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CHEMISTRY (598 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 8)
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: 32)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 17)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 23)
ACS Macro Letters     Full-text available via subscription   (Followers: 23)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 39)
ACS Nano     Full-text available via subscription   (Followers: 227)
ACS Photonics     Full-text available via subscription   (Followers: 11)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 21)
Acta Chemica Iasi     Open Access   (Followers: 2)
Acta Chimica Sinica     Full-text available via subscription   (Followers: 1)
Acta Chimica Slovaca     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: 5)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 7)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 5)
Advanced Functional Materials     Hybrid Journal   (Followers: 50)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 53)
Advances in Chemical Science     Open Access   (Followers: 13)
Advances in Chemistry     Open Access   (Followers: 14)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Enzyme Research     Open Access   (Followers: 9)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 15)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 19)
Advances in Nanoparticles     Open Access   (Followers: 14)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15)
Advances in Polymer Science     Hybrid Journal   (Followers: 41)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 19)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
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: 2)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 67)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 14)
American Journal of Chemistry     Open Access   (Followers: 26)
American Journal of Plant Physiology     Open Access   (Followers: 13)
American Mineralogist     Hybrid Journal   (Followers: 13)
Analyst     Full-text available via subscription   (Followers: 38)
Angewandte Chemie     Hybrid Journal   (Followers: 164)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 212)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 1)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 3)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 8)
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: 14)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Hybrid Journal  
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7)
Applied Spectroscopy     Full-text available via subscription   (Followers: 23)
Applied Surface Science     Hybrid Journal   (Followers: 28)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 2)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Atomization and Sprays     Full-text available via subscription   (Followers: 3)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Biochemistry     Full-text available via subscription   (Followers: 285)
Biochemistry Insights     Open Access   (Followers: 5)
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: 19)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 6)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 4)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 110)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 93)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 1)
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: 3)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 67)
Catalysis for Sustainable Energy     Open Access   (Followers: 6)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 8)
Catalysis Science and Technology     Free   (Followers: 6)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 7)
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: 12)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 70)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 23)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 19)
Chemical Reviews     Full-text available via subscription   (Followers: 174)
Chemical Science     Open Access   (Followers: 21)
Chemical Technology     Open Access   (Followers: 16)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemical Week     Full-text available via subscription   (Followers: 8)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 55)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 25)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 6)
Chemistry & Biology     Full-text available via subscription   (Followers: 30)
Chemistry & Industry     Hybrid Journal   (Followers: 5)
Chemistry - A European Journal     Hybrid Journal   (Followers: 150)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 15)
Chemistry and Materials Research     Open Access   (Followers: 18)
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: 45)
Chemistry of Materials     Full-text available via subscription   (Followers: 243)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 22)
Chemistry-Didactics-Ecology-Metrology     Open Access  
ChemistryOpen     Open Access   (Followers: 2)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 2)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 15)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 9)
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: 10)
Chromatographia     Hybrid Journal   (Followers: 24)
Chromatography Research International     Open Access   (Followers: 7)
Clay Minerals     Full-text available via subscription   (Followers: 9)
Cogent Chemistry     Open Access  
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 10)
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 8)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 3)
Combustion Science and Technology     Hybrid Journal   (Followers: 18)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Composite Interfaces     Hybrid Journal   (Followers: 6)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 2)
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: 12)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 9)
Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 2)
Copernican Letters     Open Access  
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 5)
Crystal Structure Theory and Applications     Open Access   (Followers: 3)
CrystEngComm     Full-text available via subscription   (Followers: 11)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Metabolomics     Hybrid Journal   (Followers: 5)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 56)
Dalton Transactions     Full-text available via subscription   (Followers: 19)
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  
Drying Technology: An International Journal     Hybrid Journal   (Followers: 4)
Eclética Química     Open Access   (Followers: 1)
Ecological Chemistry and Engineering S     Open Access   (Followers: 4)
Ecotoxicology and Environmental Contamination     Open Access  
Educación Química     Open Access   (Followers: 1)
Education for Chemical Engineers     Hybrid Journal   (Followers: 5)
EJNMMI Radiopharmacy and Chemistry     Open Access  
Elements     Full-text available via subscription   (Followers: 2)
Environmental Chemistry     Hybrid Journal   (Followers: 9)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 4)
Environmental Science & Technology Letters     Full-text available via subscription   (Followers: 5)

        1 2 3 | Last

Journal Cover Bioorganic & Medicinal Chemistry
  [SJR: 1.064]   [H-I: 119]   [110 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [3042 journals]
  • The medicinal chemistry of Chikungunya virus
    • Authors: Edeildo F. da Silva-Júnior; Giovanni O. Leoncini; Érica E.S. Rodrigues; Thiago M. Aquino; João X. Araújo-Júnior
      Pages: 4219 - 4244
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Edeildo F. da Silva-Júnior, Giovanni O. Leoncini, Érica E.S. Rodrigues, Thiago M. Aquino, João X. Araújo-Júnior
      Arthropod-borne viruses (arboviruses) are an important threat to human and animal health globally. Among these, zoonotic diseases account for billions of cases of human illness and millions of deaths every year, representing an increasing public health problem. Chikungunya virus belongs to the genus Alphavirus of the family Togariridae, and is transmitted mainly by the bite of female mosquitoes of the Aedes aegypti and/or A. albopictus species. The focus of this review will be on the medicinal chemistry of Chikungunya virus, including synthetic and natural products, as well as rationally designed compounds.
      Graphical abstract image

      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.049
  • Effect of replacing main-chain ureas with thiourea and guanidinium
           surrogates on the bactericidal activity of membrane active oligourea
    • Authors: Stéphanie Antunes; Jean-Philippe Corre; Guillain Mikaty; Céline Douat; Pierre L. Goossens; Gilles Guichard
      Pages: 4245 - 4252
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Stéphanie Antunes, Jean-Philippe Corre, Guillain Mikaty, Céline Douat, Pierre L. Goossens, Gilles Guichard
      Membrane-active foldamers have recently emerged as potential mimics of antimicrobial peptides (AMPs). Amphiphilic cationic helical N,N′-linked oligoureas are one such class of AMP mimics with activities in vitro against a broad range of bacteria including Bacillus anthracis, a Gram-positive sporulating bacillus and causing agent of anthrax. Here we have used site-selective chemical modifications of the oligourea backbone to gain additional insight into the relationship between structure and function and modulate anthracidal activity. A series of analogues in which urea linkages at selected positions are replaced by thiourea and guanidium surrogates have been prepared on solid support and tested against different bacterial forms of B. anthracis (germinated spores and encapsulated bacilli). Urea→thiourea and urea→guanidinium replacements close to the negative end of the helix dipole led to analogues with increased potency and selectivity for B. anthracis versus mammalian cells.
