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  • 1. Abdissa, Negera
    et al.
    Induli, Martha
    Fitzpatrick, Paul
    Alao, John Patrick
    Sunnerhagen, Per
    Landberg, Göran
    Yenesew, Abiy
    Erdelyi, Mate
    Cytotoxic quinones from the roots of Aloe dawei.2014In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 19, no 3, p. 3264-3273Article in journal (Refereed)
    Abstract [en]

    Seven naphthoquinones and nine anthraquinones were isolated from the roots of Aloe dawei by chromatographic separation. The purified metabolites were identified by NMR and MS analyses. Out of the sixteen quinones, 6-hydroxy-3,5-dimethoxy-2-methyl-1,4-naphthoquinone is a new compound. Two of the isolates, 5,8-dihydroxy-3-methoxy-2-methylnaphthalene-1,4-dione and 1-hydroxy-8-methoxy-3-methylanthraquinone showed high cytotoxic activity (IC₅₀ 1.15 and 4.85 µM) on MCF-7 breast cancer cells, whereas the others showed moderate to low cytotoxic activity against MDA-MB-231 (ER Negative) and MCF-7 (ER Positive) cancer cells.

  • 2.
    Ali, Sara E.
    et al.
    German Univ Cairo, Fac Pharm & Biotechnol, Dept Pharmaceut Biol, New Cairo 12613, Egypt.
    El Gedaily, Rania A.
    Cairo Univ, Fac Pharm, Pharmacognosy Dept, Kasr el Aini St, Cairo 11562, Egypt.
    Mocan, Andrei
    Iuliu Hatieganu Univ Med & Pharm, Dept Pharmaceut Bot, Cluj Napoca 400337, Romania.
    Farag, Mohamed A.
    Cairo Univ, Fac Pharm, Pharmacognosy Dept, Kasr el Aini St, Cairo 11562, Egypt;Amer Univ Cairo, Sch Sci & Engn, Dept Chem, New Cairo 11835, Egypt.
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi. Menoufia Univ, Fac Sci, Shibin Al Kawm 32512, Egypt.
    Profiling Metabolites and Biological Activities of Sugarcane (Saccharum officinarum Linn.) Juice and Its Product Molasses via a Multiplex Metabolomics Approach2019In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 24, no 5, article id 934Article in journal (Refereed)
    Abstract [en]

    Sugarcane (Saccharum officinarum L.) is an important perennial grass in the Poaceae family cultivated worldwide due to its economical and medicinal value. In this study, a combined approach using mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy was employed for the large-scale metabolite profiling of sugarcane juice and its by-product molasses. The polyphenols were analysed via UPLC-UV-ESI-MS, whereas the primary metabolites such as sugars and organic and amino acids were profiled using NMR spectroscopy and gas chromatography/mass spectrometry (GC/MS). UPLC/MS was more effective than NMR spectroscopy or GC/MS for determining differences among the metabolite compositions of the products. Under the optimized conditions, UPLC/MS led to the identification of 42 metabolites, including nine flavonoids, nine fatty acids, and two sterols. C/O Flavone glycosides were the main subclass detected, with tricin-7-O-deoxyhexosyl glucuronide being detected in sugarcane and molasses for the first time. Based on GC/MS analysis, disaccharides were the predominant species in the sugarcane juice and molasses, with sucrose accounting for 66% and 59%, respectively, by mass of all identified metabolites. The phenolic profiles of sugarcane and molasses were further investigated in relation to their in vitro antioxidant activities using free radical scavenging assays such as 2,2-Diphenyl-1-picrylhydrazyl free radical-scavenging ability (DPPH), Trolox equivalent antioxidant capacity (TEAC) and ferric reducing antioxidant power (FRAP). In view of its higher total phenolic content (TPC) (196 +/- 2.1 mg GAE/100 g extract) compared to that of sugarcane juice (93 +/- 2.9 mg GAE/100 g extract), molasses exhibited a substantially higher antioxidant effect. Interestingly, both extracts were also found to inhibit alpha-glucosidase and alpha-amylase enzymes, suggesting a possible antihyperglycaemic effect. These findings suggest molasses may be a new source of natural antioxidants for functional foods.

  • 3. Atilaw, Yoseph
    et al.
    Duffy, Sandra
    Heydenreich, Matthias
    Muiva-Mutisya, Lois
    Avery, Vicky M
    Erdelyi, Mate
    Yenesew, Abiy
    Three Chalconoids and a Pterocarpene from the Roots of Tephrosia aequilata.2017In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 2, article id E318Article in journal (Refereed)
    Abstract [en]

    In our search for new antiplasmodial agents, the CH₂Cl₂/CH₃OH (1:1) extract of the roots of Tephrosia aequilata was investigated, and observed to cause 100% mortality of the chloroquine-sensitive (3D7) strain of Plasmodium falciparum at a 10 mg/mL concentration. From this extract three new chalconoids, E-2',6'-dimethoxy-3',4'-(2'',2''-dimethyl)pyranoretrochalcone (1, aequichalcone A), Z-2',6'-dimethoxy-3',4'-(2'',2''-dimethyl)pyranoretrochalcone (2, aequichalcone B), 4''-ethoxy-3''-hydroxypraecansone B (3, aequichalcone C) and a new pterocarpene, 3,4:8,9-dimethylenedioxy-6a,11a-pterocarpene (4), along with seven known compounds were isolated. The purified compounds were characterized by NMR spectroscopic and mass spectrometric analyses. Compound 1 slowly converts into 2 in solution, and thus the latter may have been enriched, or formed, during the extraction and separation process. The isomeric compounds 1 and 2 were both observed in the crude extract. Some of the isolated constituents showed good to moderate antiplasmodial activity against the chloroquine-sensitive (3D7) strain of Plasmodium falciparum.

  • 4. Atilaw, Yoseph
    et al.
    Muiva-Mutisya, Lois
    Ndakala, Albert
    Akala, Hoseah M
    Yeda, Redemptah
    Wu, Yu J
    Coghi, Paolo
    Wong, Vincent K W
    Erdelyi, Mate
    Yenesew, Abiy
    Four Prenylflavone Derivatives with Antiplasmodial Activities from the Stem of Tephrosia purpurea subsp. leptostachya.2017In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 9, article id E1514Article in journal (Refereed)
    Abstract [en]

    Four new flavones with modified prenyl groups, namely (E)-5-hydroxytephrostachin (1), purleptone (2), (E)-5-hydroxyanhydrotephrostachin (3), and terpurlepflavone (4), along with seven known compounds (5-11), were isolated from the CH₂Cl₂/MeOH (1:1) extract of the stem of Tephrosia purpurea subsp. leptostachya, a widely used medicinal plant. Their structures were elucidated on the basis of NMR spectroscopic and mass spectrometric evidence. Some of the isolated compounds showed antiplasmodial activity against the chloroquine-sensitive D6 strains of Plasmodium falciparum, with (E)-5-hydroxytephrostachin (1) being the most active, IC50 1.7 ± 0.1 μM, with relatively low cytotoxicity, IC50 > 21 μM, against four cell-lines.

  • 5.
    Benchoula, Khaled
    et al.
    Int Islamic Univ Malaysia, Kulliyyah Pharm, Dept Basic Med Sci, Kuantan 25200, Pahang, Malaysia.
    Khatib, Alfi
    Int Islamic Univ Malaysia, Kulliyyah Pharm, Dept Pharmaceut Chem, Kuantan 25200, Pahang, Malaysia.
    Quzwain, Fairuz M. C.
    Univ Jambi, Fac Med, Jambi 36122, Indonesia.
    Mohamad, Che Anuar Che
    Int Islamic Univ Malaysia, Kulliyyah Pharm, Dept Basic Med Sci, Kuantan 25200, Pahang, Malaysia.
    Sulaiman, Wan Mohd Azizi Wan
    Int Islamic Univ Malaysia, Kulliyyah Pharm, Dept Basic Med Sci, Kuantan 25200, Pahang, Malaysia.
    Wahab, Ridhwan Abdul
    Int Islamic Univ Malaysia, Dept Biomed Sci, Kulliyyah Allied Hlth Sci, Kuantan 25200, Pahang, Malaysia.
    Ahmed, Qamar Uddin
    Int Islamic Univ Malaysia, Kulliyyah Pharm, Dept Pharmaceut Chem, Kuantan 25200, Pahang, Malaysia.
    Ghaffar, Majid Abdul
    Int Islamic Univ Malaysia, Kulliyyah Pharm, Dept Pharmaceut Chem, Kuantan 25200, Pahang, Malaysia.
    Saiman, Mohd Zuwairi
    Univ Malaya, Inst Biol Sci, Fac Sci, Kuala Lumpur 50603, Malaysia.
    Alajmi, Mohamed F.
    King Saud Univ, Dept Pharmacognosy, Coll Pharm, Riyadh 11451, Saudi Arabia.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Optimization of Hyperglycemic Induction in Zebrafish and Evaluation of Its Blood Glucose Level and Metabolite Fingerprint Treated with Psychotria malayana Jack Leaf Extract2019In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 24, no 8, article id 1506Article in journal (Refereed)
    Abstract [en]

    A standard protocol to develop type 1 diabetes in zebrafish is still uncertain due to unpredictable factors. In this study, an optimized protocol was developed and used to evaluate the anti-diabetic activity of Psychotria malayana leaf. The aims of this study were to develop a type 1 diabetic adult zebrafish model and to evaluate the anti-diabetic activity of the plant extract on the developed model. The ability of streptozotocin and alloxan at a different dose to elevate the blood glucose levels in zebrafish was evaluated. While the anti-diabetic activity of P. malayana aqueous extract was evaluated through analysis of blood glucose and LC-MS analysis fingerprinting. The results indicated that a single intraperitoneal injection of 300 mg/kg alloxan was the optimal dose to elevate the fasting blood glucose in zebrafish. Furthermore, the plant extract at 1, 2, and 3 g/kg significantly reduced blood glucose levels in the diabetic zebrafish. In addition, LC-MS-based fingerprinting indicated that 3 g/kg plant extract more effective than other doses. Phytosterols, sugar alcohols, sugar acid, free fatty acids, cyclitols, phenolics, and alkaloid were detected in the extract using GC-MS. In conclusion, P. malayana leaf aqueous extract showed anti-diabetic activity on the developed type 1 diabetic zebrafish model.

