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CHEMISTRY (616 journals)                  1 2 3 4 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 14)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 26)
ACS Catalysis     Full-text available via subscription   (Followers: 43)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 21)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 21)
ACS Macro Letters     Full-text available via subscription   (Followers: 26)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 41)
ACS Nano     Full-text available via subscription   (Followers: 275)
ACS Photonics     Full-text available via subscription   (Followers: 14)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 24)
Acta Chemica Iasi     Open Access   (Followers: 3)
Acta Chimica Sinica     Full-text available via subscription   (Followers: 2)
Acta Chimica Slovaca     Open Access   (Followers: 2)
Acta Chimica Slovenica     Open Access   (Followers: 1)
Acta Chromatographica     Full-text available via subscription   (Followers: 9)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 7)
Acta Scientifica Naturalis     Open Access   (Followers: 3)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 6)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 9)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 6)
Advanced Functional Materials     Hybrid Journal   (Followers: 57)
Advanced Science Focus     Free   (Followers: 5)
Advances in Chemical Engineering and Science     Open Access   (Followers: 66)
Advances in Chemical Science     Open Access   (Followers: 16)
Advances in Chemistry     Open Access   (Followers: 20)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 19)
Advances in Drug Research     Full-text available via subscription   (Followers: 21)
Advances in Enzyme Research     Open Access   (Followers: 9)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 7)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 15)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 9)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 25)
Advances in Nanoparticles     Open Access   (Followers: 15)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15)
Advances in Polymer Science     Hybrid Journal   (Followers: 43)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 17)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 18)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Science and Technology     Full-text available via subscription   (Followers: 12)
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 3)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Al-Kimia : Jurnal Penelitian Sains Kimia     Open Access  
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 62)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 15)
American Journal of Chemistry     Open Access   (Followers: 29)
American Journal of Plant Physiology     Open Access   (Followers: 11)
American Mineralogist     Hybrid Journal   (Followers: 15)
Analyst     Full-text available via subscription   (Followers: 38)
Angewandte Chemie     Hybrid Journal   (Followers: 165)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 244)
Annales UMCS, Chemia     Open Access  
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 5)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 4)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 9)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 12)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 13)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Hybrid Journal   (Followers: 1)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 8)
Applied Spectroscopy     Full-text available via subscription   (Followers: 22)
Applied Surface Science     Hybrid Journal   (Followers: 31)
Arabian Journal of Chemistry     Open Access   (Followers: 5)
ARKIVOC     Open Access   (Followers: 1)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Atomization and Sprays     Full-text available via subscription   (Followers: 4)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access  
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Biochemistry     Full-text available via subscription   (Followers: 341)
Biochemistry Insights     Open Access   (Followers: 6)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 9)
Bioinspired Materials     Open Access   (Followers: 5)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access   (Followers: 1)
Biomacromolecules     Full-text available via subscription   (Followers: 21)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 7)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 5)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 122)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 84)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 2)
Bitácora Digital     Open Access  
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 2)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 24)
Bulletin of the Korean Chemical Society     Hybrid Journal   (Followers: 1)
C - Journal of Carbon Research     Open Access   (Followers: 3)
Cakra Kimia (Indonesian E-Journal of Applied Chemistry)     Open Access  
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 2)
Canadian Journal of Chemistry     Hybrid Journal   (Followers: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 6)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 71)
Catalysis for Sustainable Energy     Open Access   (Followers: 7)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 7)
Catalysis Science and Technology     Free   (Followers: 8)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 9)
Cellulose     Hybrid Journal   (Followers: 7)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 1)
ChemCatChem     Hybrid Journal   (Followers: 8)
Chemical and Engineering News     Free   (Followers: 18)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 73)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 26)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 22)
Chemical Reviews     Full-text available via subscription   (Followers: 186)
Chemical Science     Open Access   (Followers: 23)
Chemical Technology     Open Access   (Followers: 22)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemical Week     Full-text available via subscription   (Followers: 7)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 56)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 24)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 7)
Chemistry & Biology     Full-text available via subscription   (Followers: 32)
Chemistry & Industry     Hybrid Journal   (Followers: 6)
Chemistry - A European Journal     Hybrid Journal   (Followers: 159)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 16)
Chemistry and Materials Research     Open Access   (Followers: 20)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 9)
Chemistry International     Hybrid Journal   (Followers: 2)
Chemistry Letters     Full-text available via subscription   (Followers: 44)
Chemistry of Materials     Full-text available via subscription   (Followers: 252)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 19)
Chemistry-Didactics-Ecology-Metrology     Open Access   (Followers: 1)
ChemistryOpen     Open Access   (Followers: 1)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 4)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 14)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 11)
ChemPlusChem     Hybrid Journal   (Followers: 2)
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 2)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 11)
Chromatographia     Hybrid Journal   (Followers: 24)
Chromatography     Open Access   (Followers: 2)
Chromatography Research International     Open Access   (Followers: 6)
Clay Minerals     Full-text available via subscription   (Followers: 10)
Cogent Chemistry     Open Access  
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 11)
Colloids and Interfaces     Open Access  
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 6)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 5)
Combustion Science and Technology     Hybrid Journal   (Followers: 22)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Composite Interfaces     Hybrid Journal   (Followers: 7)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 1)
Comptes Rendus Chimie     Full-text available via subscription  
Comptes Rendus Physique     Full-text available via subscription   (Followers: 1)
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 9)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 11)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 10)
Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 3)
Copernican Letters     Open Access   (Followers: 1)
Corrosion Series     Full-text available via subscription   (Followers: 6)
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 5)
Croatica Chemica Acta     Open Access  
Crystal Structure Theory and Applications     Open Access   (Followers: 4)
CrystEngComm     Full-text available via subscription   (Followers: 13)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Chromatography     Hybrid Journal  
Current Green Chemistry     Hybrid Journal  
Current Metabolomics     Hybrid Journal   (Followers: 5)
Current Microwave Chemistry     Hybrid Journal  
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 14)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 69)
Current Trends in Biotechnology and Chemical Research     Open Access   (Followers: 3)
Dalton Transactions     Full-text available via subscription   (Followers: 23)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)
Diamond and Related Materials     Hybrid Journal   (Followers: 12)
Dislocations in Solids     Full-text available via subscription  
Doklady Chemistry     Hybrid Journal  

        1 2 3 4 | Last

Journal Cover Bioorganic & Medicinal Chemistry Letters
  [SJR: 0.952]   [H-I: 112]   [84 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0960-894X
   Published by Elsevier Homepage  [3177 journals]
  • Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative
           allosteric modulators of metabotropic glutamate receptor subtype 5
    • Authors: Andrew S. Felts; Alice L. Rodriguez; Ryan D. Morrison; Anna L. Blobaum; Frank W. Byers; J. Scott Daniels; Colleen M. Niswender; P. Jeffrey Conn; Craig W. Lindsley; Kyle A. Emmitte
      Pages: 1679 - 1685
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Andrew S. Felts, Alice L. Rodriguez, Ryan D. Morrison, Anna L. Blobaum, Frank W. Byers, J. Scott Daniels, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley, Kyle A. Emmitte
      Based on previous work that established fused heterocycles as viable alternatives for the picolinamide core of our lead series of mGlu5 negative allosteric modulators (NAMs), we designed a novel series of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide mGlu5 NAMs. These new quinoline derivatives also contained carbon linkers as replacements for the diaryl ether oxygen atom common to our previously published chemotypes. Compounds were evaluated in a cell-based functional mGlu5 assay, and an exemplar analog 27 was >60-fold selective versus the other seven mGlu receptors. Selected compounds were also studied in metabolic stability assays in rat and human S9 hepatic fractions and exhibited a mixture of P450- and non-P450-mediated metabolism.
      Graphical abstract image

      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.053
  • Discovery of dimethyl pent-4-ynoic acid derivatives, as potent and orally
           bioavailable DGAT1 inhibitors that suppress body weight in diet-induced
           mouse obesity model
    • Authors: Tao Yu; Chengde Wu; NengYang Shih; Qi Li; Chichung Chan; He Pan; Dan Yao; Yan Pan; Wei Liang; Liang Shen; Hui Zhao; Jian Li; Shuhui Chen
      Pages: 1686 - 1692
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Tao Yu, Chengde Wu, NengYang Shih, Qi Li, Chichung Chan, He Pan, Dan Yao, Yan Pan, Wei Liang, Liang Shen, Hui Zhao, Jian Li, Shuhui Chen
      Diacylglycerol acyltransferase (DGAT) is expressed abundantly in intestine, liver, and adipose tissues. DGAT1 is the crucial and rate-limiting enzyme that mediates the final step in triacylglycerol (TAG) resynthesis during dietary fat absorption. However, too much triacylglycerol (TAG) reserve will lead to genetic obesity (Hubert et al., 2000). DGAT1 knockout mice could survive and displayed a reduction in the postprandial rise of plasma TG, and increased sensitivity of insulin and leptin. Here we report the discovery and characterization of a novel selective DGAT1 inhibitor 29 to potentially treat obesity. Compound 29 showed lipid lowering effect in mouse lipid tolerance test (LTT) and also reduced body weight in DIO mice without observable liver damage.
      Graphical abstract image