      Graphical abstract image

      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.04.040
  • Gerontoxanthone B from Maclura cochinchinensis var. gerontogea exhibits
           anti-inflammatory potential as an aryl hydrocarbon receptor agonist
    • Authors: Ken-ichi Nakashima; Takumi Ogiwara; Takao Hirai; Toshiyuki Tanaka; Hiroko Murata; Kouichi Kaburagi; Yoshiaki Fujii-Kuriyama; Hidetoshi Hayashi; Makoto Inoue
      Pages: 4253 - 4258
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Ken-ichi Nakashima, Takumi Ogiwara, Takao Hirai, Toshiyuki Tanaka, Hiroko Murata, Kouichi Kaburagi, Yoshiaki Fujii-Kuriyama, Hidetoshi Hayashi, Makoto Inoue
      The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcriptional factor belonging to the basic helix-loop-helix-Per-Ahr/Arnt-Sim family. In this study, we evaluated the AhR agonistic activities of 12 xanthones isolated from the roots of M. cochinchinensis var. gerontogea using HepG2 cells transfected with pX4TK–Luc reporter plasmids. Gerontoxanthone B (GXB) showed the most potent activity at a concentration of 10μM, and the activity was inhibited by AhR antagonists such as GNF-351. GXB also increased cytochrome P450 1A1 mRNA and protein levels in HepG2 cells. Similar to the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin, however, GXB suppressed the IL-1β-induced mRNA level of SAA1, an acute-phase response gene that is up-regulated AhR-dependently but XRE-independently. Thus, GXB shows XRE-dependent transcriptional activity and XRE-independent activity involving AhR.
      Graphical abstract image

      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.05.047
  • Activity cliff for 7-substituted pyrrolo-pyrimidine inhibitors of HCK
           explained in terms of predicted basicity of the amine nitrogen
    • Authors: Hitomi Yuki; Ko Kikuzato; Yasuko Koda; Junko Mikuni; Yuri Tomabechi; Mutsuko Kukimoto-Niino; Akiko Tanaka; Fumiyuki Shirai; Mikako Shirouzu; Hiroo Koyama; Teruki Honma
      Pages: 4259 - 4264
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Hitomi Yuki, Ko Kikuzato, Yasuko Koda, Junko Mikuni, Yuri Tomabechi, Mutsuko Kukimoto-Niino, Akiko Tanaka, Fumiyuki Shirai, Mikako Shirouzu, Hiroo Koyama, Teruki Honma
      We previously reported the structure-based design of a highly potent hematopoietic cell kinase (HCK) inhibitor, a pyrrolo-pyrimidine compound designated RK-20449, for treatment of recurrent leukemia. Herein we report the synthesis and structure–activity relationships of some amino acid derivatives of 7-substituted pyrrolo-pyrimidine. Although these derivatives had the same predicted binding conformation as RK-20449, their IC50 values were 100–1000 times larger than that of the parent compound. We assumed that the basicity of the amine nitrogen, which formed an ionic bond with Asp348 of HCK, markedly affected inhibitory activity against HCK. The pKa values of the nitrogen were predicted by means of an ab initio quantum mechanical method, and complexes of the derivatives with HCK were analyzed by X-ray crystallography. We observed a significant correlation between the predicted pKa and IC50 values, and the crystal structures of the less potent derivatives showed various types of defects around the ionic bond.
      Graphical abstract image

      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.05.053
  • Synthesis and biological activity of cyclolinopeptide A analogues modified
           with γ4-bis(homo-phenylalanine)
    • Authors: Karol Jędrzejczak; Paweł Hrynczyszyn; Małgorzata Szczesio; Jolanta Artym; Tomasz Jastrząbek; Maja Kocięba; Marek Główka; Krzysztof Huben; Iwona Kochanowska; Michał Zimecki; Janusz Zabrocki; Stefan Jankowski; Beata Kolesińska
      Pages: 4265 - 4276
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Karol Jędrzejczak, Paweł Hrynczyszyn, Małgorzata Szczesio, Jolanta Artym, Tomasz Jastrząbek, Maja Kocięba, Marek Główka, Krzysztof Huben, Iwona Kochanowska, Michał Zimecki, Janusz Zabrocki, Stefan Jankowski, Beata Kolesińska
      Cyclolinopeptide A (CLA), an immunosuppressive nonapeptide derived from linen seeds, was modified with S or R-γ4-bis(homo-phenylalanine) in positions 3 or 4, or both 3 and 4. These modifications changed the flexibility of new analogues and distribution of intramolecular hydrogen bonds. Analogues 11 c(Pro1-Pro2-Phe3- S-γ4 -hhPhe4 -Leu5-Ile6-Ile7-Leu8-Val9), 13 c(Pro1-Pro2- S-γ4 -hhPhe3 - R-γ4 -hhPhe4 -Leu5-Ile6-Ile7-Leu8-Val9) and 15 c(Pro1-Pro2- R -γ4 -hhPhe3 -Phe4-Leu5-Ile6-Ile7-Leu8-Val9) existed as a mixture of stable cis/trans isomers of Pro-Pro peptide bond. The comparison of the relative spatial orientations in crystal state of the two carbonyl groups, neighboring γ-amino acids, revealed conformational similarities to α-peptides. The addition of two -CH2- groups in γ-amino acids led to a more rigid conformation, although a more flexible one was expected. A significant difference in the relative orientation of the carbonyl groups was found for cyclic γ-peptides with a dominance of an antiparallel arrangement. As carbonyl groups may be engaged in the interactions with plausible receptors through hydrogen bonds, a similar biological activity of the modified peptides was expected. Our biological studies showed that certain cyclic, but not the corresponding linear peptides, lowered the viability of peripheral blood mononuclear cells (PBMC) at 100μg/mL concentration. The proliferation of PBMC induced by phytohemagglutinin A (PHA) was strongly inhibited by cyclic peptides only, in a dose-dependant manner. On the other hand, lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α) production in whole blood cell cultures was inhibited by both linear and cyclic peptides. Peptide 15 c(Pro1-Pro2- R -γ 4 -hhPhe3 -Phe4-Leu5-Ile6-Ile7-Leu8-Val9) blocked the expression of caspase-3, inhibited the expression of caspases-8 and -9 in 24h culture of Jurkat cells, and caused DNA fragmentation in these cells, as an indicator of apoptosis. Thus, we revealed a new mechanism of immunosuppressive action of a nonapeptide.
