology is simple; all that is required as the catalyst is a stock solution of palladium.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-99770 (URN)10.1021/jo048052k (DOI)000227246800035 ()15730302 (PubMedID)
    Available from: 2009-03-19 Created: 2009-03-19 Last updated: 2017-12-13Bibliographically approved
    3. Automated batch scale-up of microwave-promoted Suzuki and Heck coupling reactions in water using ultra-low catalyst concentrations
    Open this publication in new window or tab >>Automated batch scale-up of microwave-promoted Suzuki and Heck coupling reactions in water using ultra-low catalyst concentrations
    2005 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 61, no 39, p. 9349-9355Article in journal (Refereed) Published
    Abstract [en]

    Representative Suzuki and Heck couplings in water using ultra-low catalyst concentrations have been scaled-up using an automated batch stop-flow microwave apparatus. Our scale-up methodology shows proof of concept and is easy, fast and cheap to run.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-99772 (URN)10.1016/j.tet.2005.07.063 (DOI)000231782100017 ()
    Available from: 2009-03-19 Created: 2009-03-19 Last updated: 2017-12-13Bibliographically approved
    4. Suzuki coupling of aryl chlorides with phenylboronic acid in water, using microwave heating with simultaneous cooling
    Open this publication in new window or tab >>Suzuki coupling of aryl chlorides with phenylboronic acid in water, using microwave heating with simultaneous cooling
    2005 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 7, no 11, p. 2101-2104Article in journal (Refereed) Published
    Abstract [en]

    We present here a methodology for the Suzuki coupling of aryl chlorides with phenylboronic acid using Pd/C as a catalyst, water as a solvent, and microwave heating. We show that simultaneous cooling in conjunction with microwave heating prolongs the lifetime of the aryl chloride substrates during the course of the reaction and, as a result, yields of the desired biaryl as well as overall recovery of material can be increased.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-99768 (URN)10.1021/ol0503384 (DOI)000229420400006 ()15901144 (PubMedID)
    Available from: 2009-03-19 Created: 2009-03-19 Last updated: 2017-12-13Bibliographically approved
    5. Highly regioselective internal heck arylation of hydroxyalkyl vinyl ethers by aryl halides in water
    Open this publication in new window or tab >>Highly regioselective internal heck arylation of hydroxyalkyl vinyl ethers by aryl halides in water
    2007 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 72, no 17, p. 6390-6396Article in journal (Refereed) Published
    Abstract [en]

    Highly regioselective and fast Pd(0)-catalyzed internal α-arylation of ethylene glycol vinyl ether with aryl halides was shown to be possible in water without the need for any halide scavengers or ionic liquid additives. This presents, to our knowledge, the first case of water being utilized in the selective arylation of electron-rich olefins. Resulting α-products were hydrolyzed and isolated as corresponding acetophenones in good to excellent yields when using aryl bromides and with good to moderate yields in the case of aryl iodides. Microwave irradiation was shown to be beneficial in activation of aryl chlorides toward the internal Heck arylation. The scope of the protocol was further increased to include different hydroxyalkyl vinyl ethers, these all giving selectively only branched α-products. Finally, the active role of the hydroxy group in directing the regioselectivity toward internal arylation of electron-rich olefins, even in nonpolar toluene, was revealed.

    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-16616 (URN)10.1021/jo0705768 (DOI)000248793400007 ()17658848 (PubMedID)
    Available from: 2008-05-29 Created: 2008-05-29 Last updated: 2018-01-12Bibliographically approved
    6. Investigations on the 4-quinolone-3-carboxylic acid motif. 1. Synthesis and structure-activity relationship of a class of human immunodeficiency virus type 1 integrase inhibitors
    Open this publication in new window or tab >>Investigations on the 4-quinolone-3-carboxylic acid motif. 1. Synthesis and structure-activity relationship of a class of human immunodeficiency virus type 1 integrase inhibitors
    Show others...
    2008 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 16, p. 5125-9Article in journal (Refereed) Published
    Abstract [en]

    A set of 4-quinolone-3-carboxylic acids bearing different substituents on the condensed benzene ring was designed and synthesized as potential HIV-1 integrase inhibitors structurally related to elvitegravir. Some of the new compounds proved to be able to inhibit the strand transfer step of the virus integration process in the micromolar range. Docking studies and quantum mechanics calculations were used to rationalize these data.