  • 6.
    Bergman, Sara
    et al.
    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.
    Nordeman, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Synthesis of 11C-Labelled Ureas by Palladium(II)-Mediated Oxidative Carbonylation2017In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 10, article id 1688Article in journal (Refereed)
    Abstract [en]

    Positron emission tomography is an imaging technique with applications in clinical settings as well as in basic research for the study of biological processes. A PET tracer, a biologically active molecule where a positron-emitting radioisotope such as carbon-11 has been incorporated, is used for the studies. Development of robust methods for incorporation of the radioisotope is therefore of the utmost importance. The urea functional group is present in many biologically active compounds and is thus an attractive target for incorporation of carbon-11 in the form of [C-11] carbon monoxide. Starting with amines and [C-11] carbon monoxide, both symmetrical and unsymmetrical C-11-labelled ureas were synthesised via a palladium(II)-mediated oxidative carbonylation and obtained in decay-corrected radiochemical yields up to 65%. The added advantage of using [C-11] carbon monoxide was shown by the molar activity obtained for an inhibitor of soluble epoxide hydrolase (247 GBq/mu mol-319 GBq/mu mol). DFT calculations were found to support a reaction mechanism proceeding through an C-11-labelled isocyanate intermediate.

  • 7.
    Blom, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Norrehed, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Andersson, Claes-Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Huang, Hao
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Light, Mark E.
    Department of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, U.K.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Grennberg, Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Gogoll, Adolf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Synthesis and Properties of Bis-Porphyrin Molecular Tweezers: Effects of Spacer Flexibility on Binding and Supramolecular Chirogenesis2016In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 21, no 1Article in journal (Refereed)
    Abstract [en]

    Abstract: Ditopic binding of various dinitrogen compounds to three bisporphyrin molecular tweezers with spacers of varying conformational rigidity, incorporating the planar ene-diyne (1), the helical stiff stilbene (2), or the semirigid glycoluril motif fused to  the porphyrins (3) are compared. Binding constants Ka = 10^4 to 10^6 M^-1 reveal subtle  differences between these tweezers, that are discussed in terms of porphyrin dislocation  modes. Exciton coupled circular dichroism (ECCD) of complexes with chiral dinitrogen  guests provides experimental evidence for the conformational properties of the tweezers. The results are further supported and rationalized by conformational analysis.

  • 8.
    Borroto-Escuela, Dasiel O.
    et al.
    Karolinska Inst, Dept Neurosci, Retzius Vag 8, S-17177 Stockholm, Sweden;Univ Urbino Carlo Bo, Dept Biomol Sci, I-61029 Urbino, Italy;Observ Cubano Neurociencias, Grp Bohio Estudio, Zaya 50, Yaguajay 62100, Cuba.
    Narvaez, Manuel
    Univ Malaga, Inst Invest Biomed Malaga, Fac Med, E-29071 Malaga, Spain.
    Ambrogini, Patrizia
    Univ Urbino Carlo Bo, Dept Biomol Sci, I-61029 Urbino, Italy.
    Ferraro, Luca
    Univ Ferrara, SVEB, Dept Life Sci & Biotechnol, I-44121 Ferrara, Italy.
    Brito, Ismel
    Karolinska Inst, Dept Neurosci, Retzius Vag 8, S-17177 Stockholm, Sweden;Observ Cubano Neurociencias, Grp Bohio Estudio, Zaya 50, Yaguajay 62100, Cuba.
    Romero Fernandez, Wilber
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Andrade-Talavera, Yuniesky
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Neuronal Oscillat Lab, S-17177 Stockholm, Sweden.
    Flores-Burgess, Antonio
    Univ Malaga, Inst Invest Biomed Malaga, Fac Med, E-29071 Malaga, Spain.
    Millon, Carmelo
    Univ Malaga, Inst Invest Biomed Malaga, Fac Med, E-29071 Malaga, Spain.
    Gago, Belen
    Univ Malaga, Inst Invest Biomed Malaga, Fac Med, E-29071 Malaga, Spain.
    Angel Narvaez, Jose
    Univ Malaga, Inst Invest Biomed Malaga, Fac Med, E-29071 Malaga, Spain.
    Odagaki, Yuji
    Saitama Med Univ, Dept Psychiat, Saitama 3388570, Japan.
    Palkovits, Miklos
    Semmelweis Univ, Fac Med, Dept Anat Histol & Embryol, H-1094 Budapest, Hungary.
    Diaz-Cabiale, Zaida
    Univ Malaga, Inst Invest Biomed Malaga, Fac Med, E-29071 Malaga, Spain.
    Fuxe, Kjell
    Karolinska Inst, Dept Neurosci, Retzius Vag 8, S-17177 Stockholm, Sweden.
    Receptor-Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment2018In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 23, no 6, article id 1341Article, review/survey (Refereed)
    Abstract [en]

    Due to the binding to a number of proteins to the receptor protomers in receptor heteromers in the brain, the term "heteroreceptor complexes" was introduced. A number of serotonin 5-HT1A heteroreceptor complexes were recently found to be linked to the ascending 5-HT pathways known to have a significant role in depression. The 5-HT1A-FGFR1 heteroreceptor complexes were involved in synergistically enhancing neuroplasticity in the hippocampus and in the dorsal raphe 5-HT nerve cells. The 5-HT1A protomer significantly increased FGFR1 protomer signaling in wild-type rats. Disturbances in the 5-HT1A-FGFR1 heteroreceptor complexes in the raphe-hippocampal 5-HT system were found in a genetic rat model of depression (Flinders sensitive line (FSL) rats). Deficits in FSL rats were observed in the ability of combined FGFR1 and 5-HT1A agonist cotreatment to produce antidepressant-like effects. It may in part reflect a failure of FGFR1 treatment to uncouple the 5-HT1A postjunctional receptors and autoreceptors from the hippocampal and dorsal raphe GIRK channels, respectively. This may result in maintained inhibition of hippocampal pyramidal nerve cell and dorsal raphe 5-HT nerve cell firing. Also, 5-HT1A-5-HT2A isoreceptor complexes were recently demonstrated to exist in the hippocampus and limbic cortex. They may play a role in depression through an ability of 5-HT2A protomer signaling to inhibit the 5-HT1A protomer recognition and signaling. Finally, galanin (1-15) was reported to enhance the antidepressant effects of fluoxetine through the putative formation of GalR1-GalR2-5-HT1A heteroreceptor complexes. Taken together, these novel 5-HT1A receptor complexes offer new targets for treatment of depression.

  • 9.
    Denisova V, Aleksandra
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Molecular Biomimetics.
    Tibbelin, Julius
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Emanuelsson, Rikard
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Ottosson, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Molecular Biomimetics.
    A Computational Investigation of the Substituent Effects on Geometric, Electronic, and Optical Properties of Siloles and 1,4-Disilacyclohexa-2,5-dienes2017In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 3, article id 370Article in journal (Refereed)
    Abstract [en]

    Thirty two differently substituted siloles 1a–1p and 1,4-disilacyclohexa-2,5-dienes 2a–2p were investigated by quantum chemical calculations using the PBE0 hybrid density functional theory (DFT) method. The substituents included σ-electron donating and withdrawing, as well as π-electron donating and withdrawing groups, and their effects when placed at the Si atom(s) or at the C atoms were examined. Focus was placed on geometries, frontier orbital energies and the energies of the first allowed electronic excitations. We analyzed the variation in energies between the orbitals which correspond to HOMO and LUMO for the two parent species, here represented as ΔεHL, motivated by the fact that the first allowed transitions involve excitation between these orbitals. Even though ΔεHL and the excitation energies are lower for siloles than for 1,4-disilacyclohexa-2,5-dienes the latter display significantly larger variations with substitution. The ΔεHL of the siloles vary within 4.57–5.35 eV (ΔΔεHL = 0.78 eV) while for the 1,4-disilacyclohexa-2,5-dienes the range is 5.49–7.15 eV (ΔΔεHL = 1.66 eV). The excitation energy of the first allowed transitions display a moderate variation for siloles (3.60–4.41 eV) whereas the variation for 1,4-disilacyclohexa-2,5-dienes is nearly doubled (4.69–6.21 eV). Cyclobutadisiloles combine the characteristics of siloles and 1,4-disilacyclohexa-2,5-diene by having even lower excitation energies than siloles yet also extensive variation in excitation energies to substitution of 1,4-disilacyclohexa-2,5-dienes (3.47–4.77 eV, variation of 1.30 eV).