      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.051
  • Discovery of d-amino acid oxidase inhibitors based on virtual screening
           against the lid-open enzyme conformation
    • Authors: Bence Szilágyi; Žiga Skok; Anita Rácz; Rok Frlan; György G. Ferenczy; Janez Ilaš; György M. Keserű
      Pages: 1693 - 1698
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Bence Szilágyi, Žiga Skok, Anita Rácz, Rok Frlan, György G. Ferenczy, Janez Ilaš, György M. Keserű
      d-Amino acid oxidase (DAAO) inhibitors are typically small polar compounds with often suboptimal pharmacokinetic properties. Features of the native binding site limit the operational freedom of further medicinal chemistry efforts. We therefore initiated a structure based virtual screening campaign based on the X-ray structures of DAAO complexes where larger ligands shifted the loop (lid opening) covering the native binding site. The virtual screening of our in-house collection followed by the in vitro test of the best ranked compounds led to the identification of a new scaffold with micromolar IC50. Subsequent SAR explorations enabled us to identify submicromolar inhibitors. Docking studies supported by in vitro activity measurements suggest that compounds bind to the active site with a salt-bridge characteristic to DAAO inhibitor binding. In addition, displacement of and interaction with the loop covering the active site contributes significantly to the activity of the most potent compounds.
      Graphical abstract image

      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.048
  • Design, synthesis and biological evaluation of substituted (+)-SG-1
           derivatives as novel anti-HIV agents
    • Authors: Xiaoyu Liu; Panpan Chen; Xiaoyu Li; Mingyu Ba; Xiaozhen Jiao; Ying Guo; Ping Xie
      Pages: 1699 - 1703
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Xiaoyu Liu, Panpan Chen, Xiaoyu Li, Mingyu Ba, Xiaozhen Jiao, Ying Guo, Ping Xie
      SG-1 was previously identified as a potent Non-nucleoside reverse transcriptase inhibitors (NNRTI) which works through inhibition of reverse transcriptase (RT) RNA-dependent DNA polymerase activity via a direct binding event. To further investigate the relationship between its structure and activity, four series of novel analogues were designed and synthesized with 12 of them inhibiting HIV-1 replication with IC50s in the range 0.09–6.71 μM. Compound 4b, 4c, 4f, 2 and 6b were further tested on two NNRTI-resistant HIV-1 strains and one NNRTI-resistant superbug. The result showed that RT- E138K/M184V mutant virus conferred 4.7–9.1-fold resistance to 4c, 4f, 2 and 6b, but only showed slight resistance to 4b (2-fold) which was better than SG-1.
      Graphical abstract image

      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.049
  • A constraint scaffold enhances affinity of a bivalent N-acetylglucosamine
           ligand against wheat germ agglutinin
    • Authors: Takahiko Matsushita; Koji Tsuchibuchi; Tetsuo Koyama; Ken Hatano; Koji Matsuoka
      Pages: 1704 - 1707
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Takahiko Matsushita, Koji Tsuchibuchi, Tetsuo Koyama, Ken Hatano, Koji Matsuoka
      Bivalent glycoconjugates have a minimal valence with avidity potential on protein-carbohydrate interactions as well as simplicity of chemical structures enabling simple synthesis with low cost. Understanding the way to maximize the affinities of bivalent glycoconjugates is important for the development of cost-effective tools for therapeutic and diagnostic research. However, there has been little discussion about the effects of constraints imposed from ligand scaffolds on the binding abilities. We synthesized three kinds of biantennary N-acetylglucosamine glycosides with different scaffolds using isobutenyl bis(propargyl)ether as a common scaffold precursor. Decoration of the scaffold branches with GlcNAc moieties through copper-catalyzed azide-alkyne cycloaddition and grafting of the alkenyl focal point to another bivalent biotin dendron through thiol-ene and nucleophilic substitution reactions were successfully carried out in an orthogonal manner. The association constants of the ligands against wheat germ agglutinin were determined by a fluorometric titration assay. A bivalent biotin counterpart provided higher affinity than an isobutyl scaffold, whereas an isobutenyl scaffold yielded more enhancement than a bivalent biotin counterpart. The present work suggested that the constraint and steric bulk of ligand scaffolds are possible factors for improving binding properties of glycoconjugates against lectins or proteins.
      Graphical abstract image

      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.047
  • Targeting lysine specific demethylase 4A (KDM4A) tandem TUDOR domain – A
           fragment based approach
    • Authors: Anup K. Upadhyay; Russell A. Judge; Leiming Li; Ron Pithawalla; Justin Simanis; Pierre M. Bodelle; Violeta L. Marin; Rodger F. Henry; Andrew M. Petros; Chaohong Sun
      Pages: 1708 - 1713
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Anup K. Upadhyay, Russell A. Judge, Leiming Li, Ron Pithawalla, Justin Simanis, Pierre M. Bodelle, Violeta L. Marin, Rodger F. Henry, Andrew M. Petros, Chaohong Sun
      The tandem TUDOR domains present in the non-catalytic C-terminal half of the KDM4A, 4B and 4C enzymes play important roles in regulating their chromatin localizations and substrate specificities. They achieve this regulatory role by binding to different tri-methylated lysine residues on histone H3 (H3-K4me3, H3-K23me3) and histone H4 (H4-K20me3) depending upon the specific chromatin environment. In this work, we have used a 2D-NMR based fragment screening approach to identify a novel fragment (1a), which binds to the KDM4A-TUDOR domain and shows modest competition with H3-K4me3 binding in biochemical as well as in vitro cell based assays. A co-crystal structure of KDM4A TUDOR domain in complex with 1a shows that the fragment binds stereo-specifically to the methyl lysine binding pocket forming a network of strong hydrogen bonds and hydrophobic interactions. We anticipate that the fragment 1a can be further developed into a novel allosteric inhibitor of the KDM4 family of enzymes through targeting their C-terminal tandem TUDOR domain.
      Graphical abstract image

      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.050
  • Hit discovery of Mycobacterium tuberculosis inosine 5′-monophosphate
           dehydrogenase, GuaB2, inhibitors
    • Authors: Niteshkumar U. Sahu; Vinayak Singh; Davide M. Ferraris; Menico Rizzi; Prashant S. Kharkar
      Pages: 1714 - 1718
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Niteshkumar U. Sahu, Vinayak Singh, Davide M. Ferraris, Menico Rizzi, Prashant S. Kharkar
      Tuberculosis remains a global concern. There is an urgent need of newer antitubercular drugs due to the development of resistant forms of Mycobacterium tuberculosis (Mtb). Inosine 5′-monophosphate dehydrogenase (IMPDH), guaB2, of Mtb, required for guanine nucleotide biosynthesis, is an attractive target for drug development. In this study, we screened a focused library of 73 drug-like molecules with desirable calculated/predicted physicochemical properties, for growth inhibitory activity against drug-sensitive MtbH37Rv. The eight hits and mycophenolic acid, a prototype IMPDH inhibitor, were further evaluated for activity on purified Mtb-GuaB2 enzyme, target selectivity using a conditional knockdown mutant of guaB2 in Mtb, followed by cross-resistance to IMPDH inhibitor-resistant SRMV2.6 strain of Mtb, and activity on human IMPDH2 isoform. One of the hits, 13, a 5-amidophthalide derivative, has shown growth inhibitory potential and target specificity against the Mtb-GuaB2 enzyme. The hit, 13, is a promising molecule with potential for further development as an antitubercular agent.
      Graphical abstract image

      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.045
  • Benzofuran-pyran hybrids: A new class of potential bone anabolic agents
    • Authors: Sampa Gupta; Sulekha Adhikary; Ram K. Modukuri; Dharmendra Choudhary; Ritu Trivedi; Koneni V. Sashidhara
      Pages: 1719 - 1724
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Sampa Gupta, Sulekha Adhikary, Ram K. Modukuri, Dharmendra Choudhary, Ritu Trivedi, Koneni V. Sashidhara
      Benzofuran moiety is an important pharmacophore showing positive effects on bone health. In the present study, sixteen benzofuran-pyran hybrids were synthesized and were evaluated for their osteogenic effects on primary osteoblast cells isolated from calvaria. Compounds 22 and 24 were found potent in stimulating osteoblast differentiation as assessed by the alkaline phosphatase activity. These compounds were also found to be nontoxic to osteoblast cells as compared to the control cells in MTT assay. Further, Alizarin Red-S staining for visualization of calcium nodules demonstrated compounds 22 and 34 as active in enhancing mineralization in osteoblast cells. Additionally, transcriptional analysis of these compounds on osteoblast cells revealed that compound 22 up-regulated the expression of osteogenic genes RUNX2, BMP-2, COL-1, thus substantiating that compound 22 having two geminal methyl groups in its R3 position is a potent osteogenic agent. Additionally, compound 22 enhanced the ability of bone marrow stromal cells to differentiate towards osteoblast lineage and therefore can be further studied in vivo in bone loss model.
      Graphical abstract image

      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.041
  • Discovery of novel
           2-[(4-hydroxy-6-oxo-2,3-dihydro-1H-pyridine-5-carbonyl)amino]acetic acid
           derivatives as HIF prolyl hydroxylase inhibitors for treatment of renal
    • Authors: Makoto Hamada; Tetsuo Takayama; Tsuyoshi Shibata; Akira Hiratate; Masato Takahashi; Miyoko Yashiro; Noriko Takayama; Lisa Okumura-Kitajima; Hiroko Koretsune; Hiromitsu Kajiyama; Takumi Naruse; Sota Kato; Hiroki Takano; Hiroyuki Kakinuma
      Pages: 1725 - 1730
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Makoto Hamada, Tetsuo Takayama, Tsuyoshi Shibata, Akira Hiratate, Masato Takahashi, Miyoko Yashiro, Noriko Takayama, Lisa Okumura-Kitajima, Hiroko Koretsune, Hiromitsu Kajiyama, Takumi Naruse, Sota Kato, Hiroki Takano, Hiroyuki Kakinuma
      Prolyl hydroxylase domain-containing protein (PHD) inhibitors are useful as orally administered agents for the treatment of renal anemia. Based on the common structures of known PHD inhibitors, we found novel PHD inhibitor 1 with a 2-[(4-hydroxy-6-oxo-2,3-dihydro-1H-pyridine-5-carbonyl)amino]acetic acid motif. The PHD2-inhibitory activity, lipophilicity (CLogP), and PK profiles (hepatocyte metabolism, protein binding, and/or elimination half-life) of this inhibitor were used as the evaluation index to optimize the structure and eventually discovered clinical candidate 42 as the suitable compound. Compound 42 was demonstrated to promote the production of erythropoietin (EPO) following oral administration in mice and rats. The predicted half-life of this compound in humans was 1.3–5.6 h, therefore, this drug may be expected to administer once daily with few adverse effects caused by excessive EPO production.
      Graphical abstract image