    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-99766 (URN)10.1021/jm8003784 (DOI)000258637400032 ()18665580 (PubMedID)
    Available from: 2009-03-19 Created: 2009-03-19 Last updated: 2022-01-28Bibliographically approved
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  • 41. Arvidsson, Per
    et al.
    Burrows, Jeremy
    Soederman, Peter
    Yngve, Ulrika.
    Preparation of arylimidazopyridine derivatives for use as GSK3 modulators.2008Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    Title compds. I [A = (un)substituted aryl or heteroaryl; Q = halo; R1 = C(O)NR6R7; R2 and R4 independently = H, halo, CN, NO2, alkyl, or haloalkyl; R3 and R5 independently = H, halo, alkyl, or haloalkyl; R6 and R7 = together with the atoms to which they are attached form an (un)substituted heterocyclic ring contg. one or more heteroatoms selected from N, O, or S;], and their pharmaceutically acceptable salts, are prepd. and disclosed as glycogen synthase kinase-3 (GSK3) modulators. Thus, e.g., II•HCl was prepd. by cyclocondensation of 5-bromopyridine-2,3-diamine with terephthalic monomethyl ester followed by chlorination, iodination, sapon., amidation with N-methylpiperazine, and coupling with 4-methoxyphenyl boronic acid. I were evaluated in GSK3β scintillation proximity assays, e.g., II•HCl demonstrated an Ki value of 97 nM. [on SciFinder(R)]

  • 42. Arvidsson, Per
    et al.
    Burrows, Jeremy
    Soederman, Peter
    Yngve, Ulrika.
    Preparation of imidazopyridinecarboxamide derivatives for use as GSK3 modulators.2008Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    Title compds. I [Q = halo; R1 = CH2NR3R4; each R2 independently = H or alkyl; R3 and R4 = together with the atoms to which they are attached form an (un)substituted heterocyclic ring contg. one or more heteroatoms selected from N, O, or S; R6 = H or alkyl; R7 = H, (un)substituted alkyl, alkylaryl, aryl, or heteroaryl], and their pharmaceutically acceptable salts, are prepd. and disclosed as glycogen synthase kinase-3 (GSK3) modulators. Thus, e.g., II•HCl was prepd. by cyclocondensation of 5-bromopyridine-2,3-diamine with terephthalic monomethyl ester followed by chlorination, iodination, sapon., amidation with morpholine, redn., and coupling with carbon monoxide and 3-methoxy-1-propanamine. I were evaluated in GSK3β scintillation proximity assays, e.g., II•HCl demonstrated an Ki value of 390 nM. [on SciFinder(R)]

  • 43. Arvidsson, Per I.
    et al.
    Burrows, Jeremy Nicholas
    Yngve, Ulrika
    Tjerneld, Erica.
    Preparation of imidazolylpyrimidine derivatives for treatment of glycogen synthase kinase 3 related disorders such as Alzheimer's disease.2010Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    Title compds. I [R1 = H or F; R2 and R3 independently = H or Me], and their pharmaceutically acceptable salts, are prepd. and disclosed as agents for treatment of glycogen synthase kinase 3 (GSK3) related disorders such as Alzheimer's disease. Thus, e.g., II.HCl was prepd. by reductive amination of 4-bromo-3-fluorobenzaldehyde with (S)-3-methylmorpholine followed by amination with 2-amino-5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidine. Select I were evaluated for GSK3β inhibitory activity, and e.g., II·HCl demonstrated a Ki value of 30 nM. [on SciFinder(R)]