  • 10.
    Díaz-Álvarez, Alba E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Mesas-Sánchez, Laura
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Dinér, Peter
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. KTH-Royal Institute of Technology.
    Access to optically pure β-hydroxy esters via non-enzymatic kinetic resolution by a planar-chiral DMAP catalyst2014In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 19, no 9, p. 14273-14291Article in journal (Refereed)
    Abstract [en]

    The development of new approaches to obtain optically pure β-hydroxy esters is an important area in synthetic organic chemistry since they are precursors of other high value compounds. Herein, the kinetic resolution of racemic β-hydroxy esters using a planar-chiral DMAP derivative catalyst is presented. Following this procedure, a range of aromatic β-hydroxy esters was obtained in excellent selectivities (up to = 107) and high enantiomeric excess (up to 99% ee). Furthermore, the utility of the present method was demonstrated in the synthesis of (S)-3-hydroxy-N-methyl-3-phenylpropanamide, a key intermediate for bioactive molecules such as fluoxetine, tomoxetine or nisoxetine, in its enantiomerically pure form.

  • 11.
    Edueng, Khadijah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. International Islamic University Malaysia.
    Mahlin, Denny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Astra Zeneca.
    Gråsjö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Nylander, Olivia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Thakrani, Manish
    Department of Pharmacy, University College London, UK.
    Bergström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Supersaturation Potential of Amorphous Active Pharmaceutical Ingredients after Long-Term Storage2019In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 24, no 15, article id 2731Article in journal (Refereed)
    Abstract [en]

    This study explores the effect of physical aging and/or crystallization on the supersaturation potential and crystallization kinetics of amorphous active pharmaceutical ingredients (APIs). Spray-dried, fully amorphous indapamide, metolazone, glibenclamide, hydrocortisone, hydrochlorothiazide, ketoconazole, and sulfathiazole were used as model APIs. The parameters used to assess the supersaturation potential and crystallization kinetics were the maximum supersaturation concentration (Cmax,app), the area under the curve (AUC), and the crystallization rate constant (k). These were compared for freshly spray-dried and aged/crystallized samples. Aged samples were stored at 75% relative humidity for 168 days (6 months) or until they were completely crystallized, whichever came first. The solid-state changes were monitored with differential scanning calorimetry, Raman spectroscopy, and powder X-ray diffraction. Supersaturation potential and crystallization kinetics were investigated using a tenfold supersaturation ratio compared to the thermodynamic solubility using the µDISS Profiler. The physically aged indapamide and metolazone and the minimally crystallized glibenclamide and hydrocortisone did not show significant differences in their Cmax,app and AUC when compared to the freshly spray-dried samples. Ketoconazole, with a crystalline content of 23%, reduced its Cmax,app and AUC by 50%, with Cmax,app being the same as the crystalline solubility. The AUC of aged metolazone, one of the two compounds that remained completely amorphous after storage, significantly improved as the crystallization kinetics significantly decreased. Glibenclamide improved the most in its supersaturation potential from amorphization. The study also revealed that, besides solid-state crystallization during storage, crystallization during dissolution and its corresponding pathway may significantly compromise the supersaturation potential of fully amorphous APIs.

  • 12.
    El-Aarag, Bishoy
    et al.
    Menoufia Univ, Fac Sci, Chem Dept, Biochem Div, Shibin Al Kawm 32512, Egypt;Okayama Univ, Grad Sch Nat Sci & Technol, Div Chem & Biotechnol, Okayama 7008530, Japan.
    Magdy, Mohamed
    Menoufia Univ, Dept Chem, Fac Sci, Shibin Al Kawm 32512, Egypt.
    AlAjmi, Mohamed F.
    King Saud Univ, Dept Pharmacognosy, Coll Pharm, Riyadh 11451, Saudi Arabia.
    Khalifa, Shaden A. M.
    Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, S-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;Univ Karachi, Int Ctr Chem & Biol Sci, Karachi 75270, Pakistan.
    Melittin Exerts Beneficial Effects on Paraquat-Induced Lung Injuries in Mice by Modifying Oxidative Stress and Apoptosis2019In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 24, no 8, article id 1498Article in journal (Refereed)
    Abstract [en]

    Melittin (MEL) is a 26-amino acid peptide with numerous biological activities. Paraquat (PQ) is one of the most widely used herbicides, although it is extremely toxic to humans. To date, PQ poisoning has no effective treatment, and therefore the current study aimed to assess for the first time the possible effects of MEL on PQ-induced lung injuries in mice. Mice received a single intraperitoneal (IP) injection of PQ (30 mg/kg), followed by IP treatment with MEL (0.1 and 0.5 mg/kg) twice per week for four consecutive weeks. Histological alterations, oxidative stress, and apoptosis in the lungs were studied. Hematoxylin and eosin (H&E) staining indicated that MEL markedly reduced lung injuries induced by PQ. Furthermore, treatment with MEL increased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activity, and decreased malonaldehyde (MDA) and nitric oxide (NO) levels in lung tissue homogenates. Moreover, immunohistochemical staining showed that B-cell lymphoma-2 (Bcl-2) and survivin expressions were upregulated after MEL treatment, while Ki-67 expression was downregulated. The high dose of MEL was more effective than the low dose in all experiments. In summary, MEL efficiently reduced PQ-induced lung injuries in mice. Specific pharmacological examinations are required to determine the effectiveness of MEL in cases of human PQ poisoning.

  • 13. Endale, Milkyas
    et al.
    Ekberg, Annabel
    Alao, John Patrick
    Akala, Hoseah M
    Ndakala, Albert
    Sunnerhagen, Per
    Erdelyi, Mate
    Yenesew, Abiy
    Anthraquinones of the roots of Pentas micrantha.2013In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 18, p. 311-321Article in journal (Refereed)
    Abstract [en]

    Pentas micrantha is used in the East African indigenous medicine to treat malaria. In the first investigation of this plant, the crude methanol root extract showed moderate antiplasmodial activity against the W2- (3.37 μg/mL) and D6-strains (4.00 μg/mL) of Plasmodium falciparum and low cytotoxicity (>450 μg/mL, MCF-7 cell line). Chromatographic separation of the extract yielded nine anthraquinones, of which 5,6-dihydroxylucidin-11-O-methyl ether is new. Isolation of a munjistin derivative from the genus Pentas is reported here for the first time. The isolated constituents were identified by NMR and mass spectrometric techniques and showed low antiplasmodial activities.

  • 14.
    Farag, Mohamed A.
    et al.
    Cairo Univ, Pharmacognosy Dept, Coll Pharm, Kasr el Aini St,PB 11562, Cairo, Egypt..
    Ali, Sara E.
    German Univ Cairo, Fac Pharm & Biotechnol, Dept Pharmaceut Biol, PB 11835, Cairo, Egypt..
    Hodaya, Rashad H.
    Desert Res Ctr, Plant Prod Dept, PB 11714, Cairo, Egypt..
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Menoufia Univ, Fac Sci, Dept Chem, Shibin Al Kawm 32512, Egypt..
    Sultani, Haider N.
    Leibniz Inst Plant Biochem, Dept Bioorgan Chem, Weinberg 3, D-06120 Halle, Saale, Germany..
    Laub, Annegret
    Leibniz Inst Plant Biochem, Dept Bioorgan Chem, Weinberg 3, D-06120 Halle, Saale, Germany..
    Eissa, Tarek E.
    Modern Sci & Arts Univ, Coll Pharm, Pharmacognosy Dept, PB 12566, Cairo, Egypt..
    Abou-Zaid, Fouad O. F.
    Desert Res Ctr, Plant Prod Dept, PB 11714, Cairo, Egypt..
    Wessjohann, Ludger A.
    Leibniz Inst Plant Biochem, Dept Bioorgan Chem, Weinberg 3, D-06120 Halle, Saale, Germany..
    Phytochemical Profiles and Antimicrobial Activities of Allium cepa Red cv. and A. sativum Subjected to Different Drying Methods: A Comparative MS-Based Metabolomics2017In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 5, article id 761Article in journal (Refereed)
    Abstract [en]