      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.039
  • Design, synthesis and evaluation of substituted piperidine based KCNQ
           openers as novel antiepileptic agents
    • Authors: Shaoning Yang; Dingqiang Lu; Pingkai Ouyang
      Pages: 1731 - 1735
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Shaoning Yang, Dingqiang Lu, Pingkai Ouyang
      Epilepsy is a kind of disease with complicated pathogenesis. KCNQ (Kv7) is a voltage dependent potassium channel that is mostly associated with epilepsy and thus becomes an important target in the treatment of epilepsy. In this paper, a series of substituted piperidine derivatives targeting KCNQ were designed and synthesized by using scaffold hopping and active substructure hybridization. Compounds were evaluated by fluorescence-based thallium influx assay, Rb+ flow assay and electrophysiological patch-clamp assay. Results showed that some compounds possessed more potent potassium channel opening activity than Retigabine. More significantly, compound 11 was found to have good pharmacokinetic profiles in vivo.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.040
  • Structure-based design of Trifarotene (CD5789), a potent and selective
           RARγ agonist for the treatment of acne
    • Authors: Etienne Thoreau; Jean-Marie Arlabosse; Claire Bouix-Peter; Sandrine Chambon; Laurent Chantalat; Sébastien Daver; Laurence Dumais; Gwenaëlle Duvert; Angélique Feret; Gilles Ouvry; Jonathan Pascau; Catherine Raffin; Nicolas Rodeville; Catherine Soulet; Samuel Tabet; Sandrine Talano; Thibaud Portal
      Pages: 1736 - 1741
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Etienne Thoreau, Jean-Marie Arlabosse, Claire Bouix-Peter, Sandrine Chambon, Laurent Chantalat, Sébastien Daver, Laurence Dumais, Gwenaëlle Duvert, Angélique Feret, Gilles Ouvry, Jonathan Pascau, Catherine Raffin, Nicolas Rodeville, Catherine Soulet, Samuel Tabet, Sandrine Talano, Thibaud Portal
      Retinoids have a dominant role in topical acne therapy and to date, only RARβ and RARγ dual agonists have reached the market. Given the tissue distribution of RAR isoforms, it was hypothesized that developing RARγ -selective agonists could yield a new generation of topical acne treatments that would increase safety margins while maintaining the robust efficacy of previous drugs. Structural knowledge derived from the X-ray structure of known γ-selective CD437, suggested the design of a novel triaryl series of agonists which was optimized and ultimately led to the discovery of Trifarotene/CD5789.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.036
  • Antimicrobial evaluation and action mechanism of pyridinium-decorated
           1,4-pentadien-3-one derivatives
    • Authors: Jian Zhou; Qing-Qing Tao; Pei-Yi Wang; Wu-Bin Shao; Zhi-Bing Wu; Zhong Li; Song Yang
      Pages: 1742 - 1746
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Jian Zhou, Qing-Qing Tao, Pei-Yi Wang, Wu-Bin Shao, Zhi-Bing Wu, Zhong Li, Song Yang
      A type of pyridinium-decorated 1,4-pentadien-3-one derivatives possessing flexible alkyls were designed and synthesized by integrating the key scaffolds of pyridinium cations and 1,4-pentadien-3-one skeleton in a single molecular architecture. Antimicrobial bioassays indicated that some of the target molecules exerted considerable bioactivities against six phytopathogenic strains, especially for Xanthomonas oryzae pv. oryzae, the minimal EC50 value can reach to 0.504 µg/mL. A plausible action mechanism for this kind of compounds was proposed and confirmed by employing fluorescent spectroscopy, fluorescence microscopy, and scanning electron microscopy. We anticipated that this finding can promote high-efficient lead compounds discovery in the research of antimicrobial chemotherapy.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.034
  • Synthesis of some novel dimethine, bis-dimethine cyanine dyes and
           octacosamethine cyanine dyes endowed with promising biological potency
           against (HepG2), (Hela), (MCF-7), (MIA), (SN12C) and (H358) cell lines
    • Authors: Rasha E. El-Mekawy; A.A. Fadda
      Pages: 1747 - 1752
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Rasha E. El-Mekawy, A.A. Fadda
      Successfully, one step two component synthesis of dimethine cyanine dyes, bis-dimethine cyanine dyes and icosamethine cyanine dyes 2–10 via reaction of pyridinium salt 1 with some different aldehydes hope to obtain these compounds with enhanced biological potency as antitumor agents against spontaneous liver (HepG2), cervical (Hela), breast (MCF-7), pancreas (MIA), kidney (SN12C) and lung (H358). The impact of substituted drugs on the tumor cells was reflected by means of structure activity relationship (SAR). Among these dyes, icosamethine cyanine dye 8 recorded an excellent activity toward all the tested cell lines. The newly destined drugs were identified and emphasized by spectroscopy and elemental analyses.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.032
  • Synthesis of novel quinolinomatrine derivatives and their
           insecticidal/acaricidal activities
    • Authors: Jiulin Huang; Min Lv; Sunita Thapa; Hui Xu
      Pages: 1753 - 1757
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Jiulin Huang, Min Lv, Sunita Thapa, Hui Xu
      In continuation of our program to discover natural product-based pesticidal agents, a series of new quinolinomatrine derivatives were prepared. Especially three-dimensional structures of five compounds were unambiguously determined by single-crystal X-ray diffraction. Among them, 21-chloroquinolinomatrine exhibited good insecticidal and acaricidal activities against two crop-threatening insect pests, Mythimna separata and Tetranychus cinnabarinus. Their structure-activity relationships were also discussed.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.029
  • Synthesis and biological evaluation of aryl-oxadiazoles as inhibitors of
           Mycobacterium tuberculosis
    • Authors: Maria Angeles Martinez-Grau; Isabel C. Gonzalez Valcarcel; Julie V. Early; Richard Klaus Gessner; Candice Soares de Melo; Eva Maria Martin de la Nava; Aaron Korkegian; Yulia Ovechkina; Lindsay Flint; Anisa Gravelle; Jeff W. Cramer; Prashant V. Desai; Leslie J. Street; Joshua Odingo; Thierry Masquelin; Kelly Chibale; Tanya Parish
      Pages: 1758 - 1764
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Maria Angeles Martinez-Grau, Isabel C. Gonzalez Valcarcel, Julie V. Early, Richard Klaus Gessner, Candice Soares de Melo, Eva Maria Martin de la Nava, Aaron Korkegian, Yulia Ovechkina, Lindsay Flint, Anisa Gravelle, Jeff W. Cramer, Prashant V. Desai, Leslie J. Street, Joshua Odingo, Thierry Masquelin, Kelly Chibale, Tanya Parish
      Despite increased research efforts to find new treatments for tuberculosis in recent decades, compounds with novel mechanisms of action are still required. We previously identified a series of novel aryl-oxadiazoles with anti-tubercular activity specific for bacteria using butyrate as a carbon source. We explored the structure activity relationship of this series. Structural modifications were performed in all domains to improve potency and physico-chemical properties. A number of compounds displayed sub-micromolar activity against M. tuberculosis utilizing butyrate, but not glucose as the carbon source. Compounds showed no or low cytotoxicity against eukaryotic cells. Three compounds were profiled in mouse pharmacokinetic studies. Plasma clearance was low to moderate but oral exposure suggested solubility-limited drug absorption in addition to first pass metabolism. The presence of a basic nitrogen in the linker slightly increased solubility, and salt formation optimized aqueous solubility. Our findings suggest that the 1,3,4-oxadiazoles are useful tools and warrant further investigation.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.028
  • Favorable 2′-substitution in the loop region of a thrombin-binding
           DNA aptamer
    • Authors: Ragini Awachat; Atish A. Wagh; Manisha Aher; Moneesha Fernandes; Vaijayanti A. Kumar
      Pages: 1765 - 1768
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Ragini Awachat, Atish A. Wagh, Manisha Aher, Moneesha Fernandes, Vaijayanti A. Kumar
      Simple 2′-OMe-chemical modification in the loop region of the 15mer G-rich DNA sequence GGTTGGTGTGGTTGG is reported. The G-quadruplex structure of this thrombin-binding aptamer (TBA), is stabilized by single modifications (T → 2′-OMe-U), depending on the position of the modification. The structural stability also renders significantly increased inhibition of thrombin-induced fibrin polymerization, a process closely associated with blood-clotting.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.027
  • Synthesis and evaluation of new 2-chloro-4-aminopyrimidine and
           2,6-dimethyl-4-aminopyrimidine derivatives as tubulin polymerization
    • Authors: Shaoyu Xu; Baijiao An; Yuxin Li; Xunbang Luo; Xingshu Li; Xian Jia
      Pages: 1769 - 1775
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Shaoyu Xu, Baijiao An, Yuxin Li, Xunbang Luo, Xingshu Li, Xian Jia
      Eighteen new 2-chloro-4-aminopyrimidine and 2,6-dimethyl-4-aminopyrimidine derivatives were synthesized and evaluated as tubulin polymerization inhibitor for the treatment of cancer. Among them, compounds 10, 17, 20 and 21 exhibited potent antiproliferative activities against five human cancer cell lines. Microtubule dynamics assay showed that compound 17 could effectively inhibit tubulin polymerization. Molecular docking studies were also carried out to understand the binding pattern. Further mechanism studies revealed that 17 could induce G2/M phase arrest, disrupt the organization of the cellular microtubule network and induce cell apoptosis and mitochondrial dysfunction.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.026
  • Biofilm inhibition and anti-Candida activity of a cationic lipo-benzamide
           molecule with twin-nonyl chain
    • Authors: Tushar Jain; Prathap Reddy Muktapuram; Komal Sharma; Owk Ravi; Garima Pant; Kalyan Mitra; Surendar Reddy Bathula; Dibyendu Banerjee
      Pages: 1776 - 1780
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Tushar Jain, Prathap Reddy Muktapuram, Komal Sharma, Owk Ravi, Garima Pant, Kalyan Mitra, Surendar Reddy Bathula, Dibyendu Banerjee
      A series of cationic lipo-benzamide compounds with varying lengths of hydrocarbon chains (C2M–C18M) were evaluated for anti-Candida activity. Four compounds harbouring 8–11 hydrocarbon chains demonstrated concentration-dependent inhibition of fungal cell growth with Minimum Inhibitory Concentration (MIC) of ≤6.2 µg ml−1. The most active compound (C9M) inhibited growth of both Candida albicans and non-albicans strains and is equally active against pairs of azole sensitive and resistant clinical isolates of C. albicans. Compound C9M also inhibited different stages of Candida biofilms. Scanning Electron Microscopy (SEM) of Candida cells after C9M treatment was also done and no significant cell lysis was observed. Hemolysis assay was performed and only 2.5% haemolysis was observed at MIC concentration.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.024
  • Preliminary in vitro and in vivo investigation of a potent platelet
           derived growth factor receptor (PDGFR) family kinase inhibitor
    • Authors: Elizabeth A. Wilson; Wade A. Russu; Hassan M. Shallal
      Pages: 1781 - 1784
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Elizabeth A. Wilson, Wade A. Russu, Hassan M. Shallal
      Aberrant expression of wild-type and mutant forms of the platelet-derived growth factor receptor (PDGFR) family of receptor tyrosine kinases has been implicated in various oncologic indications such as leukemias, gliomas, and soft tissue sarcomas. Clinically used kinase inhibitors imatinib and sunitinib are potent inhibitors of wild-type PDGFR family members, but show reduced binding to mutant forms. Here we describe compound 5 which binds to both wild-type and oncogenic mutant forms of PDGFR family members, and demonstrates both cellular and in vivo activity.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.030
  • The photodynamic activity of 131-[2′-(2-pyridyl)ethylamine] chlorin e6
           photosensitizer in human esophageal cancer
    • Authors: Sonja Srdanović; Ying-Hua Gao; Dan-Ye Chen; Yi-Jia Yan; Davor Margetić; Zhi-Long Chen
      Pages: 1785 - 1791
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Sonja Srdanović, Ying-Hua Gao, Dan-Ye Chen, Yi-Jia Yan, Davor Margetić, Zhi-Long Chen
      A novel 131-pyridine substituted chlorin e6 derivative (Chlorin A) was synthesized. It has characteristic long wavelength absorption at 664 nm and the emission wavelength at 667 nm. The generation rate of singlet oxygen of this compound is higher than Temoporfin. In vitro, Chlorin A showed higher phototoxicity against the human esophageal cancer cells than Temoporfin while with lower dark-toxicity. Its accumulation effect in mitochondria, lysosomes and endoplasmic reticulum was traced in subcellular localization tests. In flow cytometry obvious apoptosis cells were observed after 2 h irradiation. Significant in vivo photodynamic anti-tumor efficacy was also exhibited on mice bearing esophageal cancer. So Chlorin A could be suggested as a promising anti-tumor drug candidate in photodynamic therapy.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.025
  • Thioether-bridged arylalkyl-linked N-phenylpyrazole derivatives: Design,
           synthesis, insecticidal activities, structure-activity relationship and