  • 44.
    Asiegbu, Chigoziem
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Preparation of a key intermediate for the synthesis of a chiral SGLT-1 inhibitor2022Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Obesity and type 2 diabetes (T2D) are two medical conditions which affect millions of people worldwide and are a growing concern globally. These two conditions are closely correlated to each other, where obesity is known to be one of the main risk factors for the development of T2D. Recently sodium dependent glucose cotransporter (SGLT) inhibitors have been found to be novel class of  therapeutics for treating T2D and also have potential for treating obesity. SGLT-1 inhibitors have proven to be effective against diabetes, where they are able to reduce the blood glucose level by inhibiting the glucose absorption in the small intestine. An inhibition of SGLT-1 can potentially be effective against obesity by acting as an appetite suppressant. In 2019 a patent was published with the aim to synthesize a methyl lactam ring compound with the ability to act as an SGLT-1 inhibitor. The aim of this thesis project was to synthesize a target compound which will be used as a building block in the synthesis of the methyl lactam ring based SGLT-1 inhibitor. The target compound was successfully synthesized with a total yield of 13 %. The yield was relatively low, however it was a reasonable yield considering that this synthetic pathway consisted of 6 steps and some product is expected to be lost in each reaction step. The target compound was characterized by LC-MS, 1H-NMR and 13C-NMR. In this project the stereochemistry of the target compound is important – only the R,R enantiomer is active. Unfortunately, due to time constraints, the stereochemistry of the target compound could not be determined. In order to determine the absolute configuration of the target compound further analysis by x-ray crystallography or chiral HPLC is required.

  • 45.
    Avedis, Ani
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    A high-throughput method for screening of protein binding behavior of multimodal anionic exchange ligands2021Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The biopharmaceutical industry is constantly developing biological drugs, resulting in increased levels of product related impurities having similar characteristics as the target. The aim of the ligand project was to address future challenging purifications by developing new ligands for future resins for the biopharmaceutical industry. The purpose of this study was to develop a high-throughput screening method and use it to compare 15 novel multimodal anionic exchange ligand analogues with two reference ligands, for future polishing steps in the downstream process. The protein binding behavior of the ligands were studied with alkaline phosphatase, human serum albumin, α-chymotrypsinogen A and a monoclonal antibody as model proteins, at various pH values and salt concentrations. The selection process of the model proteins was based on stability studies, a study of their adsorption to the 96 well plate, and their binding behavior on three of the ligand analogues and one reference ligand. The percent protein bound to the ligands at the various conditions was calculated and presented in plots in order to study their binding behaviors. The calculated values were also used in order to evaluate the results in principal component analysis, creating chromatographic diversity maps. The maps were used to get an overview of the differences and similarities of the ligand analogues compared to the reference resins, which can be used for selecting ligands for future research and biomanufacturing. Four analogues and one reference ligand were also studied in a column format where different gradients were used, which confirmed the obtained results in the plate experiments. 

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  • 46.
    Ax, Anna
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Cyclic Sulfamide HIV-1 Protease Inhibitors: Design, Synthesis and Modelling2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ten years ago, the first protease inhibitor targeting the human immunodeficiency virus (HIV) was approved for clinical use. Highly active antiretroviral therapy (HAART), which combined protease and reverse transcriptase inhibitors, quickly became the standard therapy for treating patients infected with HIV and Acquired Immune Deficiency Syndrome (AIDS). Nevertheless, last year the AIDS pandemic reached its highest level ever. Many infected patients, mainly in the developing countries, are still without treatment. Among those patients who receive treatment, an increase in drug resistance and new-infection with drug-resistant strains are seen. To come to terms with these problems, new drugs that are efficient against resistant strains and can be produced at low cost are needed.

    In this study, we have focused our research efforts on cyclic sulfamides active as HIV-1 protease inhibitors. Distinctive to this compound class, as compared to the inhibitors so far approved for clinical use, was the incorporation of a water mimic that displaces the structural water (W301) observed in the X-ray crystal co-complexes. The first part of the study was aimed at understanding the rationale behind the nonsymmetric binding mode that the inhibitor adopted when bound to the enzyme. Symmetric and nonsymmetric inhibitors were synthesized and the structure-activity relationships and preferable binding modes were rationalized with the help of Comparative Molecular Field Analysis (CoMFA).

    In the second part of the study, an attempt was made to reduce the size of these inhibitors. As a result, the traditional P1/P1' substituents were removed, while the P2/P2' substituents were elongated in an attempt to reach between the binding sites. The design hypothesis was shown to be successful and inhibitors possessing nanomolar activity were identified.

