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  • 1.
    Altai, Mohamed
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Honarvar, Hadis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Wållberg, Helena
    Strand, Joanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Varasteh, Zohreh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Rosestedt, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Dunås, Finn
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för medicinsk strålfysik.
    Löfblom, John
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Ståhl, Stefan
    Selection of an optimal cysteine-containing peptide-based chelator for labeling of affibody molecules with 188Re2014Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 87, s. 519-528Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Affibody molecules constitute a class of small (7 kDa) scaffold proteins that can be engineered to have excellent tumor targeting properties. High reabsorption in kidneys complicates development of affibody molecules for radionuclide therapy. In this study, we evaluated the influence of the composition of cysteine-containing C-terminal peptide-based chelators on the biodistribution and renal retention of 188Re-labeled anti-HER2 affibody molecules. Biodistribution of affibody molecules containing GGXC or GXGC peptide chelators (where X is G, S, E or K) was compared with biodistribution of a parental affibody molecule ZHER2:2395 having a KVDC peptide chelator. All constructs retained low picomolar affinity to HER2-expressing cells after labeling. The biodistribution of all 188Re-labeled affibody molecules was in general comparable, with the main observed difference found in the uptake and retention of radioactivity in excretory organs. The 188Re-ZHER2:V2 affibody molecule with a GGGC chelator provided the lowest uptake in all organs and tissues. The renal retention of 188Re-ZHER2:V2 (3.1 ± 0.5 %ID/g at 4 h after injection) was 55-fold lower than retention of the parental 188Re-ZHER2:2395 (172 ± 32 %ID/g). We show that engineering of cysteine-containing peptide-based chelators can be used for significant improvement of biodistribution of 188Re-labeled scaffold proteins, particularly reduction of their uptake in excretory organs.

  • 2.
    Aneja, Babita
    et al.
    Jamia Millia Islamia, Dept Biosci, New Delhi 110025, India;Jamia Millia Islamia, Dept Chem, New Delhi 110025, India.
    Khan, Nashrah Sharif
    Jamia Millia Islamia, Ctr Interdisciplinary Res Basic Sci, New Delhi 110025, India;Jamia Millia Islamia, Dept Biotechnol, New Delhi 110025, India.
    Khan, Parvez
    Jamia Millia Islamia, Ctr Interdisciplinary Res Basic Sci, New Delhi 110025, India.
    Queen, Aarfa
    Jamia Millia Islamia, Dept Chem, New Delhi 110025, India.
    Hussain, Afzal
    King Saud Univ, Coll Pharm, Dept Pharmacognosy, Riyadh 11451, Saudi Arabia.
    Rehman, Md. Tabish
    King Saud Univ, Coll Pharm, Dept Pharmacognosy, Riyadh 11451, Saudi Arabia.
    Alajmi, Mohamed F.
    King Saud Univ, Coll Pharm, Dept Pharmacognosy, Riyadh 11451, Saudi Arabia.
    El-Seedi, Hesham
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Ali, Sher
    Jamia Millia Islamia, Ctr Interdisciplinary Res Basic Sci, New Delhi 110025, India.
    Hassan, Md. Imtaiyaz
    Jamia Millia Islamia, Ctr Interdisciplinary Res Basic Sci, New Delhi 110025, India.
    Abid, Mohammad
    Jamia Millia Islamia, Dept Biosci, New Delhi 110025, India.
    Design and development of Isatin-triazole hydrazones as potential inhibitors of microtubule affinity-regulating kinase 4 for the therapeutic management of cell proliferation and metastasis2019Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 163, s. 840-852Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Microtubule affinity-regulating kinase 4 (MARK4) is a potential drug target as the same is found to be over expressed in several types of cancers. In search of effective MARK4 inhibitors, we have synthesized and characterized Isatin-triazole hydrazones (9a-i) and evaluated their inhibitory potential. Of all the compounds, 9g showed better binding affinity and enzyme inhibition potential in sub micromolar range. Human serum albumin (HSA) binding assay suggested an easy transportation of 9g in blood stream due to its binding affinity. In vitro anticancer studies performed on MCF-7, MDA-MB-435s and HepG2 cells using 9g showed inhibition of cell proliferation and cell migration. Further, 9g induces apoptosis in these cancerous cells, with IC50 values of 6.22, 9.94 and 8.14 mu M, respectively. Putatively, 9g seems to cause oxidative stress resulting in apoptosis. Functional assay of 9g with a panel of 26 kinases showed MARK4 specific profile. In conclusion, 9g seems to possess an effective inhibitory potential towards MARK4 adding an additional repertoire to anticancer therapeutics.