           molecular-modeling studies
    • Authors: Chengcheng Fei; Yanfei Chen; Zhiyan Jiang; Dingxin Jiang
      Pages: 1792 - 1796
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Chengcheng Fei, Yanfei Chen, Zhiyan Jiang, Dingxin Jiang
      Owing to thioether diverse physicochemical properties by non-covalent interactions with bio-macromolecules, thioether derivatives containing heterocyclic moiety are known for their interesting insecticidal bioactivities and attracting considerable attention as neuroactive insecticides. Here we synthesis a series of novel thioether bridged N-phenylpyrazole derivatives incorporating various (hetero)aromatic substituents into 4-position of the pyrazole ring. Structure-activity relationship (SAR) studies resulted in compounds 6d and 7d with the most potent insecticidal activity among the series containing various substituted benzene substituents (LC50 = 13.70–25.47 μg/g). Further optimization to increase the lipophilicity and charge density of aromatic substituents of compounds 6d and 7d resulted in compounds 12d, 14d and 16d with sulfur-containing heterocycle substituents possessing good insecticidal activity against Musca domestica L. among the series (LC50 = 0.67–1.30 μg/g). The thioether bridge N-phenylpyrazole derivatives, which exhibit different length of the spacer arm introduced between N-phenylpyrazole moiety and the (hetero)aromatic substituents, were also prepared and evaluated. By contrast, the insecticidal activities of compounds containing the short thioether bridge, 1,2-bis((hetero)aromatic thio) ethane, are higher than that containing the long thioether bridge, 1,3-bis((hetero)aromatic thio) propane. The results of molecular docking and pharmacophore analyses indicated A299, T303, and L306 of a subunit were essential to form non-covalent interactions contacts with the ligands. Specially, the sulfur-containing heterocycle substituent derivatives 12d and 14d as the sterically favored areas could form the important hydrophobic interactions with the deeper residue P295.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.022
  • Design, synthesis, evaluation, and molecular docking of ursolic acid
    • Authors: Zhi-Yu Wei; Ke-Qiang Chi; Ke-Si Wang; Jie Wu; Li-Ping Liu; Hu-Ri Piao
      Pages: 1797 - 1803
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Zhi-Yu Wei, Ke-Qiang Chi, Ke-Si Wang, Jie Wu, Li-Ping Liu, Hu-Ri Piao
      Ursolic acid derivatives containing oxadiazole, triazolone, and piperazine moieties were synthesized in an attempt to develop potent anti-inflammatory agents. Structures of the synthesized compounds were elucidated by 1H NMR, 13C NMR, and HRMS. Most of the synthesized compounds showed pronounced anti-inflammatory effects at 100 mg/kg. In particular, compound 11b, which displayed the most potent anti-inflammatory activity of all of the compounds prepared, with 69.76% inhibition after intraperitoneal administration, was more potent than the reference drugs indomethacin and ibuprofen. The cytotoxicity of the compounds was also assessed by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and no compounds showed any appreciable cytotoxic activity (IC50 >100 μmol/L). Furthermore, molecular docking studies of the synthesized compounds were performed to rationalize the obtained biological results. Overall, the results indicate that compound 11b could be a therapeutic candidate for the treatment of inflammation.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.021
  • Discovery and optimization of novel constrained pyrrolopyridone BET family
    • Authors: Steven D. Fidanze; Dachun Liu; Robert A. Mantei; Lisa A. Hasvold; John K. Pratt; George S. Sheppard; Le Wang; James H. Holms; Yujia Dai; Ana Aguirre; Andrew Bogdan; Justin D. Dietrich; Jasmina Marjanovic; Chang H. Park; Charles W. Hutchins; Xiaoyu Lin; Mai H. Bui; Xiaoli Huang; Denise Wilcox; Leiming Li; Rongqi Wang; Peter Kovar; Terrance J. Magoc; Ganesh Rajaraman; Daniel H. Albert; Yu Shen; Warren M. Kati; Keith F. McDaniel
      Pages: 1804 - 1810
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Steven D. Fidanze, Dachun Liu, Robert A. Mantei, Lisa A. Hasvold, John K. Pratt, George S. Sheppard, Le Wang, James H. Holms, Yujia Dai, Ana Aguirre, Andrew Bogdan, Justin D. Dietrich, Jasmina Marjanovic, Chang H. Park, Charles W. Hutchins, Xiaoyu Lin, Mai H. Bui, Xiaoli Huang, Denise Wilcox, Leiming Li, Rongqi Wang, Peter Kovar, Terrance J. Magoc, Ganesh Rajaraman, Daniel H. Albert, Yu Shen, Warren M. Kati, Keith F. McDaniel
      Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (B). Each series demonstrated excellent activity in binding and cellular assays, and lead compounds from each series demonstrated significant efficacy in in vivo tumor xenograft models.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.020
  • Design, synthesis and biological evaluation of novel
           4-phenylisoquinolinone BET bromodomain inhibitors
    • Authors: Michael J. Bennett; Yiqin Wu; Amogh Boloor; Jennifer Matuszkiewicz; Shawn M. O'Connell; Lihong Shi; Ryan K. Stansfield; Joselyn R. Del Rosario; James M. Veal; David J. Hosfield; Jiangchun Xu; Stephen W. Kaldor; Jeffrey A. Stafford; Juan M. Betancort
      Pages: 1811 - 1816
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Michael J. Bennett, Yiqin Wu, Amogh Boloor, Jennifer Matuszkiewicz, Shawn M. O'Connell, Lihong Shi, Ryan K. Stansfield, Joselyn R. Del Rosario, James M. Veal, David J. Hosfield, Jiangchun Xu, Stephen W. Kaldor, Jeffrey A. Stafford, Juan M. Betancort
      The bromodomain and extra-terminal (BET) family of epigenetic proteins has attracted considerable attention in drug discovery given its involvement in regulating gene transcription. Screening a focused small molecule library based on the bromodomain pharmacophore resulted in the identification of 2-methylisoquinoline-1-one as a novel BET bromodomain-binding motif. Structure guided SAR exploration resulted in >10,000-fold potency improvement for the BRD4-BD1 bromodomain. Lead compounds exhibited excellent potencies in both biochemical and cellular assays in MYC-dependent cell lines. Compound 36 demonstrated good physicochemical properties and promising exposure levels in exploratory PK studies.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.016
  • Design, synthesis and antineoplastic activity of novel hybrids of
           podophyllotoxin and indirubin against human leukaemia cancer cells as
           multifunctional anti-MDR agents
    • Authors: Jing Wang; Li Long; Yongzheng Chen; Yingshu Xu; Lei Zhang
      Pages: 1817 - 1824
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Jing Wang, Li Long, Yongzheng Chen, Yingshu Xu, Lei Zhang
      To overcome cancer drug resistance, in present study, a series of podophyllotoxin-indirubin hybrids were designed, synthesized, and evaluated for anticancer efficacy against two human chronic myeloid leukemia cell cultures. Among them, compound Da-1 was the most potent in resistent K562/VCR cells with an IC50 value of 0.076 ± 0.008 μM. Preliminary mechanism studies showed that Da-1 significantly induced apoptosis and cell cycle arrest at the G2 phase. Decrease in mitochondrial membrane potential, accompanied by activated PARP cleavage, was observed in K562/VCR cells after incubation with Da-1. Meanwhile, Da-1 caused the accumulation of intracellular ROS, regulated JNK and AKT signaling, and down-regulated the expression levels of P-gp and MRP1 proteins. Importantly, Western blotting revealed that Da-1 could induce K562/VCR cells autophagy, by increasing the levels of Beclin1 and LC3-II. Finally, Da-1 could disrupt microtubule organization, and binding mode to tubulin was investigated by using molecular modeling. Together, Da-1 was a novel hybrid with potent antiproliferative activity and might be a promising agent for the treatment of drug-resistant leukemia cancer.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.019
  • Novel 5-methyl-2-phenylphenanthridium derivatives as FtsZ-targeting
           antibacterial agents from structural simplification of natural product
    • Authors: Jingru Liu; Ruxin Ma; Fangchao Bi; Fa Zhang; Chaoyu Hu; Henrietta Venter; Susan J. Semple; Shutao Ma
      Pages: 1825 - 1831
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Jingru Liu, Ruxin Ma, Fangchao Bi, Fa Zhang, Chaoyu Hu, Henrietta Venter, Susan J. Semple, Shutao Ma
      A novel series of 5-methyl-2-phenylphenanthridium derivatives were displayed outstanding activity against a panel of antibiotic-sensitive and -resistant bacteria strains compared with their precursor sanguinarine, ciprofloxacin and oxacillin sodium. Compounds 7 l, 7m and 7n were found to display the most effective activity against five sensitive strains (0.06–2 μg/mL) and three resistant strains (0.25–4 μg/mL). The kinetic profiles indicated that compound 7l possessed the strongest bactericidal effect on S. aureus ATCC25923, with the MBC value of 16 μg/mL. The cell morphology and the FtsZ polymerization assays indicated that these compounds inhibited the bacterial proliferation by interfering the function of bacterial FtsZ. The SARs showed that all the 4-methyl-substituted 5-methyl-2-phenylphenanthridium subseries could be further investigated as the FtsZ-targeting antibacterial agents.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.015
  • Evaluation of simultaneous binding of Chromomycin A3 to the multiple sites
           of DNA by the new restriction enzyme assay
    • Authors: Hirotaka Murase; Tomoharu Noguchi; Shigeki Sasaki
      Pages: 1832 - 1835
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Hirotaka Murase, Tomoharu Noguchi, Shigeki Sasaki
      Chromomycin A3 (CMA3) is an aureolic acid-type antitumor antibiotic. CMA3 forms dimeric complexes with divalent cations, such as Mg2+, which strongly binds to the GC rich sequence of DNA to inhibit DNA replication and transcription. In this study, the binding property of CMA3 to the DNA sequence containing multiple GC-rich binding sites was investigated by measuring the protection from hydrolysis by the restriction enzymes, AccII and Fnu4HI, for the center of the CGCG site and the 5′-GC↓GGC site, respectively. In contrast to the standard DNase I footprinting method, the DNA substrates are fully hydrolyzed by the restriction enzymes, therefore, the full protection of DNA at all the cleavable sites indicates that CMA3 simultaneously binds to all the binding sites. The restriction enzyme assay has suggested that CMA3 has a high tendency to bind the successive CGCG sites and the CGG repeat.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.013
  • Synthesis of carbon-11-labeled 5-HT6R antagonists as new candidate PET
           radioligands for imaging of Alzheimer’s disease
    • Authors: Xiaohong Wang; Fugui Dong; Caihong Miao; Wei Li; Min Wang; Mingzhang Gao; Qi-Huang Zheng; Zhidong Xu
      Pages: 1836 - 1841
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Xiaohong Wang, Fugui Dong, Caihong Miao, Wei Li, Min Wang, Mingzhang Gao, Qi-Huang Zheng, Zhidong Xu
      Carbon-11-labeled serotonin (5-hydroxytryptamine) 6 receptor (5-HT6R) antagonists, 1-[(2-bromophenyl)sulfonyl]-5-[11C]methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole (O-[11C]2a) and 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-[11C]methyl-1-piperazinyl)methyl]-1H-indole (N-[11C]2a), 5-[11C]methoxy-3-((4-methylpiperazin-1-yl)methyl)-1-(phenylsulfonyl)-1H-indole (O-[11C]2b) and 5-methoxy-3-((4-[11C]methylpiperazin-1-yl)methyl)-1-(phenylsulfonyl)-1H-indole (N-[11C]2b), 1-((4-isopropylphenyl)sulfonyl)-5-[11C]methoxy-3-((4-methylpiperazin-1-yl)methyl)-1H-indole (O-[11C]2c) and 1-((4-isopropylphenyl)sulfonyl)-5-methoxy-3-((4-[11C]methylpiperazin-1-yl)methyl)-1H-indole (N-[11C]2c), 1-((4-fluorophenyl)sulfonyl)-5-[11C]methoxy-3-((4-methylpiperazin-1-yl)methyl)-1H-indole (O-[11C]2d) and 1-((4-fluorophenyl)sulfonyl)-5-methoxy-3-((4-[11C]methylpiperazin-1-yl)methyl)-1H-indole (N-[11C]2d), were prepared from their O- or N-desmethylated precursors with [11C]CH3OTf through O- or N-[11C]methylation and isolated by HPLC combined with SPE in 40–50% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (MA) at EOB was 370–740 GBq/μmol with a total synthesis time of ∼40-min from EOB.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.014
  • Synthesis, biophysical characterization, and anti-HIV-1 fusion activity of
           DNA helix-based inhibitors with a p-benzyloxyphenyl substituent at the
           5′-nucleobase site
    • Authors: Yongjia Tang; Zeye Han; Jiamei Guo; Yangli Tian; Keliang Liu; Liang Xu
      Pages: 1842 - 1845
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Yongjia Tang, Zeye Han, Jiamei Guo, Yangli Tian, Keliang Liu, Liang Xu
      DNA helix-based HIV-1 fusion inhibitors have been discovered as potent drug candidates. Introduction of hydrophobic groups to a nucleobase provides an opportunity to design inhibitors with novel structures and mechanisms of action. In this work, two novel nucleoside analogues (1 and 2) were synthesized and incorporated into four DNA duplex- and quadruplex-based inhibitors. All the molecules showed anti-HIV-1 fusion activity. The effect of the p-benzyloxyphenyl group and the attached linker on the helix formation and thermal stability were fully compared and discussed. Surface plasmon resonance analysis further indicated that inhibitors with the same DNA helix may still have variable reaction targets, mainly attributed to the different hydrophobic modifications.
      Graphical abstract image