      Graphical abstract image

      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.05.063
  • Stereospecific inhibition of nitric oxide production in macrophage cells
    • Authors: Wen-Jun Jiang; Susumu Kitanaka; Tomoko Takamiya; Hiroshi Iijima
      Pages: 4277 - 4284
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Wen-Jun Jiang, Susumu Kitanaka, Tomoko Takamiya, Hiroshi Iijima
      To explore the structure-activity relationships of flavanonols on the inhibition of nitric oxide (NO) production in RAW 264.7 cells, we have prepared a series of synthetic flavanonols. In our previous study, the 2′,3′-dihydroxyphenyl substructure was found to be the most potent B ring substructure among the flavanonols having 3,5,7-trihydroxychroman-4-one as the A/C ring. In this study, we examined the effect of diverse substitutions on the A ring of the 2-(2,3-dihydroxyphenyl)-3-hydroxychroman-4-one scaffold, i.e., by fixing the B ring to the 2′,3′-dihydroxyphenyl substructure. Eighteen stereoisomers and 4 racemic mixtures were prepared, and their inhibitory potency on NO production in RAW 264.7 cells was tested. We observed higher inhibitory activity in the (2R,3R) stereoisomers than in the (2S,3S) stereoisomers. The presence of a hydroxy or a methoxy group at the 7-postiion enhanced the inhibitory potency, and the additional substitutions at the 6- or 8-position in the A ring increased potency and stereospecificity. A representative compound, (2R,3R)-2′,3′,7,8-tetrahydroxyflavanonol 5e, had an IC50 value of 17µM, whereas its (2S,3S) stereoisomer did not inhibit NO production at all at a concentration of 100µM. In this study, it was necessary to determine the absolute configuration of the stereoisomers of the synthesized flavanonols that carry methoxy substitutions in the A ring. The procedure to determine their absolute configuration by the CD excitation chirality method is also discussed.
      Graphical abstract image

      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.05.060
  • Conformational studies of Gram-negative bacterial quorum sensing 3-oxo
           N-acyl homoserine lactone molecules
    • Authors: Darren Crowe; Alan Nicholson; Adrienne Fleming; Ed Carey; Goar Sánchez-Sanz; Fintan Kelleher
      Pages: 4285 - 4296
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Darren Crowe, Alan Nicholson, Adrienne Fleming, Ed Carey, Goar Sánchez-Sanz, Fintan Kelleher
      In their 1H NMR spectra in CDCl3 3-oxo-N-acyl homoserine lactones (OHLs) show significant downfield chemical shifts of the amide NH proton when compared to the parent N-acyl homoserine lactones (AHLs). NMR spectroscopic and DFT calculation studies have shown that this is most likely due to the presence of a stabilising intramolecular H-bond from the NH to the 3-oxo group. The 1H NMR spectra also show evidence for the enol tautomers and that the amount of enol present for a range of OHLs is 4.1–4.5% in CDCl3 and 6.5–7.2% in CD3CN. In contrast, DFT calculations show that the lowest energy enol tautomer and the keto tautomer are of equal energy in the gas phase, but that the keto tautomer is more stable in chloroform, acetonitrile and water solution. The calculations also show that there is no evidence for any n→π∗ or C5H-bonding interactions being present in either the lowest energy keto or enol tautomer of the OHLs in solution or the gas phase, which is in contrast to the reported solid-state structure.
      Graphical abstract image

      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.006
  • Synthesis and characterization of monophosphinic acid DOTA derivative: A
           smart tool with functionalities for multimodal imaging
    • Authors: Satya Narayana Murthy Chilla; Ondrej Zemek; Jan Kotek; Sébastien Boutry; Lionel Larbanoix; Coralie Sclavons; Luce Vander Elst; Ivan Lukes; Robert N. Muller; Sophie Laurent
      Pages: 4297 - 4303
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Satya Narayana Murthy Chilla, Ondrej Zemek, Jan Kotek, Sébastien Boutry, Lionel Larbanoix, Coralie Sclavons, Luce Vander Elst, Ivan Lukes, Robert N. Muller, Sophie Laurent
      A new facile synthetic strategy was developed to prepare bifunctional monophosphinic acid Ln-DOTA derivatives, Gd-DO2AGAPNBn and Gd- DO2AGAPABn. The relaxivities of the Gd-complexes are enhanced compared to Gd-DOTA. Monophosphinic acid arm of these Gd-complexes affords enhancement of inner sphere water exchange rate due to its steric bulkiness. The different functionalities of DO2AGAPNBn were appended in trans positions and are designed to conjugate identical or different vectors according to the potential applications. The conjugation of Gd-DO2AGAPABn with E3 peptide known to target apoptosis was successfully performed and in vivo MRI allowed cell death detection in a mouse model.
      Graphical abstract image

      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.008
  • Novel 4-acetamide-2-alkylthio-N-acetanilides resembling nimesulide:
           Synthesis, cell viability evaluation and in silico studies
    • Authors: Mafalda Catarro; João Serrano; Eunice Cavalheiro; Susana Ramos; Adriana O. Santos; Samuel Silvestre; Paulo Almeida
      Pages: 4304 - 4313
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Mafalda Catarro, João Serrano, Eunice Cavalheiro, Susana Ramos, Adriana O. Santos, Samuel Silvestre, Paulo Almeida
      Since nimesulide, a nonsteroidal anti-inflammatory drug, is known to be a selective inhibitor of cyclooxygenase-2 and shows activity against cancer cells, there has been much interest in developing related molecules with enhanced anticancer properties. Taking in consideration structural features of nimesulide analogues ten new ortho-(akylthio)-N-alkylacetanilides were synthesized and fully characterized. The antiproliferative effect of these acetanilides was evaluated against human breast (MCF-7) and prostate (LNCaP) cancer cell lines as well as normal human dermal fibroblasts (NHDF). In particular, acetoacetanilides with methylcyclohexyl and/or 2,4-dimethylbenzyl groups linked to amide group and/or to sulfur atom had interesting cytotoxicities against human breast cancer cells. Moreover, these groups caused an increase in the antiproliferative effect against both cancer cells. Docking studies revealed the possibility of these acetoacetanilides to be potential ligands of the androgen receptor, though hormone-independent mechanisms may be involved in antiproliferative effects shown by these acetoacetanilides. In addition, 3D-QSAR studies demonstrated that the cytotoxic activity against the human breast cancer cell line was dependent on both bulkiness and electrostatic nature of the N- and S-alkyl groups of acetoacetanilides.