    Plants of the Allium genus produce sulphur compounds that give them a characteristic (alliaceous) flavour and mediate for their medicinal use. In this study, the chemical composition and antimicrobial properties of Allium cepa red cv. and A. sativum in the context of three different drying processes were assessed using metabolomics. Bulbs were dried using either microwave, air drying, or freeze drying and further subjected to chemical analysis of their composition of volatile and non-volatile metabolites. Volatiles were collected using solid phase micro-extraction (SPME) coupled to gas chromatography-mass spectrometry (GC/MS) with 42 identified volatiles including 30 sulphur compounds, four nitriles, three aromatics, and three esters. Profiling of the polar non-volatile metabolites via ultra-performance liquid chromatography coupled to high resolution MS (UPLC/MS) annotated 51 metabolites including dipeptides, flavonoids, phenolic acids, and fatty acids. Major peaks in GC/MS or UPLC/MS contributing to the discrimination between A. sativum and A. cepa red cv. were assigned to sulphur compounds and flavonoids. Whereas sulphur conjugates amounted to the major forms in A. sativum, flavonoids predominated in the chemical composition of A. cepa red cv. With regard to drying impact on Allium metabolites, notable and clear separations among specimens were revealed using principal component analysis (PCA). The PCA scores plot of the UPLC/MS dataset showed closer metabolite composition of microwave dried specimens to freeze dried ones, and distant from air dried bulbs, observed in both A. cepa and A. sativum. Compared to GC/MS, the UPLC/MS derived PCA model was more consistent and better in assessing the impact of drying on Allium metabolism. A phthalate derivative was found exclusively in a commercial garlic preparation via GC/MS, of yet unknown origin. The freeze dried samples of both Allium species exhibited stronger antimicrobial activities compared to dried specimens with A. sativum being in general more active than A. cepa red cv.

  • 15. Irungu, Beatrice N
    et al.
    Orwa, Jennifer A
    Gruhonjic, Amra
    Fitzpatrick, Paul A
    Landberg, Göran
    Kimani, Francis
    Midiwo, Jacob
    Erdelyi, Mate
    Yenesew, Abiy
    Constituents of the roots and leaves of Ekebergia capensis and their potential antiplasmodial and cytotoxic activities.2014In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 19, no 9, p. 14235-14246Article in journal (Refereed)
    Abstract [en]

    A new triterpenoid, 3-oxo-12β-hydroxy-oleanan-28,13β-olide (1), and six known triterpenoids 2-7 were isolated from the root bark of Ekebergia capensis, an African medicinal plant. A limonoid 8 and two glycoflavonoids 9-10 were found in its leaves. The metabolites were identified by NMR and MS analyses, and their cytotoxicity was evaluated against the mammalian African monkey kidney (vero), mouse breast cancer (4T1), human larynx carcinoma (HEp2) and human breast cancer (MDA-MB-231) cell lines. Out of the isolates, oleanonic acid (2) showed the highest cytotoxicity, i.e., IC50's of 1.4 and 13.3 µM against the HEp2 and 4T1 cells, respectively. Motivated by the higher cytotoxicity of the crude bark extract as compared to the isolates, the interactions of oleanonic acid (2) with five triterpenoids 3-7 were evaluated on vero cells. In an antiplasmodial assay, seven of the metabolites were observed to possess moderate activity against the D6 and W2 strains of P. falciparum (IC50 27.1-97.1 µM), however with a low selectivity index (IC50(vero)/IC50(P. falciparum-D6)<10). The observed moderate antiplasmodial activity may be due to general cytotoxicity of the isolated triterpenoids.

  • 16.
    Jespers, Willem
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Oliveira, Ana
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Prieto-Diaz, Ruben
    Univ Santiago Compostela, Fac Farm, Dept Quim Organ, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain..
    Majellaro, Maria
    Univ Santiago Compostela, Fac Farm, Dept Quim Organ, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain..
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Sotelo, Eddy
    Univ Santiago Compostela, Fac Farm, Dept Quim Organ, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain..
    Gutiérrez-de-Terán, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Structure-Based Design of Potent and Selective Ligands at the Four Adenosine Receptors2017In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 11, article id 1945Article in journal (Refereed)
    Abstract [en]

    The four receptors that signal for adenosine, A(1), A(2A), A(2B) and A(3) ARs, belong to the superfamily of G protein-coupled receptors (GPCRs). They mediate a number of (patho)physiological functions and have attracted the interest of the biopharmaceutical sector for decades as potential drug targets. The many crystal structures of the A(2A), and lately the A(1) ARs, allow for the use of advanced computational, structure-based ligand design methodologies. Over the last decade, we have assessed the efficient synthesis of novel ligands specifically addressed to each of the four ARs. We herein review and update the results of this program with particular focus on molecular dynamics (MD) and free energy perturbation (FEP) protocols. The first in silico mutagenesis on the A(1)AR here reported allows understanding the specificity and high affinity of the xanthine-antagonist 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX). On the A(2A)AR, we demonstrate how FEP simulations can distinguish the conformational selectivity of a recent series of partial agonists. These novel results are complemented with the revision of the first series of enantiospecific antagonists on the A(2B)AR, and the use of FEP as a tool for bioisosteric design on the A(3)AR.

  • 17.
    Kalepu, Jagadeesh
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Pilarski, Lukasz T.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Weinreb Amides as Directing Groups for Transition Metal-Catalyzed C-H Functionalizations2019In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 24, no 5, article id 830Article, review/survey (Refereed)
    Abstract [en]

    Weinreb amides are a privileged, multi-functional group with well-established utility in classical synthesis. Recently, several studies have demonstrated the use of Weinreb amides as interesting substrates in transition metal-catalyzed C-H functionalization reactions. Herein, we review this part of the literature, including the metal catalysts, transformations explored so far and specific insights from mechanistic studies.

  • 18.
    Kang, Naixin
    et al.
    Soochow Univ, Coll Pharmaceut Sci, Dept Pharmacognosy, Suzhou 215123, Peoples R China.
    Shen, Wenhua
    Jiangxi Univ Tradit Chinese Med, Coll Pharmaceut Sci, Nanchang 330006, Jiangxi, Peoples R China.
    Gao, Hongwei
    Guangxi Univ Chinese Med, Coll Pharm, Nanning 530001, Peoples R China.
    Feng, Yulin
    Jiangxi Univ Tradit Chinese Med, Coll Pharmaceut Sci, Nanchang 330006, Jiangxi, Peoples R China.
    Zhu, Weifeng
    Jiangxi Univ Tradit Chinese Med, Coll Pharmaceut Sci, Nanchang 330006, Jiangxi, Peoples R China.
    Yang, Shilin
    Soochow Univ, Coll Pharmaceut Sci, Dept Pharmacognosy, Suzhou 215123, Peoples R China;Jiangxi Univ Tradit Chinese Med, Coll Pharmaceut Sci, Nanchang 330006, Jiangxi, Peoples R China.
    Liu, Yanli
    Soochow Univ, Coll Pharmaceut Sci, Dept Pharmacol, Suzhou 215123, Peoples R China.
    Xu, Qiongming
    Soochow Univ, Coll Pharmaceut Sci, Dept Pharmacognosy, Suzhou 215123, Peoples R China.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Antischistosomal Properties of Hederacolchiside A1 Isolated from Pulsatilla chinensis2018In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 23, no 6, article id 1431Article in journal (Refereed)
    Abstract [en]

    Background: Schistosomiasis is a major neglected disease for which the current control strategy involves mass treatment with praziquantel, the only available drug. Hence, there is an urgent need to develop new antischistosomal compounds.

    Methods: The antischistosomal activity of hederacolchiside A1 (HSA) were determined by total or female worm burden reductions in mice harboring Schistosoma japonicum or S. mansoni. Pathology parameters were detected on HSA against 1-day-old S. japonicum-harboring mice. Moreover, we confirmed the antischistosomal effect of HSA on newly transformed schistosomula (NTS) of S. japonicum in vitro.

    Results: HSA, a natural product isolated from Pulsatilla chinensis (Bunge) Regel, was initially corroborated to possess promising antischistosomal properties. We demonstrated that HSA had high activity against S. japonicum and S. mansoni less in 11 days old parasites harbored in mice. The antischistosomal effect was even more than the currently used drugs, praziquantel, and artesunate. Furthermore, HSA could ameliorate the pathology parameters in mice harboring 1-day-old juvenile S. japonicum. We also confirmed that HSA-mediated antischistosomal activity is partly due to the morphological changes in the tegument system when NTS are exposed to HSA.

    Conclusions: HSA may have great potential to be an antischistosomal agent for further research.

  • 19. Klein, Michael
    et al.
    Krainz, Karin
    Redwan, Itedale Namro
    Dinér, Peter
    Department of Chemistry, Medicinal Chemistry, University of Gothenburg.
    Grøtli, Morten
    Synthesis of chiral 1,4-disubstituted-1,2,3-triazole derivatives from amino acids2009In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 14, no 12, p. 5124-5143Article in journal (Refereed)
    Abstract [en]

    A versatile method for the synthesis of chiral 1,4-disubstituted-1,2,3-triazole derivatives starting from easily accessible naturally occurring D-or L-amino acids as chiral synthons is described. The amino acids were converted into azido alcohols, followed by copper catalyzed [3+2] cycloaddition reactions between the azido alcohols and methyl propiolate and subsequent ester aminolysis with primary and secondary amines furnished the target compounds, which were obtained in excellent yields with no racemization. Docking of selected target compounds shows that the chiral 1,4-disubstituted-1,2,3-triazoles derivatives has the potential of mimicking the binding mode of known purine analogues.