  • 3.
    Belfrage, Anna Karin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Läkemedelsdesign och läkemedelsutveckling.
    Abdurakhmanov, Eldar
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Åkerblom, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Läkemedelsdesign och läkemedelsutveckling.
    Brandt, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Läkemedelsdesign och läkemedelsutveckling.
    Alogheli, Hiba
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Läkemedelsdesign och läkemedelsutveckling.
    Neyts, Johan
    Rega Institute, Department of Microbiology and Immunology, University of Leuven, B-3000 Leuven, Belgium.
    Danielson, U. Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Johansson, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Läkemedelsdesign och läkemedelsutveckling.
    Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold2018Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 148, s. 453-464Artikel i tidskrift (Refereegranskat)
    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).

  • 4.
    Caraballo, Remi
    et al.
    Umea Univ, Dept Chem, SE-90187 Umea, Sweden..
    Larsson, Mikael
    Umea Univ, Dept Med Biosci, SE-90187 Umea, Sweden..
    Nilsson, Stefan K.
    Umea Univ, Dept Med Biosci, SE-90187 Umea, Sweden..
    Ericsson, Madelene
    Umea Univ, Dept Med Biosci, SE-90187 Umea, Sweden..
    Qian, Weixing
    Umea Univ, Chem Biol Consortium Sweden, Labs Chem Biol Umea, SE-90187 Umea, Sweden..
    Tran, Nam Phuong Nguyen
    Kindahl, Tomas
    Umea Univ, Dept Chem, SE-90187 Umea, Sweden..
    Svensson, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Saar, Valeria
    Umea Univ, Dept Med Biosci, SE-90187 Umea, Sweden..
    Artursson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Olivecrona, Gunilla
    Umea Univ, Dept Med Biosci, SE-90187 Umea, Sweden..
    Enquist, Per-Anders
    Umea Univ, Chem Biol Consortium Sweden, Labs Chem Biol Umea, SE-90187 Umea, Sweden..
    Elofsson, Mikael
    Umea Univ, Dept Chem, SE-90187 Umea, Sweden.;Umea Univ, Chem Biol Consortium Sweden, Labs Chem Biol Umea, SE-90187 Umea, Sweden..
    Structure-activity relationships for lipoprotein lipase agonists that lower plasma triglycerides in vivo2015Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 103, s. 191-209Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The risk of cardiovascular events increases in individuals with elevated plasma triglyceride (TG) levels, therefore advocating the need for efficient TG-lowering drugs. In the blood circulation, TG levels are regulated by lipoprotein lipase (LPL), an unstable enzyme that is only active as a non-covalently associated homodimer. We recently reported on a N-phenylphthalimide derivative (1) that stabilizes LPL in vitro, and moderately lowers triglycerides in vivo (Biochem. Biophys. Res. Common. 2014, 450, 1063). Herein, we establish structure activity relationships of 51 N-phenylphthalimide analogs of the screening hit 1. In vitro evaluation highlighted that modifications on the phthalimide moiety were not tolerated and that lipophilic substituents on the central phenyl ring were functionally essential. The substitution pattern on the central phenyl ring also proved important to stabilize LPL However, in vitro testing demonstrated rapid degradation of the phthalimide fragment in plasma which was addressed by replacing the phthalimide scaffold with other heterocyclic fragments. The in vitro potency was retained or improved and substance 80 proved stable in plasma and efficiently lowered plasma TGs in vivo.

  • 5. MacGregor, Kylie A
    et al.
    Abdel-Hamid, Mohammed K
    Odell, Luke R
    Centre for Chemical Biology, Chemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia.
    Chau, Ngoc
    Whiting, Ainslie
    Robinson, Phillip J
    McCluskey, Adam
    Development of quinone analogues as dynamin GTPase inhibitors2014Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 85, s. 191-206Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Virtual screening of the ChemDiversity and ChemBridge compound databases against dynamin I (dynI) GTPase activity identified 2,5-bis-(benzylamino)-1,4-benzoquinone 1 as a 273 ± 106 μM inhibitor. In silico lead optimization and focused library-led synthesis resulted in the development of four discrete benzoquinone/naphthoquinone based compound libraries comprising 54 compounds in total. Sixteen analogues were more potent than lead 1, with 2,5-bis-(4-hydroxyanilino)-1,4-benzoquinone (45) and 2,5-bis(4-carboxyanilino)-1,4-benzoquinone (49) the most active with IC50 values of 11.1 ± 3.6 and 10.6 ± 1.6 μM respectively. Molecular modelling suggested a number of hydrogen bonding and hydrophobic interactions were involved in stabilization of 49 within the dynI GTP binding site. Six of the most active inhibitors were evaluated for potential inhibition of clathrin-mediated endocytosis (CME). Quinone 45 was the most effective CME inhibitor with an IC50(CME) of 36 ± 16 μM.