    List of papers
    1. Synthesis and comperative molecular field analysis (CoMFA) of symmetric and nonsymmetric cyclic sulfamide HIV-1 protease inhibitors
    Open this publication in new window or tab >>Synthesis and comperative molecular field analysis (CoMFA) of symmetric and nonsymmetric cyclic sulfamide HIV-1 protease inhibitors
    Show others...
    2001 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 44, no 2, p. 155-169Article in journal (Refereed) Published
    National Category
    Pharmaceutical Sciences Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-93068 (URN)10.1021/jm001024j (DOI)
    Available from: 2005-05-12 Created: 2005-05-12 Last updated: 2018-03-05Bibliographically approved
    2. Cyclic sulfamide HIV-1 protease inhibitors, with sidechains spanning from P2/P2' to P1/P1'
    Open this publication in new window or tab >>Cyclic sulfamide HIV-1 protease inhibitors, with sidechains spanning from P2/P2' to P1/P1'
    Show others...
    2005 In: Bioorganic & Medicinal Chemistry, Vol. 13, no 3, p. 755-764Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-93069 (URN)
    Available from: 2005-05-12 Created: 2005-05-12Bibliographically approved
    3. Nonsymmetric cyclic sulfamide HIV-1 protease inhibitors with sidechains spanning from P2/P2' to P1/P1'
    Open this publication in new window or tab >>Nonsymmetric cyclic sulfamide HIV-1 protease inhibitors with sidechains spanning from P2/P2' to P1/P1'
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-93070 (URN)
    Available from: 2005-05-12 Created: 2005-05-12 Last updated: 2010-01-13Bibliographically approved
    4. Fast and selective synthesis of novel cyclic sulfamide HIV-1 protease inhibitors under controlled microwave heating
    Open this publication in new window or tab >>Fast and selective synthesis of novel cyclic sulfamide HIV-1 protease inhibitors under controlled microwave heating
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    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-93071 (URN)
    Available from: 2005-05-12 Created: 2005-05-12 Last updated: 2010-01-13Bibliographically approved
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    COVER01
  • 47.
    Axelsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Development of HIV-1 Protease Inhibitors and Palladium-Catalyzed Synthesis of Aryl Ketones and N-Allylbenzamides2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The use of palladium-catalyzed reactions to introduce new carbon-carbon bonds is a fundamental synthetic strategy that has been widely embraced due to its high chemo- and regioselectivity and functional group tolerance. In this context, Pd(0)-catalyzed aminocarbonylations using Mo(CO)6 instead of toxic and gaseous CO and with allylamine as the nucleophile were investigated. The aminocarbonylated product dominated over the Mizoroki-Heck product, and (hetero)aryl iodides, bromides and chlorides gave N-allylbenzamides in good yields.

    In this thesis improvements to an existing protocol for the Pd(II)-catalyzed synthesis of aryl ketones from five benzoic acids and a variety of nitriles are also presented. Addition of TFA improved the yields and employing THF as solvent enabled the use of solid nitriles, and the aryl ketones were isolated in good yields.

    The pandemic of HIV infection is one of the greatest public health issues of our time and approximately 35.3 million people worldwide are living with HIV. There are currently many drugs on the market targeting various parts of the viral reproduction cycle, but the problems of resistance warrant the search for new drugs. HIV-1 protease makes the virus mature into infectious particles. In this thesis a new type of HIV-1 protease inhibitor (PI) is presented, based on two of the PIs on the market, atazanavir and indinavir, but it has a tertiary alcohol, as well as a two-carbon tether between the quaternary carbon and the hydrazide β-nitrogen. A total of 25 new inhibitors were designed, synthesized and biologically evaluated, the best compound had an EC50 value of 3 nM.

    Based on this series a project aimed at synthesizing macrocycles spanning the P1-P3 area was initiated. Macrocycles often tend to have an improved affinity and metabolic profile compared to their linear analogs. Introduction of a handle in the para position of the P1 benzyl group proved difficult, despite efforts to synthesize intermediates containing either a bromo-, hydroxy-, methoxy-, silyl-group protected hydroxy- or an alkyne-group. The lactone intermediate was abandoned in favor of an alternative synthetic route and initial studies were found to be promising. This new approach requires further investigation before the target macrocycles can be synthesized. 