  • 20.
    Martins, Ernane de Freitas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory. Sao Paulo State Univ UNESP, Inst Theoret Phys, Campus Sao Paulo, BR-01140070 Sao Paulo, Brazil;Univ Sao Paulo, Inst Phys, Sao Paulo, SP, Brazil.
    Feliciano, Gustavo Troiano
    Sao Paulo State Univ UNESP, Inst Chem, Campus Araraquara, BR-14800060 Araraquara, Brazil.
    Scheicher, Ralph H.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Rocha, Alexandre Reily
    Sao Paulo State Univ UNESP, Inst Theoret Phys, Campus Sao Paulo, BR-01140070 Sao Paulo, Brazil.
    Simulating DNA Chip Design Using All-Electronic Graphene-Based Substrates2019In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 24, no 5, article id 951Article in journal (Refereed)
    Abstract [en]

    In this paper, we present a theoretical investigation of an all-electronic biochip based on graphene to detect DNA including a full dynamical treatment for the environment. Our proposed device design is based on the changes in the electronic transport properties of graphene interacting with DNA strands under the effect of the solvent. To investigate these systems, we applied a hybrid methodology, combining quantum and classical mechanics (QM/MM) coupled to non-equilibrium Green's functions, allowing for the calculations of electronic transport. Our results show that the proposed device has high sensitivity towards the presence of DNA, and, combined with the presence of a specific DNA probe in the form of a single-strand, it presents good selectivity towards specific nucleotide sequences.

  • 21.
    Mowbray, Sherry L
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kathiravan, Muthu K
    Pandey, Abhishek A
    Odell, Luke R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Inhibition of Glutamine Synthetase: A Potential Drug Target in Mycobacterium tuberculosis2014In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 19, no 9, p. 13161-13176Article, review/survey (Refereed)
    Abstract [en]

    Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. Globally, tuberculosis is second only to AIDS in mortality and the disease is responsible for over 1.3 million deaths each year. The impractically long treatment schedules (generally 6-9 months) and unpleasant side effects of the current drugs often lead to poor patient compliance, which in turn has resulted in the emergence of multi-, extensively- and totally-drug resistant strains. The development of new classes of anti-tuberculosis drugs and new drug targets is of global importance, since attacking the bacterium using multiple strategies provides the best means to prevent resistance. This review presents an overview of the various strategies and compounds utilized to inhibit glutamine synthetase, a promising target for the development of drugs for TB therapy.

  • 22.
    Murugesu, Suganya
    et al.
    Kulliyyah Pharm Int Islamic Univ Malaysia, Dept Pharmaceut Chem, Kuantan 25200, Pahang Darul Ma, Malaysia.
    Ibrahim, Zalikha
    Kulliyyah Pharm Int Islamic Univ Malaysia, Dept Pharmaceut Chem, Kuantan 25200, Pahang Darul Ma, Malaysia.
    Ahmed, Qamar-Uddin
    Kulliyyah Pharm Int Islamic Univ Malaysia, Dept Pharmaceut Chem, Kuantan 25200, Pahang Darul Ma, Malaysia.
    Yusoff, Nik-Idris Nik
    Kulliyyah Pharm Int Islamic Univ Malaysia, Dept Pharmaceut Chem, Kuantan 25200, Pahang Darul Ma, Malaysia.
    Uzir, Bisha-Fathamah
    Kulliyyah Pharm Int Islamic Univ Malaysia, Dept Pharmaceut Chem, Kuantan 25200, Pahang Darul Ma, Malaysia.
    Perumal, Vikneswari
    Univ Kuala Lumpur, Royal Coll Med Perak, Fac Pharm & Hlth Sci, Ipoh 30450, Perak Darul Rid, Malaysia.
    Abas, Faridah
    Univ Putra Malaysia, Lab Nat Prod, Inst Biosci, Serdang 43300, Selangor Darul, Malaysia.
    Saari, Khozirah
    Univ Putra Malaysia, Lab Nat Prod, Inst Biosci, Serdang 43300, Selangor Darul, Malaysia.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi. Univ Karachi, HEJ Res Inst Chem, Int Ctr Chem & Biol Sci, Karachi 75270, Pakistan.
    Khatib, Alfi
    Kulliyyah Pharm Int Islamic Univ Malaysia, Dept Pharmaceut Chem, Kuantan 25200, Pahang Darul Ma, Malaysia;Univ Putra Malaysia, Lab Nat Prod, Inst Biosci, Serdang 43300, Selangor Darul, Malaysia.
    Characterization of alpha-Glucosidase Inhibitors from Clinacanthus nutans Lindau Leaves by Gas Chromatography-Mass Spectrometry-Based Metabolomics and Molecular Docking Simulation2018In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 23, no 9, article id 2402Article in journal (Refereed)
    Abstract [en]

    Background: Clinacanthus nutans (C. nutans) is an Acanthaceae herbal shrub traditionally consumed to treat various diseases including diabetes in Malaysia. This study was designed to evaluate the alpha-glucosidase inhibitory activity of C. nutans leaves extracts, and to identify the metabolites responsible for the bioactivity. Methods: Crude extract obtained from the dried leaves using 80% methanolic solution was further partitioned using different polarity solvents. The resultant extracts were investigated for their alpha-glucosidase inhibitory potential followed by metabolites profiling using the gas chromatography tandem with mass spectrometry (GC-MS). Results: Multivariate data analysis was developed by correlating the bioactivity, and GC-MS data generated a suitable partial least square (PLS) model resulting in 11 bioactive compounds, namely, palmitic acid, phytol, hexadecanoic acid (methyl ester), 1-monopalmitin, stigmast-5-ene, pentadecanoic acid, heptadecanoic acid, 1-linolenoylglycerol, glycerol monostearate, alpha-tocospiro B, and stigmasterol. In-silico study via molecular docking was carried out using the crystal structure Saccharomyces cerevisiae isomaltase (PDB code: 3A4A). Interactions between the inhibitors and the protein were predicted involving residues, namely LYS156, THR310, PRO312, LEU313, GLU411, and ASN415 with hydrogen bond, while PHE314 and ARG315 with hydrophobic bonding. Conclusion: The study provides informative data on the potential alpha-glucosidase inhibitors identified in C. nutans leaves, indicating the plant's therapeutic effect to manage hyperglycemia.

  • 23.
    Mutulis, Felikss
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Gogoll, Adolf
    Mutule, Ilze
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Yahorava, Sviatlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Yahorau, Aleh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Liepinsh, Edvards
    Wikberg, Jarl E S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Oligomerization of indole derivatives with incorporation of thiols2008In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 13, no 8, p. 1846-63Article in journal (Refereed)
    Abstract [ar]

    Two molecules of indole derivative, e.g. indole-5-carboxylic acid, reacted with one molecule of thiol, e.g. 1,2-ethanedithiol, in the presence of trifluoroacetic acid to yield adducts such as 3-[2-(2-amino-5-carboxyphenyl)-1-(2-mercaptoethylthio)ethyl]-1Hindole-5-carboxylic acid. Parallel formation of dimers, such as 2,3-dihydro-1H,1'H-2,3'-biindole-5,5'-dicarboxylic acid and trimers, such as 3,3'-[2-(2-amino-5-carboxyphenyl) ethane-1,1-diyl]bis(1H-indole-5-carboxylic acid) of the indole derivatives was also observed. Reaction of a mixture of indole and indole-5-carboxylic acid with 2-phenylethanethiol proceeded in a regioselective way, affording 3-[2-(2-aminophenyl)-1-(phenethylthio)ethyl]-1H-indole-5-carboxylic acid. An additional product of this reaction was 3-[2-(2-aminophenyl)-1-(phenethylthio)ethyl]-2,3-dihydro-1H,1'H-2,3'-biindole-5'-carboxylic acid, which upon standing in DMSO-d6 solution gave 3-[2-(2-aminophenyl)-1-(phenethylthio)ethyl]-1H,1'H-2,3'-biindole-5'-carboxylic acid. Structures of all compounds were elucidated by NMR, and a mechanism for their formation was suggested.