      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.012
  • Development of piperazine-based hydroxamic acid inhibitors against
           falcilysin, an essential malarial protease
    • Authors: Jeffrey P. Chance; Hannah Fejzic; Obiel Hernandez; Eva S. Istvan; Armann Andaya; Nikolay Maslov; Ruby Aispuro; Teodulo Crisanto; Huyen Nguyen; Brian Vidal; Whitney Serrano; Bradley Kuwahara; Corey Pugne Andanado; Daniel E. Goldberg; Jeremy P. Mallari
      Pages: 1846 - 1848
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Jeffrey P. Chance, Hannah Fejzic, Obiel Hernandez, Eva S. Istvan, Armann Andaya, Nikolay Maslov, Ruby Aispuro, Teodulo Crisanto, Huyen Nguyen, Brian Vidal, Whitney Serrano, Bradley Kuwahara, Corey Pugne Andanado, Daniel E. Goldberg, Jeremy P. Mallari
      The human parasite Plasmodium falciparum kills an estimated 445,000 people a year, with the most fatalities occurring in African children. Previous studies identified falcilysin (FLN) as a malarial metalloprotease essential for parasite development in the human host. Despite its essentiality, the biological roles of this protease are not well understood. Here we describe the optimization of a piperazine-based hydroxamic acid scaffold to develop the first reported inhibitors of FLN. Inhibitors were tested against cultured parasites, and parasiticidal activity correlated with potency against FLN. This suggests these compounds kill P. falciparum by blocking FLN, and that FLN is a druggable target. These compounds represent an important step towards validating FLN as a therapeutic target and towards the development of chemical tools to investigate the function of this protease.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.010
  • Evaluation of novel TGR5 agonist in combination with Sitagliptin for
           possible treatment of type 2 diabetes
    • Authors: Sameer Agarwal; Santosh Sasane; Jeevan Kumar; Prashant Deshmukh; Hitesh Bhayani; Poonam Giri; Suresh Giri; Shubhangi Soman; Neelima Kulkarni; Mukul Jain
      Pages: 1849 - 1852
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Sameer Agarwal, Santosh Sasane, Jeevan Kumar, Prashant Deshmukh, Hitesh Bhayani, Poonam Giri, Suresh Giri, Shubhangi Soman, Neelima Kulkarni, Mukul Jain
      TGR5 is a member of G protein-coupled receptor (GPCR) superfamily, a promising molecular target for metabolic diseases. Activation of TGR5 promotes secretion of glucagon-like peptide-1 (GLP-1), which activates insulin secretion. A series of 2-thio-imidazole derivatives have been identified as novel, potent and orally efficacious TGR5 agonists. Compound 4d, a novel TGR5 agonist, in combination with Sitagliptin, a DPP-4 inhibitor, has demonstrated an adequate GLP-1 secretion and glucose lowering effect in animal models, suggesting a potential clinical option in treatment of type-2 diabetes.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.011
  • P3-P4 ureas and reverse carbamates as potent HCV NS3 protease inhibitors:
           Effective transposition of the P4 hydrogen bond donor
    • Authors: Brian L. Venables; Ny Sin; Alan Xiangdong Wang; Li-Qiang Sun; Yong Tu; Dennis Hernandez; Amy Sheaffer; Min Lee; Cindy Dunaj; Guangzhi Zhai; Diana Barry; Jacques Friborg; Fei Yu; Jay Knipe; Jason Sandquist; Paul Falk; Dawn Parker; Andrew C. Good; Ramkumar Rajamani; Fiona McPhee; Nicholas A. Meanwell; Paul M. Scola
      Pages: 1853 - 1859
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Brian L. Venables, Ny Sin, Alan Xiangdong Wang, Li-Qiang Sun, Yong Tu, Dennis Hernandez, Amy Sheaffer, Min Lee, Cindy Dunaj, Guangzhi Zhai, Diana Barry, Jacques Friborg, Fei Yu, Jay Knipe, Jason Sandquist, Paul Falk, Dawn Parker, Andrew C. Good, Ramkumar Rajamani, Fiona McPhee, Nicholas A. Meanwell, Paul M. Scola
      A series of tripeptidic acylsulfonamide inhibitors of HCV NS3 protease were prepared that explored structure-activity relationships (SARs) at the P4 position, and their in vitro and in vivo properties were evaluated. Enhanced potency was observed in a series of P4 ureas; however, the PK profiles of these analogues were less than optimal. In an effort to overcome the PK shortcomings, modifications to the P3-P4 junction were made. This included a strategy in which one of the two urea N–H groups was either N-methylated or replaced with an oxygen atom. The former approach provided a series of regioisomeric N-methylated ureas while the latter gave rise to P4 reverse carbamates, both of which retained potent NS3 inhibitory properties while relying upon an alternative H-bond donor topology. Details of the SARs and PK profiles of these analogues are provided.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.009
  • Polyprenylated polycyclic acylphloroglucinol: Angiogenesis inhibitor from
           Garcinia multiflora
    • Authors: Lin-Yang Cheng; Chun-Lin Chen; Yueh-Hsiung Kuo; Tsung-Hsien Chang; I-Wei Lin; Shih-Wei Wang; Mei-Ing Chung; Jih-Jung Chen
      Pages: 1860 - 1863
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Lin-Yang Cheng, Chun-Lin Chen, Yueh-Hsiung Kuo, Tsung-Hsien Chang, I-Wei Lin, Shih-Wei Wang, Mei-Ing Chung, Jih-Jung Chen
      A new polyprenylated polycyclic acylphloroglucinol, garcimultiflorone K (1), has been isolated from the stems of Garcinia multiflora, together with two known compounds, garcimultiflorone A (2) and garcimultiflorone B (3). The structure of new compound 1 was determined through spectroscopic methods including 1D and 2D NMR and MS analyses. The anti-angiogenic and anti-cancer effects of compounds 1–3 were evaluated in human endothelial progenitor cells (EPCs) and cancer cells. Of these, garcimultiflorone K (1) displayed the most potent anti-angiogenic property by suppressing cell growth and tube formation of EPCs. Compound 1 also exhibited growth-inhibitory activities against human hepatocellular carcinoma cell line SK-Hep-1 and hormone refractory prostate cancer cell line PC-3 with GI50 values of 4.3 ± 1.6 and 6.6 ± 0.4 μM, respectively.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.006
  • Quinone skeleton as a new class of irreversible inhibitors against
           Staphylococcus aureus sortase A
    • Authors: Xiaochen Hou; Meining Wang; Yi Wen; Tengfeng Ni; Xiangna Guan; Lefu Lan; Naixia Zhang; Ao Zhang; Cai-Guang Yang
      Pages: 1864 - 1869
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Xiaochen Hou, Meining Wang, Yi Wen, Tengfeng Ni, Xiangna Guan, Lefu Lan, Naixia Zhang, Ao Zhang, Cai-Guang Yang
      Sortase A (SrtA) anchors surface proteins to the cell wall and aids biofilm formation during infection, which functions as a key virulence factor of important Gram-positive pathogens, such as Staphylococcus aureus. At present researchers need a way in which to validate whether or not SrtA is a druggable target alternative to the conventional antibiotic targets in the mechanism. In this study, we performed a high-throughput screening and identified a new class of potential inhibitors of S. aureus SrtA, which are derived from natural products and contain the quinone skeleton. Compound 283 functions as an irreversible inhibitor that covalently alkylates the active site Cys184 of SrtA. NMR analysis confirms the direct interaction of the small-molecule inhibitor towards SrtA protein. The anchoring of protein A (SpA) to the cell wall and the biofilm formation are significantly attenuated when the S. aureus Newman strain is cultured in the presence of inhibitor. Our study indicates that compound 283 could be a potential hit for the development of new anti-virulence agents against S. aureus infections by covalently targeting SrtA.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.005
  • A new Chlorin formulation promotes efficient photodynamic action in
           choriocapillaris of rabbit’s eyes
    • Authors: Gustavo H.A. Salomao; Adjaci U. Fernandes; Mauricio S. Baptista; João Paulo Tardivo; Stella Gianssante; Juliana Mora Veridiano; Olga Maria S. Toledo; Giuliana Petri; Denise Maria Christofolini; João Antonio Correa
      Pages: 1870 - 1873
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Gustavo H.A. Salomao, Adjaci U. Fernandes, Mauricio S. Baptista, João Paulo Tardivo, Stella Gianssante, Juliana Mora Veridiano, Olga Maria S. Toledo, Giuliana Petri, Denise Maria Christofolini, João Antonio Correa
      Age-related macular degeneration (AMD) as well as other choroidal diseases, demand novel therapeutic methods. Photodynamic therapy (PDT), which uses light and photosensitizer (PS) to cause specific vascular occlusion in the macula, is an interesting alternative. The only drug approved for the PDT treatment of AMD (Verteporfin) has a natural tendency to aggregate, demanding an expensive separation procedure during purification. We report a novel and affordable PS that is intrinsically protected against aggregation, the Monomeric Chlorin at High Concentration (MCHC-Chlorin), whose liposomal formulation was developed to provoke effective photodynamic action on the choroidal vasculature. Our report starts by stablishing the conditions to allow the efficient synthesis of MCHC-Chlorin in high yields (92%). We then tested the light stimulated occlusion of choriocapillary vessels in rabbit’s eyes induced by the two MCHC-Chlorin isomers, which are directly obtained from the synthetic route. The PS formulation was infused in the rabbit’s ear vein and eyes were immediately irradiated at 650 nm. Indirect ophthalmoscopy, fundus photography, fluorescein angiography and histopathological evaluations were used to evaluate levels of photo-thrombosis and collateral damage. Choriocapillary occlusion was achieved in all treated rabbits’ eyes, while retina and sclera were completely preserved. There was no photochemical reaction in none of the eyes that received LASER without PS. Both MCHC-Chlorin isomers were separately tested and exhibited similar positive results with no systemic toxicity. Therefore, PDT occurred equally well in all treated eyes and none of the controls showed any effect in the ophthalmological exams. MCHC-Chlorin offers great potential and should be further studied as an alternative drug for choroidal diseases.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.007
  • Structure-activity relationship study of a series of caspase inhibitors
           containing γ-amino acid moiety for treatment of cholestatic liver disease
    • Authors: Jianfeng Mou; Songliang Wu; Zhi Luo; Fengying Guo; Haiying He; Jianhua Wang; Fusen Lin; Fengxun Guo; Jianping Sun; Liang Shen; Minggao Zeng; Chuan Wang; Deming Xu; Zhengxian Gu; Xin Tian; Aiming Zhang; Hongjiang Xu; Ling Yang; Xiquan Zhang; Jian Li; Shuhui Chen
      Pages: 1874 - 1878
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Jianfeng Mou, Songliang Wu, Zhi Luo, Fengying Guo, Haiying He, Jianhua Wang, Fusen Lin, Fengxun Guo, Jianping Sun, Liang Shen, Minggao Zeng, Chuan Wang, Deming Xu, Zhengxian Gu, Xin Tian, Aiming Zhang, Hongjiang Xu, Ling Yang, Xiquan Zhang, Jian Li, Shuhui Chen
      A series of caspase inhibitors containing γ-amino acid moiety have been synthesized. A systemic study on their structure-activity relationship of anti-apoptotic cellular activity is presented. These efforts led to the discovery of compound 20o as a potent caspase inhibitor, which demonstrated preclinical ameliorating total bilirubin efficacy with a significantly improved pharmacokinetic profile.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.002
  • Photoactivated 2,3-distyrylindoles kill multi-drug resistant bacteria
    • Authors: Leslie Edwards; Danielle Turner; Cody Champion; Megha Khandelwal; Kailee Zingler; Cassidy Stone; Ruwini D. Rajapaksha; Jing Yang; Mahinda I. Ranasinghe; Alexander Kornienko; Liliya V. Frolova; Snezna Rogelj
      Pages: 1879 - 1886
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Leslie Edwards, Danielle Turner, Cody Champion, Megha Khandelwal, Kailee Zingler, Cassidy Stone, Ruwini D. Rajapaksha, Jing Yang, Mahinda I. Ranasinghe, Alexander Kornienko, Liliya V. Frolova, Snezna Rogelj
      Compounds based on the 2,3-distyrylindole scaffold were found to exhibit bactericidal properties upon irradiation with white light. At the concentration of 1 μM, the lead compound 1 completely (ca. 109 CFU/mL) eradicated such Gram-positive organisms as S. aureus (MRSA, MSSA), E. faecalis (VRE), S. pyogenes and S. mutans when irradiated with white light for 2 min. At the concentration of 5 μM and in the presence of polymyxin E at non-bactericidal 1.25 μg/mL concentration, 1 also showed a 7-log to 9-log reductions in bacterial counts of such Gram-negative organisms as multi-drug resistant (MDR) A. baumannii, MDR P. aeruginosa, E. coli and Klebsiella pneumoniae (CRE: KPC and NDM-1), also when irradiated with white light for 2 min. The structure-activity relationship studies revealed that unsubstituted at benzene rings 2,3-distyrylindole 2 was most potent and gave a 5-order of magnitude eradication of a MRSA strain at the concentration of 30 nM upon irradiation with white light. Initial mechanistic experiments revealed the disruption of bacterial cell membrane, but indicated that singlet oxygen production, which is commonly associated with photodynamic therapy, may not play a role in the bactericidal effects of the 2,3-distyrylindoles.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.04.001
  • Discovery of chiral dihydropyridopyrimidinones as potent, selective and
           orally bioavailable inhibitors of AKT
    • Authors: Saravanan Parthasarathy; Kenneth Henry; Huaxing Pei; Josh Clayton; Mark Rempala; Deidre Johns; Oscar De Frutos; Pablo Garcia; Carlos Mateos; Sehila Pleite; Yong Wang; Stephanie Stout; Bradley Condon; Sheela Ashok; Zhohai Lu; William Ehlhardt; Tom Raub; Mei Lai; Sandaruwan Geeganage; Timothy P. Burkholder