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.009
  • Synthesis and evaluation of
           derivatives as HCA2 receptor agonists
    • Authors: Olga Bobileva; Martins Ikaunieks; Gunars Duburs; Ilona Mandrika; Ramona Petrovska; Janis Klovins; Einars Loza
      Pages: 4314 - 4329
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Olga Bobileva, Martins Ikaunieks, Gunars Duburs, Ilona Mandrika, Ramona Petrovska, Janis Klovins, Einars Loza
      Novel series of compounds consisting of 2-amidocyclohex-1-ene carboxylate and phenyl parts which are connected by enyne (compounds 2a–f), but-1-yne (compounds 4a–j), and phenylethylene (compounds 5a–f) linkers as HCA2 full agonists were designed and their functional activity using cAMP assay and binding affinity using radioligand (3H-niacin) binding assay were evaluated. In general, compounds of all three series exhibit similar HCA2 binding and activation profile. However, the activity is strongly dependent on the substituent at the aromatic part of the structure. Among the structures evaluated, the highest affinity and potency in all series were exhibited by compounds containing 4-hydroxy and/or 2-chloro or 2-fluoro substituents. The most active compounds in the enyne and but-1-yne series in the cAMP assay are 2-fluoro,4-hydroxy and 2-chloro,4-hydroxy phenyl derivatives 2f, 4f, and 4g showing potency similar to the previously described 4-hydroxy-biphenyl analogue 5c.
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.028
  • Novel analogs of N-acylhydroxyethylaminomethyl-4H-chromen-4-one scaffold
           as IL-5 inhibitors
    • Authors: Hyun-Sun Yang; Eeda Venkateswararao; Pulla Reddy Boggu; Vinay K. Sharma; Youngsoo Kim; Sang-Hun Jung
      Pages: 4330 - 4338
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Hyun-Sun Yang, Eeda Venkateswararao, Pulla Reddy Boggu, Vinay K. Sharma, Youngsoo Kim, Sang-Hun Jung
      A number of N-acyl substituted hydroxyethylaminomethyl-4H-chromen-4-ones 6a–u were prepared and evaluated for their IL-5 inhibitory activity. Among them, the compound 6r (95.0% inhibition at 30µM, IC50 =10.0µM, ClogP=4.1549) showed most potent inhibitory activity. The structure activity relationship revealed that the bulkier or hydrophobic substituents at urea, carbamate or amide group resulted in good inhibitory activity against IL-5. Moreover, electron donating group at phenyl ring (6g and 6s) is much more active than electron withdrawing group (6f). Finally, replacement of cyclohexylmethoxy group at 5th position of ring A with bulky aliphatic substituents resulted in the loss of activity.
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.018
  • Novel 3H-[1,2,3]triazolo[4,5-c]pyridine derivatives as GPR119 agonists:
           Synthesis and structure-activity/solubility relationships
    • Authors: Daisuke Matsuda; Yohei Kobashi; Ayako Mikami; Madoka Kawamura; Fumiyasu Shiozawa; Kenichi Kawabe; Makoto Hamada; Shinichi Nishimoto; Kayo Kimura; Masako Miyoshi; Noriko Takayama; Hiroyuki Kakinuma; Norikazu Ohtake
      Pages: 4339 - 4354
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Daisuke Matsuda, Yohei Kobashi, Ayako Mikami, Madoka Kawamura, Fumiyasu Shiozawa, Kenichi Kawabe, Makoto Hamada, Shinichi Nishimoto, Kayo Kimura, Masako Miyoshi, Noriko Takayama, Hiroyuki Kakinuma, Norikazu Ohtake
      We previously reported a novel series of 1H-pyrazolo[3,4-c]pyridine derivatives and the identification of compound 4b as a highly potent GPR119 agonist. However, the advancement of preclinical evaluations of compound 4b is expected to be difficult because of the compound’s significantly poor aqueous solubility (0.71μM at pH6.8). In this article, we describe the further optimization of compound 4b focusing on the improvement of its aqueous solubility. Optimization of the central spacer, left-hand aryl group and right-hand piperidine N-capping group led to the identification of a potent GPR119 agonist, 3H-[1,2,3]triazolo[4,5-c]pyridine derivative 32o, with improved solubility (15.9μM at pH6.8).
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.014
  • Design, synthesis and biological evaluation of GPR55 agonists
    • Authors: Lara Fakhouri; Christopher D. Cook; Mohammed H. Al-Huniti; Linda M. Console-Bram; Dow P. Hurst; Michael B.S. Spano; Daniel J. Nasrallah; Marc G. Caron; Larry S. Barak; Patricia H. Reggio; Mary E. Abood; Mitchell P. Croatt
      Pages: 4355 - 4367
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Lara Fakhouri, Christopher D. Cook, Mohammed H. Al-Huniti, Linda M. Console-Bram, Dow P. Hurst, Michael B.S. Spano, Daniel J. Nasrallah, Marc G. Caron, Larry S. Barak, Patricia H. Reggio, Mary E. Abood, Mitchell P. Croatt
      GPR55, a G protein-coupled receptor, is an attractive target to alleviate inflammatory and neuropathic pain and treat osteoporosis and cancer. Identifying a potent and selective ligand will aid to further establish the specific physiological roles and pharmacology of the receptor. Towards this goal, a targeted library of 22 compounds was synthesized in a modular fashion to obtain structure-activity relationship information. The general route consisted of coupling a variety of p-aminophenyl sulfonamides to isothiocyanates to form acylthioureas. For the synthesis of a known naphthyl ethyl alcohol motif, route modification led to a shorter and more efficient process. The 22 analogues were analyzed for their ability to serve as agonists at GPR55 and valuable information for both ends of the molecule was ascertained.
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.016
  • Phosphonodifluoropyruvate is a mechanism-based inhibitor of
           phosphonopyruvate decarboxylase from Bacteroides fragilis
    • Authors: Katharina Pallitsch; Megan P. Rogers; Forest H. Andrews; Friedrich Hammerschmidt; Michael J. McLeish
      Pages: 4368 - 4374
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Katharina Pallitsch, Megan P. Rogers, Forest H. Andrews, Friedrich Hammerschmidt, Michael J. McLeish
      Bacteroides fragilis, a human pathogen, helps in the formation of intra-abdominal abscesses and is involved in 90% of anaerobic peritoneal infections. Phosphonopyruvate decarboxylase (PnPDC), a thiamin diphosphate (ThDP)-dependent enzyme, plays a key role in the formation of 2-aminoethylphosphonate, a component of the cell wall of B. fragilis. As such PnPDC is a possible target for therapeutic intervention in this, and other phosphonate producing organisms. However, the enzyme is of more general interest as it appears to be an evolutionary forerunner to the decarboxylase family of ThDP-dependent enzymes. To date, PnPDC has proved difficult to crystallize and no X-ray structures are available. In the past we have shown that ThDP-dependent enzymes will often crystallize if the cofactor has been irreversibly inactivated. To explore this possibility, and the utility of inhibitors of phosphonate biosynthesis as potential antibiotics, we synthesized phosphonodifluoropyruvate (PnDFP) as a prospective mechanism-based inhibitor of PnPDC. Here we provide evidence that PnDFP indeed inactivates the enzyme, that the inactivation is irreversible, and is accompanied by release of fluoride ion, i.e., PnDFP bears all the hallmarks of a mechanism-based inhibitor. Unfortunately, the enzyme remains refractive to crystallization.