  • 24. Nichols, Parker J.
    et al.
    Born, Alexandra
    Henen, Morkos A.
    Strotz, Dean
    Orts, Julien
    Olsson, Simon
    Güntert, Peter
    Chi, Celestine N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. ETH.
    Vögeli, Beat
    The Exact Nuclear Overhauser Enhancement: Recent Advances2017In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 7, article id 1176Article, review/survey (Refereed)
    Abstract [en]

    Although often depicted as rigid structures, proteins are highly dynamic systems, whose motions are essential to their functions. Despite this, it is difficult to investigate protein dynamics due to the rapid timescale at which they sample their conformational space, leading most NMR-determined structures to represent only an averaged snapshot of the dynamic picture. While NMR relaxation measurements can help to determine local dynamics, it is difficult to detect translational or concerted motion, and only recently have significant advances been made to make it possible to acquire a more holistic representation of the dynamics and structural landscapes of proteins. Here, we briefly revisit our most recent progress in the theory and use of exact nuclear Overhauser enhancements (eNOEs) for the calculation of structural ensembles that describe their conformational space. New developments are primarily targeted at increasing the number and improving the quality of extracted eNOE distance restraints, such that the multi-state structure calculation can be applied to proteins of higher molecular weights. We then review the implications of the exact NOE to the protein dynamics and function of cyclophilin A and the WW domain of Pin1, and finally discuss our current research and future directions.

  • 25.
    Rocha, Igor
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials. CAPES Foundation, Ministry of Education of Brazil, Brasília, DF 70040-020, Brazil.
    Lindh, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Strömme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Mihranyan, Albert
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Ferraz, Natalia
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Blood Compatibility of Sulfonated Cladophora Nanocellulose Beads2018In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 23, no 3, article id 601Article in journal (Refereed)
    Abstract [en]

    Sulfonated cellulose beads were prepared by oxidation of Cladophora nanocellulose to 2,3-dialdehyde cellulose followed by sulfonation using bisulfite. The physicochemical properties of the sulfonated beads, i.e., high surface area, high degree of oxidation, spherical shape, and the possibility of tailoring the porosity, make them interesting candidates for the development of immunosorbent platforms, including their application in extracorporeal blood treatments. A desired property for materials used in such applications is blood compatibility; therefore in the present work, we investigate the hemocompatibility of the sulfonated cellulose beads using an in vitro whole blood model. Complement system activation (C3a and sC5b-9 levels), coagulation activation (thrombin-antithrombin (TAT) levels) and hemolysis were evaluated after whole blood contact with the sulfonated beads and the results were compared with the values obtained with the unmodified Cladophora nanocellulose. Results showed that neither of the cellulosic materials presented hemolytic activity. A marked decrease in TAT levels was observed after blood contact with the sulfonated beads, compared with Cladophora nanocellulose. However, the chemical modification did not promote an improvement in Cladophora nanocellulose hemocompatibility in terms of complement system activation. Even though the sulfonated beads presented a significant reduction in pro-coagulant activity compared with the unmodified material, further modification strategies need to be investigated to control the complement activation by the cellulosic materials.

  • 26.
    Rouf, Alvi Muhammad
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Ottosson, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Silaphenolates and Silaphenylthiolates: Two Unexplored Unsaturated Silicon Compound Classes Influenced by Aromaticity2012In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 17, no 1, p. 369-389Article in journal (Refereed)
    Abstract [en]

    Monosilicon analogs of phenolates and phenylthiolates are studied by quantum chemical calculations. Three different silaphenolates and three different silaphenylthiolates are possible; the ortho-, meta-, and para-isomers. For the silaphenolates, the meta- isomer is the thermodynamically most stable, regardless if the substituent R at Si is H, t-Bu or SiMe3. However, with R = H and SiMe3 the energy differences between the three isomers are small, whereas with R = t-Bu the meta- isomer is similar to 5 kcal/mol more stable than the ortho- isomer. For the silaphenylthiolates the ortho- isomer is of lowest energy, although with R = H the ortho- and meta- isomers are isoenergetic. The calculated nucleus independent chemical shifts (NICS) indicate that the silaphenolates and silaphenylthiolates are influenced by aromaticity, but they are less aromatic than the parent silabenzene. The geometries and charge distributions suggest that all silaphenolates and silaphenylthiolates to substantial degrees are described by resonance structures with an exocyclic C=O double bond and a silapentadienyl anionic segment. Indeed, they resemble the all-carbon phenolate and phenylthiolate. Silaphenylthiolates are less bond alternate and have slightly more negative NICS values than analogous silaphenolates, suggesting that this compound class is a bit more aromatic. Dimerization of the silaphenolates and silaphenylthiolates is hampered due to intramolecular Coulomb repulsion in the dimers, and silaphenolates with a moderately bulky SiMe3 group as substituent at Si should prefer the monomeric form.

  • 27.
    Ruan, Chang-Qing
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Gustafsson, Simon
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Strömme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Mihranyan, Albert
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Lindh, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Cellulose Nanofibers Prepared via Pretreatment Based on Oxone® Oxidation2017In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, p. 2177-Article in journal (Refereed)
    Abstract [en]

    Softwood sulfite bleached cellulose pulp was oxidized with Oxone® and cellulose nanofibers (CNF) were produced after mechanical treatment with a high-shear homogenizer. UV-vis transmittance of dispersions of oxidized cellulose with different degrees of mechanical treatment was recorded. Scanning electron microscopy (SEM) micrographs and atomic force microscopy (AFM) images of samples prepared from the translucent dispersions showed individualized cellulose nanofibers with a width of about 10 nm and lengths of a few hundred nm. All results demonstrated that more translucent CNF dispersions could be obtained after the pretreatment of cellulose pulp by Oxone® oxidation compared with the samples produced without pretreatment. The intrinsic viscosity of the cellulose decreased after oxidation and was further reduced after mechanical treatment. Almost translucent cellulose films were prepared from the dispersions of individualized cellulose nanofibers. The procedure described herein constitutes a green, novel, and efficient route to access CNF.

  • 28.
    Ruan, Changqing
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Gustafsson, Simon
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Strømme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Mihranyan, Albert
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Lindh, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Cellulose nanofibers prepared via pretreatment based on Oxone® oxidation2017In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 12, article id 2177Article in journal (Refereed)
    Abstract [sv]

    Softwood sulfite bleached cellulose pulp was oxidized with Oxone (R) and cellulose nanofibers (CNF) were produced after mechanical treatment with a high-shear homogenizer. UV-vis transmittance of dispersions of oxidized cellulose with different degrees of mechanical treatment was recorded. Scanning electron microscopy (SEM) micrographs and atomic force microscopy (AFM) images of samples prepared from the translucent dispersions showed individualized cellulose nanofibers with a width of about 10 nm and lengths of a few hundred nm. All results demonstrated that more translucent CNF dispersions could be obtained after the pretreatment of cellulose pulp by Oxone (R) oxidation compared with the samples produced without pretreatment. The intrinsic viscosity of the cellulose decreased after oxidation and was further reduced after mechanical treatment. Almost translucent cellulose films were prepared from the dispersions of individualized cellulose nanofibers. The procedure described herein constitutes a green, novel, and efficient route to access CNF.

  • 29.
    Shahzad, Danish
    et al.
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.
    Saeed, Aamer
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.
    Larik, Fayaz Ali
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.
    Channar, Pervaiz Ali
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.
    Abbas, Qamar
    Univ Sindh, Dept Physiol, Jamshoro 76080, Pakistan.
    Alajmi, Mohamed F.
    King Saud Univ, Dept Pharmacognosy, Coll Pharm, Riyadh 11451, Saudi Arabia.
    Arshad, M. Ifzan
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.
    Erben, Mauricio F.
    UNLP, CONICET, CEQUINOR, Dept Quim,Fac Ciencias Exactas,CCT La Plata, Blvd 120 E-60 & 64 1465, RA-1900 La Plata, Argentina.
    Hassan, Mubashir
    Kongju Natl Univ, Coll Nat Sci, Dept Biol Sci, 56 Gongjudehak Ro, Gongju 32588, Chungnam, South Korea.
    Raza, Hussain
    Kongju Natl Univ, Coll Nat Sci, Dept Biol Sci, 56 Gongjudehak Ro, Gongju 32588, Chungnam, South Korea.
    Seo, Sung-Yum
    Kongju Natl Univ, Coll Nat Sci, Dept Biol Sci, 56 Gongjudehak Ro, Gongju 32588, Chungnam, South Korea.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Novel C-2 Symmetric Molecules as -Glucosidase and -Amylase Inhibitors: Design, Synthesis, Kinetic Evaluation, Molecular Docking and Pharmacokinetics2019In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 24, no 8, article id 1511Article in journal (Refereed)
    Abstract [en]

    A series of symmetrical salicylaldehyde-bishydrazine azo molecules, 5a-5h, have been synthesized, characterized by H-1-NMR and C-13-NMR, and evaluated for their in vitro -glucosidase and -amylase inhibitory activities. All the synthesized compounds efficiently inhibited both enzymes. Compound 5g was the most potent derivative in the series, and powerfully inhibited both -glucosidase and -amylase. The IC50 of 5g against -glucosidase was 0.35917 +/- 0.0189 mu M (standard acarbose IC50 = 6.109 +/- 0.329 mu M), and the IC50 value of 5g against -amylase was 0.4379 +/- 0.0423 mu M (standard acarbose IC50 = 33.178 +/- 2.392 mu M). The Lineweaver-Burk plot indicated that compound 5g is a competitive inhibitor of -glucosidase. The binding interactions of the most active analogues were confirmed through molecular docking studies. Docking studies showed that 5g interacts with the residues Trp690, Asp548, Arg425, and Glu426, which form hydrogen bonds to 5g with distances of 2.05, 2.20, 2.10 and 2.18 angstrom, respectively. All compounds showed high mutagenic and tumorigenic behaviors, and only 5e showed irritant properties. In addition, all the derivatives showed good antioxidant activities. The pharmacokinetic evaluation also revealed promising results