  • 6. Makatini, Maya M.
    et al.
    Petzold, Katja
    Arvidsson, Per I.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Honarparvar, Bahareh
    Govender, Thavendran
    Maguire, Glenn E. M.
    Parboosing, Raveen
    Sayed, Yasien
    Soliman, Mahmoud E. S.
    Kruger, Hendrik G.
    Synthesis, screening and computational investigation of pentacycloundecane-peptoids as potent CSA-HIV PR inhibitors2012Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 57, s. 459-467Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Herein, we present the first pentacycloundecane (PCU) diol peptoid derived HIV protease inhibitors with IC50 values ranging from 6.5 to 0.075 mu M. Five derivatives were synthesized in an attempt to understand the structure activity relationship of this class of compounds for HIV protease inhibition. NMR spectroscopy (new Efficient Adiabatic Symmetrized Rotating Overhauser Effect Spectroscopy, EASY-ROESY) was employed to determine the predominant conformation of the active compound. In this study docking studies and MD simulations provided insight into the binding theme of this class of peptoid inhibitors to the CSA-HIV PR active site. Conserved and stable hydrogen bonding between the hydroxyl groups of the inhibitors and the active site Asp25/Asp25' residues were observed from the docking and along the MD trajectories.

  • 7. Makatini, Maya M.
    et al.
    Petzold, Katja
    Sriharsha, Shimoga N.
    Ndlovu, N.
    Soliman, Mahmoud E. S.
    Honarparvar, Bahareh
    Parboosing, Raveen
    Naidoo, Anneta
    Arvidsson, Per I.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sayed, Yasien
    Govender, Patrick
    Maguire, Glenn E. M.
    Kruger, Hendrik G.
    Govender, Thavendran
    Synthesis and structural studies of pentacycloundecane-based HIV-1 PR inhibitors: A hybrid 2D NMR and docking/QM/MM/MD approach2011Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 46, nr 9, s. 3976-3985Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pentacycloundecane (PCU) lactam-peptide based HIV protease inhibitors were synthesized and nanomolar activity against the resistance-prone wild type C-South African HIV protease is reported. NMR investigations indicated that the activity is related to the chirality of the PCU moiety and its ability to induce conformations of the coupled peptide side chain. EASY-ROESY NMR experiments gave information about the 3D structure of the cage peptides and 3D solution structure could be linked to the experimental IC(50) activity profile of the considered inhibitors. QM/MM/MD simulations of the inhibitors in solution confirmed the NMR observed conformations. Docking experiments and QM/MM/MD simulations of the inhibitor-HIV PR complexes were also performed. These computational results complimented the experimental inhibition activities and enabled us to report a unique binding mode for PCU-based inhibitors at the active site of HIV-protease enzyme. A conserved hydrogen bonding pattern between the norstatine type functional group of the PCU hydroxylactam and active site residues, ASP25/ASP25', was observed in all active compounds. The biological significance and possible mode of inhibition by PCU-based HIV PR inhibitors discussed herein provide us with a deeper understanding of the mode of action of these novel inhibitors. The PCU-peptides are between 6000 and 8500 time less toxic to human MT-4 cells than Lopinavir. This potentially creates new application avenues for these putative inhibitors to be investigated against a vast number of other disease-related proteases.

  • 8. Meredith, Jenny Adrian
    et al.
    Björklund, Catarina
    Adolfsson, Hans
    Jansson, Katarina
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Rosenquist, Åsa
    Samuelsson, Bertil
    P2 '-truncated BACE-1 inhibitors with a novel hydroxethylene-like core2010Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 45, nr 2, s. 542-554Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Highly potent BACE-1 protease inhibitors derived from a novel hydroxyethylene-like core structure were recently developed by our group using X-ray crystal structure data and molecular modelling. In a continuation of this work guided by molecular modelling we have explored a truncated core motif where the P2' amide group is replaced by an ether linkage resulting in a set of alkoxy, aryloxy and alkylaryl groups, with the overall aim to reduce molecular weight and the number of amide bonds to increase permeability and bestow the inhibitors with drug-like features. The most potent of these inhibitors displayed a BACE-I IC50 value of 140 nM. The synthesis of these BACE-I inhibitors utilizes readily available starting materials, furnishing the target compounds in good overall yields.