      Pages: 1887 - 1891
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Saravanan Parthasarathy, Kenneth Henry, Huaxing Pei, Josh Clayton, Mark Rempala, Deidre Johns, Oscar De Frutos, Pablo Garcia, Carlos Mateos, Sehila Pleite, Yong Wang, Stephanie Stout, Bradley Condon, Sheela Ashok, Zhohai Lu, William Ehlhardt, Tom Raub, Mei Lai, Sandaruwan Geeganage, Timothy P. Burkholder
      During the course of our research efforts to develop potent and selective AKT inhibitors, we discovered enatiomerically pure substituted dihydropyridopyrimidinones (DHP) as potent inhibitors of protein kinase B/AKT with excellent selectivity against ROCK2. A key challenge in this program was the poor physicochemical properties of the initial lead compound 5. Integration of structure-based drug design and physical properties-based design resulted in replacement of a highly hydrophobic poly fluorinated aryl ring by a simple trifluoromethyl that led to identification of compound 6 with much improved physicochemical properties. Subsequent SAR studies led to the synthesis of new pyran analog 7 with improved cell potency. Further optimization of pharmacokintetics properties by increasing permeability with appropriate fluorinated alkyl led to compound 8 as a potent, selective AKT inhibitors that blocks the phosphorylation of GSK3β in vivo and had robust, dose and concentration dependent efficacy in the U87MG tumor xenograft model.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.03.092
  • Discovery of
           acid (GSK726701A), a novel EP4 receptor partial agonist for the treatment
           of pain
    • Authors: Mark P. Healy; Amanda C. Allan; Kristin Bailey; Andy Billinton; Iain P. Chessell; Nicholas M. Clayton; Gerard M.P. Giblin; Melanie A. Kay; Tarik Khaznadar; Anton D. Michel; Alan Naylor; Helen Price; David J. Spalding; David A. Stevens; Martin E. Swarbrick; Alexander W. Wilson
      Pages: 1892 - 1896
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Mark P. Healy, Amanda C. Allan, Kristin Bailey, Andy Billinton, Iain P. Chessell, Nicholas M. Clayton, Gerard M.P. Giblin, Melanie A. Kay, Tarik Khaznadar, Anton D. Michel, Alan Naylor, Helen Price, David J. Spalding, David A. Stevens, Martin E. Swarbrick, Alexander W. Wilson
      A novel series of EP4 agonists and antagonists have been identified, and then used to validate their potential in the treatment of inflammatory pain. This paper describes these novel ligands and their activity within a number of pre-clinical models of pain, ultimately leading to the identification of the EP4 partial agonist GSK726701A.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.03.091
  • Synthesis of 3-(3-hydroxyphenyl)pyrrolidine dopamine D3 receptor ligands
           with extended functionality for probing the secondary binding pocket
    • Authors: Anahid Omran; Shakiba Eslamimehr; A. Michael Crider; William L. Neumann
      Pages: 1897 - 1902
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Anahid Omran, Shakiba Eslamimehr, A. Michael Crider, William L. Neumann
      A series of 3-(3-hydroxyphenyl)pyrrolidine analogues which incorporate N-alkyl groups and N-butylamide-linked benzamide functionality have been synthesized and their in vitro binding affinities at human dopamine receptors have been evaluated. Our ligand design strategy was to take the 3-(3-hydroxyphenyl)pyrrolidine scaffold and extend functionality from the orthosteric binding site to the secondary binding pocket for enhancing affinity and selectivity for the D3 receptor. The N-alkyl analogues constitute a homologous series from N-pentyl to N-decyl to probe the length/bulk tolerance of the secondary binding pocket of the D3 receptor. Enantiomeric 3-(3-hydroxyphenyl)pyrrolidine analogues were also prepared in order to test the chirality preference of the orthosteric binding site for this scaffold. Benzamide analogues were prepared to enhance affinity and/or selectivity based upon the results of the homologous series.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.03.084
  • Design, synthesis, and evaluation of novel N-1 fluoroquinolone
           derivatives: Probing for binding contact with the active site tyrosine of
    • Authors: Tyrell R. Towle; Chaitanya A. Kulkarni; Lisa M. Oppegard; Bridget P. Williams; Taylor A. Picha; Hiroshi Hiasa; Robert J. Kerns
      Pages: 1903 - 1910
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Tyrell R. Towle, Chaitanya A. Kulkarni, Lisa M. Oppegard, Bridget P. Williams, Taylor A. Picha, Hiroshi Hiasa, Robert J. Kerns
      Structural studies of topoisomerase-fluoroquinolone-DNA ternary complexes revealed a cavity between the quinolone N-1 position and the active site tyrosine. Fluoroquinolone derivatives having positively charged or aromatic moieties extended from the N-1 position were designed to probe for binding contacts with the phosphotyrosine residue in ternary complex. While alkylamine, alkylphthalimide, and alkylphenyl groups introduced at the N-1 position afforded derivatives that maintained modest inhibition of the supercoiling activity of DNA gyrase, none retained ability to poison DNA gyrase. Thus, the addition of a large and/or long moiety at the N-1 position disrupts ternary complex formation, and retained ability to inhibit supercoiling is likely through interference with the strand breakage reaction. Two derivatives were found to possess inhibitory effects on the decatenation activity of human topoisomerase II.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.03.085
  • Callyspongiamides A and B, sterol O-acyltransferase inhibitors, from the
           Indonesian marine sponge Callyspongia sp.
    • Authors: Magie M. Kapojos; Delfly B. Abdjul; Hiroyuki Yamazaki; Taichi Ohshiro; Henki Rotinsulu; Defny S. Wewengkang; Deiske A. Sumilat; Hiroshi Tomoda; Michio Namikoshi; Ryuji Uchida
      Pages: 1911 - 1914
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Magie M. Kapojos, Delfly B. Abdjul, Hiroyuki Yamazaki, Taichi Ohshiro, Henki Rotinsulu, Defny S. Wewengkang, Deiske A. Sumilat, Hiroshi Tomoda, Michio Namikoshi, Ryuji Uchida
      Callyspongiamides A (1) and B (2), two new sterol O-acyltransferase (SOAT) inhibitors, were isolated from the Indonesian marine sponge Callyspongia sp. together with a known congener, dysamide A (3). The structures of 1 and 2 were elucidated to be polychlorine-containing modified dipeptides based on their spectroscopic data. Compounds 1–3 inhibited both of the SOAT isozymes, SOAT1 and SOAT2, in cell-based and enzyme-based assays.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.03.077
  • Catalytic asymmetric synthesis of α-methyl-p-boronophenylalanine
    • Authors: Shingo Harada; Ryota Kajihara; Risa Muramoto; Promsuk Jutabha; Naohiko Anzai; Tetsuhiro Nemoto
      Pages: 1915 - 1918
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Shingo Harada, Ryota Kajihara, Risa Muramoto, Promsuk Jutabha, Naohiko Anzai, Tetsuhiro Nemoto
      p-Boronophenylalanine (l-BPA) is applied in clinical settings as a boron carrier for boron neutron capture therapy (BNCT) to cure malignant melanomas. Structural modification or derivatization of l-BPA, however, to improve its uptake efficiency into tumor cells has scarcely been investigated. We successfully synthesized (S)-2-amino-3-(4-boronophenyl)-2-methylpropanoic acid in enantioenriched form as a novel candidate molecule for BNCT. Key steps to enhance the efficiency of this synthesis were enantioselective alkylation of N-protected alanine tert-butyl ester with a Maruoka catalyst and Miyaura borylation reaction to install the boron functionality.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.03.075
  • Synthesis of 1,2,4-triazole-linked urea/thiourea conjugates as cytotoxic
           and apoptosis inducing agents
    • Authors: Ramya Tokala; Swarna Bale; Ingle Pavan Janrao; Aluri Vennela; Niggula Praveen Kumar; Kishna Ram Senwar; Chandraiah Godugu; Nagula Shankaraiah
      Pages: 1919 - 1924
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Ramya Tokala, Swarna Bale, Ingle Pavan Janrao, Aluri Vennela, Niggula Praveen Kumar, Kishna Ram Senwar, Chandraiah Godugu, Nagula Shankaraiah
      A new series of 1,2,4-triazole-linked urea and thiourea conjugates have been synthesized and evaluated for their in vitro cytotoxicity against selected human cancer cell lines namely, breast (MCF-7, MDA-MB-231), lung (A549) prostate (DU145) and one mouse melanoma (B16-F10) cell line and compared with reference drug. The compound 5t showed significant cytotoxicity on MCF-7 breast cancer cell line with a IC50 value of 7.22 ± 0.47 µM among all the tested compounds. Notably, induction of apoptosis by compound 5t on MCF-7 cells was evaluated using different staining techniques such as acridine orange/ethidium bromide (AO/EB), annexin V-FITC/PI, and DAPI. Further, clonogenic assay indicates the inhibition of colony formation on MCF-7 cells by compound 5t. Moreover, the flow-cytometric analysis also revealed that compound 5t caused the arrest of cells at G0/G1 phase of cell cycle. In addition, the compounds when tested on normal human cells (L-132) were found to be safer with low cytotoxicity profile.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.03.074
  • Inhibitory effects of methyl-3,5-di-O-caffeoyl-epi-quinate on
           RANKL-induced osteoclast differentiation
    • Authors: Tae Hoon Kim; Hye Jung Ihn; Kiryeong Kim; Hye-Sung Cho; Hong-In Shin; Yong Chul Bae; Eui Kyun Park
      Pages: 1925 - 1930
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Tae Hoon Kim, Hye Jung Ihn, Kiryeong Kim, Hye-Sung Cho, Hong-In Shin, Yong Chul Bae, Eui Kyun Park
      In this study, we have shown that methyl-3,5-di-O-caffeoyl-epi-quinate, a naturally occurring compound isolated from Ainsliaea acerifolia, inhibits receptor activator of nuclear factor-κB ligand (RANKL)-induced formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts and the expression of osteoclast marker genes. Methyl-3,5-di-O-caffeoyl-epi-quinate also inhibited RANKL-induced activation of p38, Akt and extracellular signal-regulated kinase (ERK) as well as the expression of nuclear factor of activated T-cell (NFATc1), the key regulator of osteoclast differentiation. Negative regulators for osteoclast differentiation was upregulated by methyl-3,5-di-O-caffeoyl-epi-quinate. Collectively, our results suggested that methyl-3,5-di-O-caffeoyl-epi-quinate suppresses osteoclast differentiation via downregulation of RANK signaling pathways and NFATc1.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.03.072
  • Modular synthesis of new C-aryl-nucleosides and their anti-CML activity
    • Authors: Hamid Marzag; Marwa Zerhouni; Hamza Tachallait; Luc Demange; Guillaume Robert; Khalid Bougrin; Patrick Auberger; Rachid Benhida
      Pages: 1931 - 1936
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Hamid Marzag, Marwa Zerhouni, Hamza Tachallait, Luc Demange, Guillaume Robert, Khalid Bougrin, Patrick Auberger, Rachid Benhida
      The C-aryl-ribosyles are of utmost interest for the development of antiviral and anticancer agents. Even if several synthetic pathways have been disclosed for the preparation of these nucleosides, a direct, few steps and modular approaches are still lacking. In line with our previous efforts, we report herein a one step - eco-friendly β-ribosylation of aryles and heteroaryles through a direct Friedel-Craft ribosylation mediated by bismuth triflate, Bi(OTf)3. The resulting carbohydrates have been functionalized by cross-coupling reactions, leading to a series of new C-aryl-nucleosides (32 compounds). Among them, we observed that 5d exerts promising anti-proliferative effects against two human Chronic Myeloid Leukemia (CML) cell lines, both sensitive (K562-S) or resistant (K562-R) to imatinib, the “gold standard of care” used in this pathology. Moreover, we demonstrated that 5d kills CML cells by a non-conventional mechanism of cell death.
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      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.03.063
  • Novel compounds that target lipoprotein lipase and mediate growth arrest
           in acute lymphoblastic leukemia
    • Authors: Rajesh R. Nair; Werner J. Geldenhuys; Debbie Piktel; Prabodh Sadana; Laura F. Gibson
      Pages: 1937 - 1942
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Rajesh R. Nair, Werner J. Geldenhuys, Debbie Piktel, Prabodh Sadana, Laura F. Gibson
      Over the past decade, the therapeutic strategies employed to treat B-precursor acute lymphoblastic leukemia (ALL) have been progressively successful in treating the disease. Unfortunately, the treatment associated dyslipidemia, either acute or chronic, is very prevalent and a cause for decreased quality of life in the surviving patients. To overcome this hurdle, we tested a series of cylopropanecarboxamides, a family demonstrated to target lipid metabolism, for their anti-leukemic activity in ALL. Several of the compounds tested showed anti-proliferative activity, with one, compound 22, inhibiting both Philadelphia chromosome negative REH and Philadelphia chromosome positive SupB15 ALL cell division. The novel advantage of these compounds is the potential synergy with standard chemotherapeutic agents, while concomitantly blunting the emergence of dyslipidemia. Thus, the cylopropanecarboxamides represent a novel class of compounds that can be potentially used in combination with the present standard-of-care to limit treatment associated dyslipidemia in ALL patients.
      Graphical abstract image