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.013
  • Antitrichomonal activity of δ opioid receptor antagonists,
           7-benzylidenenaltrexone derivatives
    • Authors: Noriki Kutsumura; Yasuaki Koyama; Yasuyuki Nagumo; Ryo Nakajima; Yoshiyuki Miyata; Naoshi Yamamoto; Tsuyoshi Saitoh; Naoko Yoshida; Satoshi Iwata; Hiroshi Nagase
      Pages: 4375 - 4383
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Noriki Kutsumura, Yasuaki Koyama, Yasuyuki Nagumo, Ryo Nakajima, Yoshiyuki Miyata, Naoshi Yamamoto, Tsuyoshi Saitoh, Naoko Yoshida, Satoshi Iwata, Hiroshi Nagase
      The 7-benzylidenenaltrexone (BNTX) derivatives 2a–v, 3a–c, 13a–c, and 14a were synthesized from naltrexone (1) and evaluated for their antitrichomonal activity. The structure-activity-relationship studies found that 4-iodo-BNTX (2g) showed the highest activity (IC50 =10.5µM) and the affinity for the opioid receptor was less important for antitrichomonal activity against Trichomonas vaginalis. The morphinan skeleton bearing both the double bond for a Michael acceptor and the phenolic hydroxy group would be a specific template for development of antitrichomonal agents. In addition, the mechanism of the antitrichomonal activity of the BNTX derivatives may differ from that of the standard drug, metronidazole.
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.026
  • Structure-activity relationships of 3-O-β-chacotriosyl oleanic acid
           derivatives as entry inhibitors for highly pathogenic H5N1 influenza virus
    • Authors: Sumei Li; Xiuhua Jia; Xintian Shen; Zhuwen Wei; Zhiyan Jiang; Yixian Liao; Yiming Guo; Xiaojun Zheng; Guohua Zhong; Gaopeng Song
      Pages: 4384 - 4396
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Sumei Li, Xiuhua Jia, Xintian Shen, Zhuwen Wei, Zhiyan Jiang, Yixian Liao, Yiming Guo, Xiaojun Zheng, Guohua Zhong, Gaopeng Song
      Highly pathogenic H5N1 virus (H5N1) entry is a key target for the development of novel anti-influenza agents with new mechanisms of action. In our continuing efforts to identify novel potential anti-H5N1 entry inhibitors, a series of 3-O-β-chacotriosyl oleanolic acid analogs have been designed, synthesized and evaluated as H5N1 entry inhibitors based on two small molecule inhibitors 1 and 2 previously discovered by us. The anti-H5N1 entry activities were determined based on HA/HIV and VSVG/HIV entry assays. Compound 15 displayed the most promising anti-H5N1 entry activities with average IC50 values of 4.05μM and good selective index (22.9). Detailed structure-activity relationships (SARs) studies suggested that either the introduction of an additional oxo group to position 11 at OA or alteration of the C-3 configuration of OA from 3β- to 3α-forms can significantly enhance the selective index while maintaining their antiviral activities in vitro. Molecular simulation analysis confirmed that the compounds exert their inhibitory activity through binding tightly to hemagglutinin (HA2) protein near the fusion peptide and prevent virus entry.
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.025
  • Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1
           inhibitors using molecular hybridization based on crystallographic
    • Authors: Boshi Huang; Xueshun Wang; Xinhao Liu; Zihui Chen; Wanzhuo Li; Songkai Sun; Huiqing Liu; Dirk Daelemans; Erik De Clercq; Christophe Pannecouque; Peng Zhan; Xinyong Liu
      Pages: 4397 - 4406
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Boshi Huang, Xueshun Wang, Xinhao Liu, Zihui Chen, Wanzhuo Li, Songkai Sun, Huiqing Liu, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
      Crystallographic overlap studies and pharmacophoric analysis indicated that diarylpyrimidine (DAPY)-based HIV-1 NNRTIs showed a similar binding mode and pharmacophoric features as indolylarylsulfones (IASs), another class of potent NNRTIs. Thus, a novel series of DAPY-IAS hybrid derivatives were identified as newer NNRTIs using structure-based molecular hybridization. Some target compounds exhibited moderate activities against HIV-1 IIIB strain, among which the two most potent inhibitors possessed EC50 values of 1.48μM and 1.61μM, respectively. They were much potent than the reference drug ddI (EC50 =76.0μM) and comparable to 3TC (EC50 =2.54μM). Compound 7a also exhibited the favorable selectivity index (SI=80). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships, molecular modeling studies, and in silico calculation of physicochemical properties of these new inhibitors were also discussed.
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.022
  • Phenylsulfonylfuroxan NO-donor phenols: Synthesis and multifunctional
           activities evaluation
    • Authors: Yundong Xie; Yaping Yang; Sen Li; Yanhong Xu; Wenfang Lu; Zizhang Chen; Guangde Yang; Yiping Li; Yongxiao Cao; Xiaoli Bian
      Pages: 4407 - 4413
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Yundong Xie, Yaping Yang, Sen Li, Yanhong Xu, Wenfang Lu, Zizhang Chen, Guangde Yang, Yiping Li, Yongxiao Cao, Xiaoli Bian
      Phenylsulfonyfuroxan nitric oxide (NO)-donor phenols were designed, synthesized and evaluated. The compounds were designed through a symbiotic approach using selected phenols and phenylsulfonylfuroxan NO-donor. The antioxidant activities of the hybrid compounds T2 –T6 showed to be good in vivo. Compounds T4 and T6 revealed excellent yeast α-glucosidase inhibitory activity and anti-glycosylation activity. All of the compounds exhibited strong NO releasing activity and significant anti-platelet aggregation activity. The inhibition of platelet aggregation was more than 50% at low concentration (1.5μM) and 95% at higher concentration (15μM and 150μM). The vasodilatation experiment demonstrated that the six compounds under test exhibited definite vasodilation activity (pIC50 ranged from 5.698 to 6.383), especially compound T6 (pIC50 was 6.383) which was similar to sodium nitroprusside (pIC50 was 6.786). Both anticoagulant and vasodilatation effects were correlated with their NO releasing activities. These hybrid phenylsulfonyfuroxan-based NO-donor phenols offer a multifunctional prodrug design concept for the development of therapeutic or preventive agents for metabolic syndrome.