  • 9. Meredith, Jenny Adrian
    et al.
    Wallberg, Hans
    Vrang, Lotta
    Oscarson, Stefan
    Parkes, Kevin
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Samuelsson, Bertil
    Design and synthesis of novel P2 substituents in diol-based HIV protease inhibitors2010Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 45, nr 1, s. 160-170Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The synthesis and SAR of HIV-1 protease inhibitors containing novel P2 structural elements are presented. The inhibitors were designed having hydrogen bond accepting P2 substituents to probe potential favorable interactions to Asp-29/Asp-30 of the HIV-1 protease backbone utilizing inhibitor 3 as a model template. Several inhibitors were synthesized from an L-Val methyl amide P2 motif by appending hydrogen bonding moieties from either the isopropyl side-chain or from the methyl amide portion. The most promising inhibitors 4a and 4e displayed K-i values of 1.0 nM and 0.7 nM respectively and EC50 values in the MT4 cell-based assay of 0.17 mu M and 0.33 mu M respectively, a slight loss in potency compared to lead inhibitor 3. These inhibitors were also tested against an HIV protease inhibitor resistant strain carrying the M461, V82F, and 184V mutations. Inhibitors 4a and 4e displayed a 3 and 4 fold change respectively compared with HIV wild type, whereas lead inhibitor 3 showed a higher 9 fold change. This study further demonstrate the chemical tractability of the approach where various P2 substituents can be introduced in just one chemical step from lactone 21 enabling facile modifications of the overall properties in this inhibitor class.

  • 10.
    Motwani, Hitesh V.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    De Rosa, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Odell, Luke R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Aspartic protease inhibitors containing tertiary alcohol transition-state mimics2014Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 90, s. 462-490Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Aspartic proteases (APs) are a class of enzymes engaged in the proteolytic digestion of peptide substrates. APs play important roles in physiological and infectious pathways, making them plausible drug targets. For instance in the treatment of HIV infections, access to an efficient combination of protease and reverse transcriptase inhibitors have changed a terminal illness to a chronic but manageable disease. However, the benefits have been limited due to the emergence of drug resistant viral strains, poor pharmacokinetic properties of peptidomimetic inhibitors and adverse effects associated with the treatment. In the 1980s, D. Rich and co-workers proposed a novel strategy for the development of AP inhibitors by replacing the secondary hydroxyl group with a tertiary alcohol as part of the transition state (TS) mimicking moiety. This strategy has been extensively explored over the last decade with a common belief that masking of the polar group, e.g. by intramolecular hydrogen bonding, has the potential to enhance transcellular transport. This is the first review presenting the advances of AP inhibitors comprising a tertiary hydroxyl group. The inhibitors have been classified into different tert-hydroxy TS mimics and their design strategies, synthesis, biological activities, structure-activity-relationships and X-ray structures are discussed.