      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.03.061
  • The synthesis and antistaphylococcal activity of N-sulfonaminoethyloxime
           derivatives of dehydroabietic acid
    • Authors: Wen-Ming Zhang; Yang Yao; Teng Yang; Xue-Ying Wang; Zhen-Yun Zhu; Wen-Tao Xu; Hai-Xia Lin; Zhao-Bing Gao; Hu Zhou; Cai-Guang Yang; Yong-Mei Cui
      Pages: 1943 - 1948
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Wen-Ming Zhang, Yang Yao, Teng Yang, Xue-Ying Wang, Zhen-Yun Zhu, Wen-Tao Xu, Hai-Xia Lin, Zhao-Bing Gao, Hu Zhou, Cai-Guang Yang, Yong-Mei Cui
      A series of N-sulfonaminoethyloxime derivatives of dehydroabietic acid were synthesized and investigated for their antibacterial activity against Staphylococcus aureus Newman strain and multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108 and NRS-271). Most of the target compounds having chloro, bromo, trifluoromethyl phenyl moiety exhibited potent in vitro antistaphylococcal activity. The meta-CF3 phenyl derivative T23 showed the highest activity with MIC of 0.39–0.78 μg/mL against S. aureus Newman, while several analogues showed similar potent antibacterial activity with MIC values between 0.78 and 1.56 μg/mL against five multidrug-resistant S. aureus. The stability of T35 in plasma of SD rat and the cellular cytotoxicity were also evaluated.
      Graphical abstract image