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.023
  • Design, synthesis, and biological evaluation of some novel indolizine
           derivatives as dual cyclooxygenase and lipoxygenase inhibitor for
           anti-inflammatory activity
    • Authors: Sushant K. Shrivastava; Pavan Srivastava; Robin Bandresh; Prabhash Nath Tripathi; Avanish Tripathi
      Pages: 4424 - 4432
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Sushant K. Shrivastava, Pavan Srivastava, Robin Bandresh, Prabhash Nath Tripathi, Avanish Tripathi
      Some novel indolizine derivatives were synthesized by bioisosteric modification of imidazo[1,2-a]pyridine for anti-inflammatory activity. The physicochemical characterization and structure of compounds were elucidated by state of the art spectroscopic technique. Induced fit docking was performed for initial screening to elucidate the interactions with corresponding amino acids of cyclooxygenase (COX-1, COX-2) and lipoxygenase (LOX) enzymes. The target compounds 53–60 were then evaluated against in vivo carrageenan and arachidonic acid induced rat paw edema models for anti-inflammatory activity. Amongst all the synthesized derivatives, compound 56 showed the significant anti-inflammatory activity in both rat paw edema models with very less ulcerogenic liability in comparison to standard diclofenac, celecoxib, and zileuton. The compounds 56 was further assessed to observe in vitro enzyme inhibition assay on both cyclooxygenase and lipoxygenase enzyme where it showed a preferential and selective non-competitive enzyme inhibition towards the COX-2 (IC50 =14.91μM, Ki=0.72µM) over COX-1 (IC50 >50μM) and a significant non-competitive inhibition of soybean lipoxygenase enzyme (IC50 =13.09μM, Ki=0.92µM). Thus, in silico, in vivo, and in vitro findings suggested that the synthesized indolizine compound 56 has a dual COX-2 and LOX inhibition characteristic and parallel in vivo anti-inflammatory activity in comparison to the standard drugs.
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.027
  • Structure-activity relationship studies on thiaplidiaquinones A and B as
           novel inhibitors of Plasmodium falciparum and farnesyltransferase
    • Authors: Melissa M. Cadelis; Marie-Lise Bourguet-Kondracki; Joëlle Dubois; Marcel Kaiser; Jean Michel Brunel; David Barker; Brent R. Copp
      Pages: 4433 - 4443
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Melissa M. Cadelis, Marie-Lise Bourguet-Kondracki, Joëlle Dubois, Marcel Kaiser, Jean Michel Brunel, David Barker, Brent R. Copp
      Marine meroterpenoids, thiaplidiaquinones A and B and their respective non-natural dioxothiazine regioisomers have been shown to inhibit mammalian and protozoal farnesyltransferase (FTase) with the regioisomers exhibiting activity in the nanomolar range. In order to explore the structure-activity relationship (SAR) of this class of marine natural products, analogues of thiaplidiaquinones A and B and their regioisomers were synthesised, with variation in the number of isoprene units present in their side chains to afford prenyl and farnesyl analogues. The previously reported geranyl series of compounds were found to be the most potent FTase inhibitors closely followed by the novel farnesyl series. The prenyl series exhibited the most potent anti-plasmodial activity but the series was also the most cytotoxic. Overall, the farnesyl series exhibited moderate anti-plasmodial activity with one analogue, 14 also exhibiting low cytotoxicity, identifying it as a scaffold worthy of further exploration.
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.029
  • CRM1 inhibitory and antiproliferative activities of novel 4′-alkyl
           substituted klavuzon derivatives
    • Authors: Tuğçe Kanbur; Murat Kara; Meltem Kutluer; Ayhan Şen; Murat Delman; Aylin Alkan; Hasan Ozan Otaş; İsmail Akçok; Ali Çağır
      Pages: 4444 - 4451
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Tuğçe Kanbur, Murat Kara, Meltem Kutluer, Ayhan Şen, Murat Delman, Aylin Alkan, Hasan Ozan Otaş, İsmail Akçok, Ali Çağır
      Klavuzons are 6-(naphthalen-1-yl) substituted 5,6-dihydro-2H-pyran-2-one derivatives showing promising antiproliferative activities in variety of cancer cell lines. In this work, racemic syntheses of nine novel 4′-alkyl substituted klavuzon derivatives were completed in eight steps and anticancer properties of these compounds were evaluated. It is found that size of the substituent has dramatic effect over the potency and selectivity of the cytotoxic activity in cancerous and healthy pancreatic cell lines. The size of the substituent can also effect the CRM1 inhibitory properties of klavuzon derivatives. Strong cytotoxic activity and CRM1 inhibition can be observed only when a small substituent present at 4′-position of naphthalen-1-yl group. However, these substituents makes the molecule more cytotoxic in healthy pancreatic cells rather than cancerous pancreatic cells. Among the tested compounds 1,2,3,4-tetrahydrophenanthren-9-yl substituted lactone was the most cytotoxic compound and its antiproliferative activity was also tested in 3D spheroids generated from HuH-7 cell lines.
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.030
  • Targeting progesterone metabolism in breast cancer with l-proline derived
           new 14-azasteroids
    • Authors: Jyotsana Singh; Ritesh Singh; Preeti Gupta; Smita Rai; Asha Ganesher; Preethi Badrinarayan; G. Narahari Sastry; Rituraj Konwar; Gautam Panda
      Pages: 4452 - 4463
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Jyotsana Singh, Ritesh Singh, Preeti Gupta, Smita Rai, Asha Ganesher, Preethi Badrinarayan, G. Narahari Sastry, Rituraj Konwar, Gautam Panda
      Breast cancer cell proliferation is promoted by a variety of mitogenic signals. Classically estrogen is considered as most predominant mitogenic signal in hormone-dependent breast cancer and progesterone is primarily considered to have protective effect. However, it is suggested that some progesterone metabolite may promote breast cancer and progesterone metabolites like 5α-pregnane and 4-pregnene could serve as regulators of estrogen-responsiveness of breast cancer cells. Here, we estimated the potential of alternate targeting of breast cancer via progesterone signalling. l-Proline derived novel 14-azasteroid compounds were screened against MCF-7 and MDA-MB-231 cell lines using MTT assay. In silico studies, cell cycle, Annexin-V-FITC/PI, JC-1 mitochondrial assay, ROS analysis were performed to analyse the impact of hit compound 3b on breast cancer cells. Further, we analysed the impact of hit 3b on the progesterone, its metabolites and enzymes responsible for the conversion of progesterone and its metabolites using ELISA. Data suggests that compound 3b binds and down regulates of 5α-reductase by specifically inhibiting production of progesterone metabolites that are capable of promoting breast cancer proliferation, epithelial mesenchymal transition and migration. This study establishes the proof of concept and generation of new leads for additional targeting of breast cancer.