  • 11.
    Perspicace, Enrico
    et al.
    Laboratoire d ’ Ingénierie Moléculaire et Biochimie Pharmacologique, UMR CNRS 7565 SRSMC, Institut Jean Barriol, FR CNRS 2843, Université de Lorraine, 1 Boulevard Arago, 57070 Metz, France.
    Jouan-Hureaux, Valérie
    EA 4421 SiGReTO, Université de Lorraine, Faculté de pharmacie, 5-7 Rue Albert Lebrun, BP80403, 54001 Nancy cedex, France.
    Ragno, Rino
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma “ La Sapienza ” , P. le A. Moro 5, 00185 Roma, Italy.
    Ballante, Flavio
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma “ La Sapienza ” , P. le A. Moro 5, 00185 Roma, Italy.
    Sartini, Stefania
    Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
    La Motta, Concettina
    Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
    Da Settimo, Federico
    Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
    Chen, Binbin
    Laboratoire d ’ Ingénierie Moléculaire et Biochimie Pharmacologique, UMR CNRS 7565 SRSMC, Institut Jean Barriol, FR CNRS 2843, Université de Lorraine, 1 Boulevard Arago, 57070 Metz, France.
    Kirsch, Gilbert
    Laboratoire d ’ Ingénierie Moléculaire et Biochimie Pharmacologique, UMR CNRS 7565 SRSMC, Institut Jean Barriol, FR CNRS 2843, Université de Lorraine, 1 Boulevard Arago, 57070 Metz, France.
    Schneider, Serge
    Laboratoire National de Santé, Division de Toxicologie, Université de Luxembourg, 162a Avenue de la Faïencerie, L-1511 Luxembourg, Luxembourg.
    Faivre, Béatrice
    EA 4421 SiGReTO, Université de Lorraine, Faculté de pharmacie, 5-7 Rue Albert Lebrun, BP80403, 54001 Nancy cedex, France.
    Hesse, Stéphanie
    Laboratoire d ’ Ingénierie Moléculaire et Biochimie Pharmacologique, UMR CNRS 7565 SRSMC, Institut Jean Barriol, FR CNRS 2843, Université de Lorraine, 1 Boulevard Arago, 57070 Metz, France.
    Design, synthesis and biological evaluation of new classes of thieno[3,2-d]pyrimidinone and thieno[1,2,3]triazine as inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2).2013Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 63, s. 765-81, artikel-id S0223-5234(13)00170-0Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Driven by a multidisciplinary approach combination (Structure-Based (SB) Three-Dimensional Quantitative Structure-Activity Relationships (3-D QSAR), molecular modeling, organic chemistry and various biological evaluations) here is reported the disclosure of new thienopyrimidines 1-3 as inhibitors of KDR activity and human umbilical vein endothelial cell (HUVEC) proliferation. More specifically, compound 2f represents a new lead compound that inhibits VEGFR-2 and HUVEC at μM concentration. Moreover by the mean of an endothelial cell tube formation in vitro model 2f tartaric acid salt proved to block angiogenesis of HUVEC at μM level.

  • 12.
    Reddy, D Rajasekhar
    et al.
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States.
    Ballante, Flavio
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States.
    Zhou, Nancy J
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States.
    Marshall, Garland R
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States.
    Design and synthesis of benzodiazepine analogs as isoform-selective human lysine deacetylase inhibitors.2017Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 127, s. 531-553, artikel-id S0223-5234(16)31038-8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A comprehensive investigation was performed to identify new benzodiazepine (BZD) derivatives as potent and selective human lysine deacetylase inhibitors (hKDACis). A total of 108 BZD compounds were designed, synthesized and from that 104 compounds were biologically evaluated against human lysine deacetylases (hKDACs) 1, 3 and 8 (class I) and 6 (class IIb). The most active compounds showed mid-nanomolar potencies against hKDACs 1, 3 and 6 and micromolar activity against hKDAC8, while a promising compound (6q) showed selectivity towards hKDAC3 among the different enzyme isoforms. An hKDAC6 homology model, refined by molecular dynamics simulation was generated, and molecular docking studies performed to rationalize the dominant ligand-residue interactions as well as to define structure-activity-relationships. Experimental results confirmed the usefulness of the benzodiazepine moiety as capping group when pursuing hKDAC isoform-selectivity inhibition, suggesting its continued use when designing new hKDACis.

  • 13.
    Szałaj, Natalia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Lu, Lu
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Strukturbiologi.
    Benediktsdottir, Andrea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Zamaratski, Edouard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Cao, Sha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Olanders, Gustav
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Hedgecock, Charles
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Karlen, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Erdélyi, Máté
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Hughes, Diarmaid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Mowbray, Sherry L
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Brandt, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Boronic ester-linked macrocyclic lipopeptides as serine protease inhibitors targeting Escherichia coli type I signal peptidase.2018Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 157, s. 1346-1360Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Type I signal peptidase, with its vital role in bacterial viability, is a promising but underexploited antibacterial drug target. In the light of steadily increasing rates of antimicrobial resistance, we have developed novel macrocyclic lipopeptides, linking P2 and P1' by a boronic ester warhead, capable of inhibiting Escherichia coli type I signal peptidase (EcLepB) and exhibiting good antibacterial activity. Structural modifications of the macrocyclic ring, the peptide sequence and the lipophilic tail led us to 14 novel macrocyclic boronic esters. It could be shown that macrocyclization is well tolerated in terms of EcLepB inhibition and antibacterial activity. Among the synthesized macrocycles, potent enzyme inhibitors in the low nanomolar range (e.g. compound 42f, EcLepB IC50 = 29 nM) were identified also showing good antimicrobial activity (e.g. compound 42b, E. coli WT MIC = 16 μg/mL). The unique macrocyclic boronic esters described here were based on previously published linear lipopeptidic EcLepB inhibitors in an attempt to address cytotoxicity and hemolysis. We show herein that structural changes to the macrocyclic ring influence both the cytotoxicity and hemolytic activity suggesting that the P2 to P1' linker provide means for optimizing off-target effects. However, for the present set of compounds we were not able to separate the antibacterial activity and cytotoxic effect.