    List of papers
    1. Microwave-assisted, Mo(CO)(6)-mediated, palladium-catalyzed amino-carbonylation of aryl halides using allylamine: from exploration to scale-up
    Open this publication in new window or tab >>Microwave-assisted, Mo(CO)(6)-mediated, palladium-catalyzed amino-carbonylation of aryl halides using allylamine: from exploration to scale-up
    2008 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 49, no 39, p. 5625-5628Article in journal (Refereed) Published
    Abstract [en]

    Palladium-catalyzed aminocarbonylations of various (hetero)aryl halides with allylamine using Mo(CO)(6) as a solid, in situ CO source, were explored. Microwave-enhanced conditions proved to be highly useful in promoting the conversions in a mere 10-20 min with various (hetero)aryl iodides, bromides and chlorides. The scale-up of a microwave-enhanced aminocarbonylation to 25 mmol scale was performed successfully. (C) 2008 Elsevier Ltd. All rights reserved.

    Keywords
    carbonylation, microwave, palladium, aryl chloride, scale-up
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-104304 (URN)10.1016/j.tetlet.2008.07.053 (DOI)000259309700018 ()0040-4039 (ISBN)
    Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2022-01-28Bibliographically approved
    2. An Improved Palladium(II)-Catalyzed Method for the Synthesis of Aryl Ketones from Aryl Carboxylic Acids and Organonitriles
    Open this publication in new window or tab >>An Improved Palladium(II)-Catalyzed Method for the Synthesis of Aryl Ketones from Aryl Carboxylic Acids and Organonitriles
    Show others...
    2014 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 55, no 15, p. 2376-2380Article in journal (Refereed) Published
    Abstract [en]

    A palladium(II)-catalyzed decarboxylative protocol for the synthesis of aryl ketones has been developed. The addition of TFA was shown to improve the reaction yield and employing THF as solvent enabled the use of solid nitriles and in only a small excess. Using this method, five different benzoic acids reacted with a wide range of nitriles to produce 29 diverse (hetero)aryl ketone derivatives in up to 94% yield.

    National Category
    Organic Chemistry Engineering and Technology
    Research subject
    Engineering Science with specialization in Nanotechnology and Functional Materials
    Identifiers
    urn:nbn:se:uu:diva-211660 (URN)10.1016/j.tetlet.2014.02.109 (DOI)000334977100012 ()
    Funder
    Knut and Alice Wallenberg Foundation
    Available from: 2013-11-27 Created: 2013-11-27 Last updated: 2017-12-06Bibliographically approved
    3. HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol: Improved Antiviral Activity in Cells
    Open this publication in new window or tab >>HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol: Improved Antiviral Activity in Cells
    Show others...
    2010 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 2, p. 607-615Article in journal (Refereed) Published
    Abstract [en]

    By a small modification in the core structure of the previously reported series of HIV-1 protease inhibitors that encompasses a tertiary alcohol as part of the transition-state mimicking scaffold, up to 56 times more potent compounds were obtained exhibiting EC50 values down to 3 nM. Three of the inhibitors also displayed excellent activity against selected resistant isolates of HIV-1. The synthesis of 25 new and optically pure HIV-1 protease inhibitors is reported, along with methods for elongation of the inhibitor Pl' side chain using microwave-accelerated, palladium-catalyzed cross-coupling reactions, the biological evaluation, and X-ray data obtained from one of the most potent analogues cocrystallized with both the wild type and the L63P, V82T, 184 V mutant of the HIV-1 protease.

    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-137907 (URN)10.1021/jm901165g (DOI)000273672100007 ()
    Available from: 2010-12-17 Created: 2010-12-16 Last updated: 2018-01-12Bibliographically approved
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  • 48. Ayesa, S.
    et al.
    Belfrage, Anna Karin
    Classon, B.
    Grabowska, U.
    Hewitt, E.
    Ivanov, V.
    Jönsson, D.
    Kahnberg, P.
    Lind, P.
    Nilsson, M.
    Odén, L.
    Pelcman, M.
    Wähling, H.
    CYSTEINE PROTEASE INHIBITORS2011Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    Compounds of the formula I

    wherein

    R1a is H; and R1b is C1-C6 alkyl, Carbocyclyl or Het; or

    R1a and R1b together define a saturated cyclic amine with 3-6 ring atoms;