  • 30.
    Ujan, Rabail
    et al.
    Univ Sindh, Dr MA Kazi Inst Chem, Jamshoro 76080, Pakistan.
    Saeed, Aamer
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.
    Channar, Pervaiz Ali
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.
    Larik, Fayaz Ali
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.
    Abbas, Qamar
    Univ Sindh, Dept Physiol, Jamshoro 76080, Pakistan.
    Alajmi, Mohamed F.
    King Saud Univ, Dept Pharmacognosy, Coll Pharm, Riyadh 11451, Saudi Arabia.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Rind, Mahboob Ali
    Univ Sindh, Dr MA Kazi Inst Chem, Jamshoro 76080, Pakistan.
    Hassan, Mubashir
    Kongju Natl Univ, Coll Nat Sci, Dept Biol Sci, Gongju 314701, Chungnam, South Korea.
    Raza, Hussain
    Kongju Natl Univ, Coll Nat Sci, Dept Biol Sci, Gongju 314701, Chungnam, South Korea.
    Seo, Sung-Yum
    Kongju Natl Univ, Coll Nat Sci, Dept Biol Sci, Gongju 314701, Chungnam, South Korea.
    Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation2019In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 24, no 5, article id 860Article in journal (Refereed)
    Abstract [en]

    A small library of new drug-1,3,4-thiazidazole hybrid compounds (3a-3i) was synthesized, characterized, and assessed for their acetyl cholinesterase enzyme (AChE) inhibitory and free radical scavenging activities. The newly synthesized derivatives showed promising activities against AChE, especially compound 3b (IC50 18.1 +/- 0.9 nM), which was the most promising molecule in the series, and was substantially more active than the reference drug (neostigmine methyl sulfate; IC50 2186.5 +/- 98.0 nM). Kinetic studies were performed to elucidate the mode of inhibition of the enzyme, and the compounds showed mixed-type mechanisms for inhibiting AChE. The Ki of 3b (0.0031 mu M) indicates that it can be very effective, even at low concentrations. Compounds 3a-3i all complied with Lipinski's Rule of Five, and showed high drug-likeness scores. The pharmacokinetic parameters revealed notable lead-like properties with insignificant liver and skin-penetrating effects. The structure-activity relationship (SAR) analysis indicated pi-pi interactions with key amino acid residues related to Tyr124, Trp286, and Tyr341.

  • 31.
    Vall, Maria
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Ferraz, Natalia
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Cheung, Ocean
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Strømme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Zardán Gómez de la Torre, Teresa
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Exploring the use of amine modified mesoporous magnesium carbonate for the delivery of salicylic acid in topical formulations: in vitro cytotoxicity and drug release studies2019In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 24, no 9, article id 1820Article in journal (Refereed)
  • 32.
    Varasteh, Zohreh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Altai, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Rosestedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    The Effect of Mini-PEG-Based Spacer Length on Binding and Pharmacokinetic Properties of a Ga-68-Labeled NOTA-Conjugated Antagonistic Analog of Bombesin2014In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 19, no 7, p. 10455-10472Article in journal (Refereed)
    Abstract [en]

    The overexpression of gastrin-releasing peptide receptor (GRPR) in cancer can be used for peptide-receptor mediated radionuclide imaging and therapy. We have previously shown that an antagonist analog of bombesin RM26 conjugated to 1,4,7-triazacyclononane-N, N', N ''-triacetic acid (NOTA) via a diethyleneglycol (PEG(2)) spacer (NOTA-PEG(2)-RM26) and labeled with Ga-68 can be used for imaging of GRPR-expressing tumors. In this study, we evaluated if a variation of mini-PEG spacer length can be used for optimization of targeting properties of the NOTA-conjugated RM26. A series of analogs with different PEG-length (n = 2, 3, 4, 6) was synthesized, radiolabeled and evaluated in vitro and in vivo. The IC50 values of Ga-nat-NOTA-PEG(n)-RM26 (n = 2, 3, 4, 6) were 3.1 +/- 0.2, 3.9 +/- 0.3, 5.4 +/- 0.4 and 5.8 +/- 0.3 nM, respectively. In normal mice all conjugates demonstrated similar biodistribution pattern, however Ga-68-NOTA-PEG(3)-RM26 showed lower liver uptake. Biodistribution of Ga-68-NOTA-PEG(3)-RM26 was evaluated in nude mice bearing PC-3 (prostate cancer) and BT-474 (breast cancer) xenografts. High uptake in tumors (4.6 +/- 0.6% ID/g and 2.8 +/- 0.4% ID/g for PC-3 and BT-474 xenografts, respectively) and high tumor-to-background ratios (tumor/ blood of 44 +/- 12 and 42 +/- 5 for PC-3 and BT-474 xenografts, respectively) were found already at 2 h p.i. of Ga-68-NOTA-PEG(3)-RM26. Results of this study suggest that variation in the length of the PEG spacer can be used for optimization of targeting properties of peptide-chelator conjugates. However, the influence of the mini-PEG length on biodistribution is minor when di-, tri-, tetra- and hexaethylene glycol are compared.

  • 33.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    68Ga-Based radiopharmaceuticals: production and application relationship2015In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 20, no 7, p. 12913-12943Article, review/survey (Refereed)
    Abstract [en]

    The contribution of 68Ga to the promotion and expansion of clinical research and routine positron emission tomography (PET) for earlier better diagnostics and individualized medicine is considerable. The potential applications of 68Ga-comprising imaging agents include targeted, pre-targeted and non-targeted imaging. This review discusses the key aspects of the production of 68Ga and 68Ga-based radiopharmaceuticals in the light of the impact of regulatory requirements and endpoint pre-clinical and clinical applications.

  • 34.
    Yang, Lu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. China Pharmaceut Univ, Dept Complex Prescript TCM, Jiangsu Prov Key Lab TCM Evaluat & Translat Res, 639 Longmian Rd, Nanjing 211198, Jiangsu, Peoples R China..
    Chai, Cheng-Zhi
    China Pharmaceut Univ, Dept Complex Prescript TCM, Jiangsu Prov Key Lab TCM Evaluat & Translat Res, 639 Longmian Rd, Nanjing 211198, Jiangsu, Peoples R China..
    Yan, Yan
    Shanxi Univ, Modern Res Ctr Tradit Chinese Med, 92,Wucheng Rd, Taiyuan 030006, Shanxi, Peoples R China..
    Duan, Ying-Dan
    China Pharmaceut Univ, Dept Complex Prescript TCM, Jiangsu Prov Key Lab TCM Evaluat & Translat Res, 639 Longmian Rd, Nanjing 211198, Jiangsu, Peoples R China..
    Henz, Astrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Zhang, Bo-Li
    Tianjin Univ Tradit Chinese Med, Inst Tradit Chinese Med, Tianjin 300193, Peoples R China..
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Yu, Bo-Yang
    China Pharmaceut Univ, Dept Complex Prescript TCM, Jiangsu Prov Key Lab TCM Evaluat & Translat Res, 639 Longmian Rd, Nanjing 211198, Jiangsu, Peoples R China..
    Spasmolytic Mechanism of Aqueous Licorice Extract on Oxytocin-Induced Uterine Contraction through Inhibiting the Phosphorylation of Heat Shock Protein 272017In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 9, article id 1392Article in journal (Refereed)
    Abstract [en]

    Licorice derived from the roots and rhizomes of Glycyrrhiza uralensis Fisch. (Fabaceae), is one of the most widely-used traditional herbal medicines in China. It has been reported to possess significant analgesic activity for treating spastic pain. The aim of this study is to investigate the spasmolytic molecular mechanism of licorice on oxytocin-induced uterine contractions and predict the relevant bioactive constituents in the aqueous extract. The aqueous extraction from licorice inhibited the amplitude and frequency of uterine contraction in a concentration-dependent manner. A morphological examination showed that myometrial smooth muscle cells of oxytocin-stimulated group were oval-shaped and arranged irregularly, while those with a single centrally located nucleus of control and licorice-treated groups were fusiform and arranged orderly. The percentage of phosphorylation of HSP27 at Ser-15 residue increased up to 50.33% at 60 min after oxytocin stimulation. Furthermore, this increase was significantly suppressed by licorice treatment at the concentration of 0.2 and 0.4 mg/mL. Colocalization between HSP27 and alpha-SMA was observed in the myometrial tissues, especially along the actin bundles in the oxytocin-stimulated group. On the contrary, the colocalization was no longer shown after treatment with licorice. Additionally, employing ChemGPS-NP provided support for a preliminary assignment of liquiritigenin and isoliquiritigenin as protein kinase C (PKC) inhibitors in addition to liquiritigenin, isoliquiritigenin, liquiritin and isoliquiritin as MAPK-activated protein kinase 2 (MK2) inhibitors. These assigned compounds were docked with corresponding crystal structures of respective proteins with negative and low binding energy, which indicated a high affinity and tight binding capacity for the active site of the kinases. These results suggest that licorice exerts its spasmolytic effect through inhibiting the phosphorylation of HSP27 to alter the interaction between HSP27 and actin. Furthermore, our results provide support for the prediction that potential bioactive constituents from aqueous licorice extract inhibit the relevant up-stream kinases that phosphorylate HSP27.