  • 14. Upadhayaya, Ram Shankar
    et al.
    Shinde, Popat D.
    Kadam, Sandip A.
    Bawane, Amit N.
    Sayyed, Aftab Y.
    Kardile, Ramakant A.
    Gitay, Pallavi N.
    Lahore, Santosh V.
    Dixit, Shailesh S.
    Földesi, András
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Kemisk biologi.
    Chattopadhyaya, Jyoti
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Kemisk biologi.
    Synthesis and antimycobacterial activity of prodrugs of indeno[2,1-c]quinoline derivatives2011Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 46, nr 4, s. 1306-1324Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recently we have reported anti-TB properties of a new class of conformationally-constrained indeno[2,1-c]quinolines, which are although considerably active (MIC 0.39-0.78 mu g/mL) suffered from intense solubility problems. We thought of improving their bioavailability by prodrugs approach. Accordingly esters of the "Lead" indeno[2,1-c]quinolines 1,15 and 27 derivatives were synthesized and their prodrug nature at the physiological pH were confirmed. Prodrugs were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv by MABA assay to show that they have 2- to 4-fold improved anti-TB activities, increased aqueous solubility and superior selectivity index over their respective parent compounds. MIC of these prodrugs was in the range of <0.20-6.0 mu g/mL and in general, no cytotoxicity was observed in VERO cells.

  • 15. Upadhayaya, Ram Shankar
    et al.
    Vandavasi, Jaya Kishore
    Kardile, Ramakant A.
    Lahore, Santosh V.
    Dixit, Shailesh S.
    Deokar, Hemantkumar S.
    Shinde, Popat D.
    Sarmah, Manash P.
    Chattopadhyaya, Jyoti
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Bioorganisk kemi.
    Novel quinoline and naphthalene derivatives as potent antimycobacterial agents2010Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 45, nr 5, s. 1854-1867Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have designed and synthesized both the quinoline and naphthalene based molecules influenced by the unique structural make-up of mefloquine and TMC207, respectively. These compounds were evaluated for their anti-mycobacterial activity against drug sensitive Mycobacterium tuberculosis H37Rv in vitro at single-dose concentration (6.25 mu g/mL). The compounds 22,23, 26 and 27 inhibited the growth of M. tuberculosis H37Rv 99%, 90%, 98% and 91% respectively. Minimum inhibitory concentration of compounds 22, 23, 26 and 27 was found to be 6.25 mu g/mL.. Our molecular modeling and docking studies of designed compounds showed hydrogen bonding with Glu-61, Tyr-64 and Asn-190 amino acid residues at the putative binding site of ATP synthase, these interactions were coherent as shown by Mefloquine and TMC207, where hydrogen bonding was found with Tyr-64 and Glu-61 respectively. SAR analysis indicates importance of hydroxyl group and nature of substituents on piperazinyl-phenyl ring was critical in dictating the biological activity of newly synthesized compounds. (C) 2010 Elsevier Masson SAS. All rights reserved.

  • 16.
    Wångsell, Fredrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Gustafsson, Karin
    Kvarnström, Ingemar
    Borkakoti, Neera
    Edlund, Michael
    Jansson, Katarina
    Lindberg, Jimmy
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Rosenquist, Åsa
    Samuelsson, Bertil
    Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core2010Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 45, nr 3, s. 870-882Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We herein describe the design and synthesis of a series of BACE-1 inhibitors incorporating a P1-substituted hydroxylethylene transition state isostere. The synthetic route starting from commercially available carbohydrates yielded a pivotal lactone intermediate with excellent stereochemical control which subsequently could be diversified at the P1-position. The final inhibitors were optimized using three different amines to provide the residues in the P2′-P3′ position and three different acids affording the residues in the P2-P3 position. In addition we report on the stereochemical preference of the P1′-methyl substituent in the synthesized inhibitors. All inhibitors were evaluated in an in vitro BACE-1 assay where the most potent inhibitor, 34-(R), exhibited a BACE-1 IC50 value of 3.1 nM.

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