    R2a and R2b are H, halo, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy; or

    R2a and R2b together with the carbon atom to which they are attached form a C3-C6cycloalkyl;

    R3 is a branched C5-C10alkyl chain, C2-C4haloalkyl or C3-C7cycloalkylmethyl,

    R4 is Het, Carbocyclyl,

    optionally substituted as defined in the specification and pharmaceutically acceptable salts,

    hydrates and N-oxides thereof; are inhibitors of cathepsin S and have utility in the treatment of psoriasis, autoimmune disorders and other disorders such as asthma, arteriosclerosis, COPD and chronic pain.

  • 49.
    Bajat, Bedat Elif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Undersökning om aminosyran på position 6 i peptidkedjan LRELHLNNN är viktig vid inbindning till kollagen I och för utveckling av ny fibrosdiagnostik.2020Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Vid fibros sker en överdriven sårläkning vilket resulterar i höga koncentrationer av ECM-komponenter, där normal vävnad (parenkymalvävnad) ersätts med permanent ärrvävnad (bindvävnad). Fibros kan uppstå exempelvis i njure, lunga, hjärta och hud, där exempelvis lungfibros kan leda till organdysfunktion eller organdöd.

    Traditionellt har nålbaserade biopsier (vävnadsprover) varit den tillgängliga metoden för diagnostik av fibros. Dock har metoden många nackdelar såsom icke-representativ för hela organet och komplikationer. Därför finns ett behov av att utveckla nya tekniker som underlättar diagnostiken, exempelvis via positronemission tomography (PET) avbildning. För att möjliggöra en undersökning med PET krävs det att hitta en tracer som binder till målproteinet för sjukdomen.

    Tracer i detta projekt var en analog till en peptidkedja från en publicerad studie. I studien har olika peptidkedjor utvecklats för att undersöka vilken peptidkedja som binder starkast till Kollagen I, vilket visade sig vara peptidkedjan LRELHLNNN. För att möjliggöra en PET undersökning gjordes en modifiering av peptidkedjan där kelatorn DOTA har sats på via en linker. I detta projekt har aminosyra nummer 6, leucine, bytts ut mot alanin för att efter inmärkning med 68Ga avgöra om den aminosyrasidokedjan är viktig för inbindning till Kollagen I.

    Detta gjordes med hjälp av en metod kallad solid-phase peptide synthesis (SPPS). Peptidsyntesen sker på en fastfas (resin) vilket peptiden binder kovalent till. Syntesen byggs upp med en aminosyra i taget och börjar från C-terminalen och görs mot N-terminalen. Varje aminosyra hade skyddsgrupper sittande på sidokedjorna och en skyddsgrupp på N-terminalen. Skyddsgrupperna på sidokedjorna sitter kvar under hela syntesen för att förhindra oönskade sidoreaktioner och skyddsgruppern på N-terminalen avskyddas alltid inför en koppling av en ny aminosyra. När önskad längd av peptidkedjan erhölls kopplades linkern PEG och kelatorn DOTA.

    För att rena produkten användes high-performance liquid chromatography (HPLC) och produkten analyserades med masspektorskopi (MS). Önskad produkt kunde isoleras men nu behöver den märkas in med en radioaktiv isotop och undersökas med PET. Den radioaktiva märkta substansen ska fungera som en tracer och därmed möjliggöra detektion med PET. Om det fungerar innebär detta ett steg framåt i utveckling av ny fibrosdiagnostik.

  • 50.
    Balgoma, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Common Fatty Markers in Diseases with Dysregulated Lipogenesis2019In: Trends in endocrinology and metabolism, ISSN 1043-2760, E-ISSN 1879-3061, Vol. 30, no 5, p. 283-285Article in journal (Refereed)
    Abstract [en]

    Recent studies have reported the upregulation of a subgroup of triacylglycerides as markers of different diseases with dysregulated lipogenesis, which means that these markers are not selective. This observation has a deep impact on their use as diagnostic tools in clinical practice (e.g., markers of risk of type 2 diabetes).

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