  • 35. Yaouba, Souaibou
    et al.
    Valkonen, Arto
    Coghi, Paolo
    Gao, Jiaying
    Guantai, Eric M
    Derese, Solomon
    Wong, Vincent K W
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. The Swedish NMR Centre, Gothenburg, Sweden; Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden .
    Yenesew, Abiy
    Crystal Structures and Cytotoxicity of ent-Kaurane-Type Diterpenoids from Two Aspilia Species.2018In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 23, no 12, article id 3199Article in journal (Refereed)
    Abstract [en]

    A phytochemical investigation of the roots of Aspilia pluriseta led to the isolation of ent-kaurane-type diterpenoids and additional phytochemicals (123). The structures of the isolated compounds were elucidated based on Nuclear Magnetic Resonance (NMR) spectroscopic and mass spectrometric analyses. The absolute configurations of seven of the ent-kaurane-type diterpenoids (36, 6b, 7 and 8) were determined by single crystal X-ray diffraction studies. Eleven of the compounds were also isolated from the roots and the aerial parts of Aspilia mossambicensis. The literature NMR assignments for compounds 1 and 5 were revised. In a cytotoxicity assay, 12α-methoxy-ent-kaur-9(11),16-dien-19-oic acid (1) (IC50 = 27.3 ± 1.9 µM) and 9β-hydroxy-15α-angeloyloxy-ent-kaur-16-en-19-oic acid (3) (IC50 = 24.7 ± 2.8 µM) were the most cytotoxic against the hepatocellular carcinoma (Hep-G2) cell line, while 15α-angeloyloxy-16β,17-epoxy-ent-kauran-19-oic acid (5) (IC50 = 30.7 ± 1.7 µM) was the most cytotoxic against adenocarcinomic human alveolar basal epithelial (A549) cells.

  • 36.
    Zahra, Maram Hussein
    et al.
    Okayama Univ, Grad Sch Nat Sci & Technol, Div Chem & Biotechnol, Okayama 7008530, Japan.
    Salem, Tarek A. R.
    Qassim Univ, Dept Biochem, Coll Med, Al Qassim 51452, Saudi Arabia;Univ Sadat City, Genet Engn & Biotechnol Inst, Dept Mol Biol, Sadat City 32958, Egypt.
    El-Aarag, Bishoy
    Okayama Univ, Grad Sch Nat Sci & Technol, Div Chem & Biotechnol, Okayama 7008530, Japan;Menoufia Univ, Div Biochem, Dept Chem, Fac Sci, Shibin Al Kawm 32512, Egypt.
    Yosri, Nermeen
    Menoufia Univ, Dept Chem, Fac Sci, Shibin Al Kawm 32512, Egypt.
    EL-Ghlban, Samah
    Menoufia Univ, Div Biochem, Dept Chem, Fac Sci, Shibin Al Kawm 32512, Egypt.
    Zaki, Kholoud
    Menoufia Univ, Dept Chem, Fac Sci, Shibin Al Kawm 32512, Egypt.
    Marei, Amel H.
    Menoufia Univ, Dept Chem, Fac Sci, Shibin Al Kawm 32512, Egypt.
    Abd El-Wahed, Aida
    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;Agr Res Ctr, Plant Protect Res Inst, Dept Bee Res, Giza 12627, Egypt.
    Saeed, Aamer
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.
    Khatib, Alfi
    Int Islamic Univ Malaysia, Dept Pharmaceut Chem, Fac Pharm, Kuantan 25200, Pahang, Malaysia.
    AlAjmi, Mohamed F.
    King Saud Univ, Coll Pharm, Pharmacognosy Grp, Riyadh 11451, Saudi Arabia.
    Shathili, Abdulrahman M.
    Al Rayan Coll, Al Rayan Res & Innovat Ctr, Medina 42541, Saudi Arabia.
    Xiao, Jianbo
    Univ Macau, Inst Chinese Med Sci, Taipa 999078, Macau, Peoples R China.
    Khalifa, Shaden A. M.
    Karolinska Univ Hosp, Clin Res Ctr, S-14186 Huddinge, Sweden;Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, 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;Al Rayan Coll, Al Rayan Res & Innovat Ctr, Medina 42541, Saudi Arabia;Jiangsu Univ, Coll Food & Biol Engn, Zhenjiang 212013, Jiangsu, Peoples R China.
    Alpinia zerumbet (Pers.): Food and Medicinal Plant with Potential In Vitro and In Vivo Anti-Cancer Activities2019In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 24, no 13, article id 2495Article in journal (Refereed)
    Abstract [en]

    Background/Aim: Plants play an important role in anti-cancer drug discovery, therefore, the current study aimed to evaluate the biological activity of Alpinia zerumbet (A. zerumbet) flowers.

    Methods: The phytochemical and biological criteria of A. zerumbet were in vitro investigated as well as in mouse xenograft model.

    Results: A. zerumbet extracts, specially CH2Cl2 and MeOH extracts, exhibited the highest potent anti-tumor activity against Ehrlich ascites carcinoma (EAC) cells. The most active CH2Cl2 extract was subjected to bioassay-guided fractionation leading to isolatation of the naturally occurring 5,6-dehydrokawain (DK) which was characterized by IR, MS, H-1-NMR and C-13-NMR. A. zerumbet extracts, specially MeOH and CH2Cl2 extracts, exhibited significant inhibitory activity towards tumor volume (TV). Furthermore, A. zerumbet extracts declined the high level of malonaldehyde (MDA) as well as elevated the levels of superoxide dismutase (SOD) and catalase (CAT) in liver tissue homogenate. Moreover, DK showed anti-proliferative action on different human cancer cell lines. The recorded IC50 values against breast carcinoma (MCF-7), liver carcinoma (Hep-G2) and larynx carcinoma cells (HEP-2) were 3.08, 6.8, and 8.7 mu g/mL, respectively.

    Conclusion: Taken together, these findings open the door for further investigations in order to explore the potential medicinal properties of A. zerumbet.

  • 37.
    Zhang, Yi
    et al.
    Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, Beijing 100010, Peoples R China..
    Zhang, Gan-Lin
    Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, Beijing 100010, Peoples R China..
    Sun, Xu
    Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, Beijing 100010, Peoples R China..
    Cao, Ke-Xin
    Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, Beijing 100010, Peoples R China..
    Shang, Ya-Wen
    Capital Med Univ, Sch Tradit Chinese Med, Beijing 100069, Peoples R China..
    Gong, Mu-Xin
    Capital Med Univ, Sch Tradit Chinese Med, Beijing 100069, Peoples R China..
    Ma, Cong
    Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, Beijing 100010, Peoples R China..
    Nan, Nan
    Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, Beijing 100010, Peoples R China..
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, Beijing 100010, Peoples R China..
    Yu, Ming-Wei
    Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, Beijing 100010, Peoples R China..
    Yang, Guo-Wang
    Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, Beijing 100010, Peoples R China..
    Wang, Xiao-Min
    Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, Beijing 100010, Peoples R China..
    Gubenyiliu II Inhibits Breast Tumor Growth and Metastasis Associated with Decreased Heparanase Expression and Phosphorylation of ERK and AKT Pathways2017In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 5, article id 787Article in journal (Refereed)
    Abstract [en]

    Gubenyiliu II (GYII), a Traditional Chinese Medicine (TCM) formula used in our hospital, has shown beneficial effects in cancer patients. In this study, we investigated the molecular mechanisms underlying the beneficial effects of GYII on murine breast cancer models. GYII showed significant inhibitory effects on tumor growth and metastasis in the murine breast cancer model. Additionally, GYII suppressed the proliferation of 4T1 and MCF-7 cells in a dose-dependent manner. A better inhibitory effect on 4T1 cell proliferation and migration was found in the decomposed recipes (DR) of GYII. Moreover, heparanase expression and the degree of angiogenesis were reduced in tumor tissues. Western blot analysis showed decreased expression of heparanase and growth factors in the cells treated with GYII and its decomposed recipes (DR2 and DR3), and thereby a reduction in the phosphorylation of extracellular signal-regulated kinase (ERK) and serine-threonine kinase (AKT). These results suggest that GYII exerts anti-tumor growth and anti-metastatic effects in the murine breast cancer model. The anti-tumor activity of GYII and its decomposed recipes is, at least partly, associated with decreased heparanase and growth factor expression, which subsequently suppressed the activation of the ERK and AKT pathways.

1 - 37 of 37
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