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.031
  • Selective opioid growth factor receptor antagonists based on a stilbene
    • Authors: David P. Stockdale; Michelle B. Titunick; Jessica M. Biegler; Jessie L. Reed; Alyssa M. Hartung; David F. Wiemer; Patricia J. McLaughlin; Jeffrey D. Neighbors
      Pages: 4464 - 4474
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): David P. Stockdale, Michelle B. Titunick, Jessica M. Biegler, Jessie L. Reed, Alyssa M. Hartung, David F. Wiemer, Patricia J. McLaughlin, Jeffrey D. Neighbors
      As part of an ongoing drug development effort aimed at selective opioid receptor ligands based on the pawhuskin natural products we have synthesized a small set of amide isosteres. These amides were centered on lead compounds which are selective antagonists for the delta and kappa opioid receptors. The amide isomers revealed here show dramatically different activity from the parent stilbene compounds. Three of the isomers synthesized showed antagonist activity for the opioid growth factor (OGF)/opioid growth factor receptor (OGFR) axis which is involved in cellular and organ growth control. This cellular signaling mechanism is targeted by “low-dose” naltrexone therapy which is being tested clinically for multiple sclerosis, Crohn’s disease, cancer, and wound healing disorders. The compounds described here are the first selective small molecule ligands for the OGF/OGFR system and will serve as important leads and probes for further study.
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.035
  • Design, synthesis and biological evaluation of novel 4-phenoxyquinoline
           derivatives containing 3-oxo-3,4-dihydroquinoxaline moiety as c-Met kinase
    • Authors: Ju Liu; Di Yang; Xiuxiu Yang; Minhua Nie; Guodong Wu; Zhunchao Wang; Wei Li; Yajing Liu; Ping Gong
      Pages: 4475 - 4486
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Ju Liu, Di Yang, Xiuxiu Yang, Minhua Nie, Guodong Wu, Zhunchao Wang, Wei Li, Yajing Liu, Ping Gong
      A series of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydroquinoxaline moiety were synthesized and evaluated for their c-Met kinase inhibitory activity and antiproliferative activity against five cancer cell lines (HT-29, H460, A549, MKN-45 and U87MG) in vitro. Most of the compounds exhibited moderate-to-significant cytotoxicity as compared with foretinib. The most promising compound 41 (with c-Met IC50 value of 0.90nM) showed remarkable cytotoxicity against HT-29, H460, A549, MKN-45 and U87MG cell lines with IC50 values of 0.06μM, 0.05μM, 0.18μM, 0.023μM and 0.66μM, respectively, and thus it was 1.22- to 3.50-fold more potent than foretinib. Their preliminary structure-activity relationships (SARs) studies indicate that electron-withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity.
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.037
  • Nanoparticle-macrophage interactions: A balance between clearance and
           cell-specific targeting
    • Authors: Rahul Rattan; Somnath Bhattacharjee; Hong Zong; Corban Swain; Muneeb A. Siddiqui; Scott H. Visovatti; Yogendra Kanthi; Sajani Desai; David J. Pinsky; Sascha N. Goonewardena
      Pages: 4487 - 4496
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Rahul Rattan, Somnath Bhattacharjee, Hong Zong, Corban Swain, Muneeb A. Siddiqui, Scott H. Visovatti, Yogendra Kanthi, Sajani Desai, David J. Pinsky, Sascha N. Goonewardena
      The surface properties of nanoparticles (NPs) are a major factor that influences how these nanomaterials interact with biological systems. Interactions between NPs and macrophages of the reticuloendothelial system (RES) can reduce the efficacy of NP diagnostics and therapeutics. Traditionally, to limit NP clearance by the RES system, the NP surface is neutralized with molecules like poly(ethylene glycol) (PEG) which are known to resist protein adsorption and RES clearance. Unfortunately, PEG modification is not without drawbacks including difficulties with the synthesis and associations with immune reactions. To overcome some of these obstacles, we neutralized the NP surface by acetylation and compared this modification to PEGylation for RES clearance and tumor-specific targeting. We found that acetylation was comparable to PEGylation in reducing RES clearance. Additionally, we found that dendrimer acetylation did not impact folic acid (FA)-mediated targeting of tumor cells whereas PEG surface modification reduced the targeting ability of the NP. These results clarify the impact of different NP surface modifications on RES clearance and cell-specific targeting and provide insights into the design of more effective NPs.
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.040
  • Conjugates of salicylaldoximes and peripheral site ligands: Novel
           efficient nonquaternary reactivators for nerve agent-inhibited
    • Authors: Zhao Wei; Yan-qin Liu; Sheng-zheng Wang; Lin Yao; Hui-fang Nie; Yong-an Wang; Xue-Ying Liu; Zhi-bing Zheng; Song Li
      Pages: 4497 - 4505
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Zhao Wei, Yan-qin Liu, Sheng-zheng Wang, Lin Yao, Hui-fang Nie, Yong-an Wang, Xue-Ying Liu, Zhi-bing Zheng, Song Li
      A new family of nonquaternary reactivators for nerve agent-inhibited human acetylcholinesterase (hAChE) were designed, synthesized and tested in this paper. It was found that salicylaldoximes were able to quickly cleave the P–S bond of organophosphate and avoid the reinhibition phenomenon in the reactivation process, but they lacked reactivating ability due to poor affinity for AChE. Based on a dual site binding strategy, different peripheral site ligands of AChE were introduced to achieve extra affinity. The in vitro reactivation experiments demonstrated that some of the yielding conjugates exhibited similar or even superior ability to reactivate sarin-, VX- or tabun-inhibited hAChE in comparison with the mono- and bis-pyridinium aldoximes currently used. Moreover, due to greatly improved lipophilicity, these nonquaternary conjugates hold promise for the development of efficient centrally activating reactivators.
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.041
  • Stable C–N axial chirality in 1-aryluracil scaffold and differences in
           in vitro metabolic clearance between atropisomers of PDE4 inhibitor
    • Authors: Futoshi Hasegawa; Kazushi Kawamura; Hiroshi Tsuchikawa; Michio Murata
      Pages: 4506 - 4511
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Futoshi Hasegawa, Kazushi Kawamura, Hiroshi Tsuchikawa, Michio Murata
      We report herein the stable C–N axial chirality in a 1-phenyl-6-aminouracil scaffold owing to the presence of various functional groups at the ortho-position of the N(1)-phenyl group. Racemic 1-phenyl-6-aminouracils were first separated by chiral HPLC or converting them to the corresponding diastereomers using a chiral resolving agent. We then determined the rotational barrier of each atropisomer by a thermal racemization method and found that these compounds have rotational barriers similar to other C–N axially chiral biaryls. In addition, there was a good correlation between the rotational barriers and van der Waals radii of an ortho-substituent of the N(1)-phenyl group. To explore the possibility of the chiral 1-phenyl-6-aminouracil scaffold as a drug lead, we synthesized both atropisomers as phosphodiesterase-4 inhibitors 10. The atropisomers showed significantly different metabolic stabilities while their PDE4 inhibitory activities were somewhat similar. This finding demonstrates the potential utility of stable C–N bond atropisomers in the development of chiral drugs.