      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.03.062
  • Kröhnke pyridines: Rapid and facile access to Mcl-1 inhibitors
    • Authors: Ivie L. Conlon; Daniel Van Eker; Sameh Abdelmalak; William A. Murphy; Hassan Bashir; Michael Sun; Jay Chauhan; Kristen M. Varney; Raquel Godoy-Ruiz; Paul T. Wilder; Steven Fletcher
      Pages: 1949 - 1953
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10
      Author(s): Ivie L. Conlon, Daniel Van Eker, Sameh Abdelmalak, William A. Murphy, Hassan Bashir, Michael Sun, Jay Chauhan, Kristen M. Varney, Raquel Godoy-Ruiz, Paul T. Wilder, Steven Fletcher
      The tumorigenic activity of upregulated Mcl-1 is manifested by binding the BH3 α-helical death domains of opposing Bcl-2 family members, neutralizing them and preventing apoptosis. Accordingly, the development of Mcl-1 inhibitors largely focuses on synthetic BH3 mimicry. The condensation of α-pyridinium methyl ketone salts and α,β-unsaturated carbonyl compounds in the presence of a source of ammonia, or the Kröhnke pyridine synthesis, is a simple approach to afford highly functionalized pyridines. We adapted this chemistry to rapidly generate low-micromolar inhibitors of Mcl-1 wherein the 2,4,6-substituents were predicted to mimic the i, i + 2 and i + 7 side chains of the BH3 α-helix.
      Graphical abstract image

      PubDate: 2018-05-17T05:10:50Z
      DOI: 10.1016/j.bmcl.2018.03.050
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