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.042
  • Design and synthesis of potent and orally active GPR4 antagonists with
           modulatory effects on nociception, inflammation, and angiogenesis
    • Authors: Wolfgang Miltz; Juraj Velcicky; Janet Dawson; Amanda Littlewood-Evans; Marie-Gabrielle Ludwig; Klaus Seuwen; Roland Feifel; Berndt Oberhauser; Arndt Meyer; Daniela Gabriel; Mark Nash; Pius Loetscher
      Pages: 4512 - 4525
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Wolfgang Miltz, Juraj Velcicky, Janet Dawson, Amanda Littlewood-Evans, Marie-Gabrielle Ludwig, Klaus Seuwen, Roland Feifel, Berndt Oberhauser, Arndt Meyer, Daniela Gabriel, Mark Nash, Pius Loetscher
      GPR4, a G-protein coupled receptor, functions as a proton sensor being activated by extracellular acidic pH and has been implicated in playing a key role in acidosis associated with a variety of inflammatory conditions. An orally active GPR4 antagonist 39c was developed, starting from a high throughput screening hit 1. The compound shows potent cellular activity and is efficacious in animal models of angiogenesis, inflammation and pain.
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.050
  • Bistacrines as potential antitrypanosomal agents
    • Authors: Ines Schmidt; Sarah Göllner; Antje Fuß; August Stich; Anna Kucharski; Tanja Schirmeister; Elena Katzowitsch; Heike Bruhn; Alexandra Miliu; R. Luise Krauth-Siegel; Ulrike Holzgrabe
      Pages: 4526 - 4531
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Ines Schmidt, Sarah Göllner, Antje Fuß, August Stich, Anna Kucharski, Tanja Schirmeister, Elena Katzowitsch, Heike Bruhn, Alexandra Miliu, R. Luise Krauth-Siegel, Ulrike Holzgrabe
      Human African Trypanosomiasis (HAT) is caused by two subspecies of the genus Trypanosoma, namely Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. The disease is fatal if left untreated and therapy is limited due to only five non-adequate drugs currently available. In preliminary studies, dimeric tacrine derivatives were found to inhibit parasite growth with IC50-values in the nanomolar concentration range. This prompted the synthesis of a small, but smart library of monomeric and dimeric tacrine-type compounds and their evaluation of antiprotozoal activity. Rhodesain, a lysosomal cathepsin-L like cysteine protease of T. brucei rhodesiense is essential for parasite survival and likely target of the tacrine derivatives. In addition, the inhibition of trypanothione reductase by bistacrines was found. This flavoprotein oxidoreductase is the main defense against oxidative stress in the thiol redox system unique for protozoa.
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      PubDate: 2017-07-20T22:26:29Z
      DOI: 10.1016/j.bmc.2017.06.051
  • Application of in-vitro screening methods on hypoxia inducible factor
           prolyl hydroxylase inhibitors
    • Authors: Yue Wu; Zhensheng Jiang; Qidong You; Xiaojin Zhang
      Pages: 3891 - 3899
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
      Author(s): Yue Wu, Zhensheng Jiang, Qidong You, Xiaojin Zhang
      Anemia resulting from the reduced expression of erythropoietin (EPO) is a common complication of patients with chronic kidney diseases (CKD). Hypoxia inducible transcription factor-α (HIF-α), which adapts cellular hypoxia condition, regulates the expression of many downstream genes including the EPO gene. Hypoxia inducible transcription factor prolyl hydroxylase 2 (HIF-PHD2), as the key regulator of hypoxia response, is function of hydroxylating specify proline residues of HIF-α, which may lead to the degradation of HIF-α and eventually cause disenabling the expression of erythropoietin. Therefore, it is valid to improve anemia by inhibiting HIF-PHD2. In-vitro screening plays a vital role in searching for novel small molecule HIF-PHD2 inhibitors, thus, this review classified in-vitro screening methods which are used to hit novel HIF-PHD2 inhibitors.
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      PubDate: 2017-07-08T09:08:14Z
      DOI: 10.1016/j.bmc.2017.05.026
  • The selective cytotoxicity of new triazene compounds to human melanoma
    • Authors: Ana Sousa; Fábio Santos; Maria Manuela Gaspar; Susana Calado; João D. Pereira; Eduarda Mendes; Ana Paula Francisco; Maria Jesus Perry
      Pages: 3900 - 3910
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
      Author(s): Ana Sousa, Fábio Santos, Maria Manuela Gaspar, Susana Calado, João D. Pereira, Eduarda Mendes, Ana Paula Francisco, Maria Jesus Perry
      Metastatic melanoma still remains one the most difficult cancers to overcome. The aim of our research was the design of anti-tumour triazene compounds 3 for application to a melanoma-specific therapy. The strategy exploits the unique enzyme pathway of melanin biosynthesis for conversion of non-toxic prodrugs into toxic drugs in the melanoma cell. The compounds 3 were designed by coupling two active moieties, the alkylating triazenes and different tyrosinase substrates. All compounds 3 revealed to be chemically stable in isotonic phosphate buffer (PBS) at physiologic pH (t½ ≥48h), and most of them showed to be slowly hydrolysed in human plasma (1.5≤t½ (h)≤161). Compounds 3c–n revealed to be excellent tyrosinase substrates (0.74≤t½ (min)≤6) with the best tyrosinase substrate 3l releasing MMT 45s after tyrosinase activation. Structure-activity relationship studies allowed the identification of the better structural features for enzyme affinity. Furthermore, the derivatives 3l and 3m showed cell selectivity with significant cytotoxic effects (IC50 values of 46–65μM) against melanoma cell lines with tyrosinase overexpression MNT-1 and B16F10.
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      PubDate: 2017-07-08T09:08:14Z
      DOI: 10.1016/j.bmc.2017.04.049
  • The tobacco cembranoid (1S,2E,4S,7E,11E)-2,7,11-cembratriene-4,6-diol as a
    • Authors: Mohammad M. Hailat; Hassan Y. Ebrahim; Mohamed M. Mohyeldin; Amira A. Goda; Abu Bakar Siddique; Khalid A. El Sayed
      Pages: 3911 - 3921
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
      Author(s): Mohammad M. Hailat, Hassan Y. Ebrahim, Mohamed M. Mohyeldin, Amira A. Goda, Abu Bakar Siddique, Khalid A. El Sayed
      (1S,2E,4 S,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (1) and its 4-epi-analog (2) are diterpene precursors of the key flavor components in most Nicotiana (tobacco) species that purposely degraded during commercial tobacco fermentation. Angiogenesis, recruitment of new blood vessels, is important for tumor growth, survival and metastasis that can be targeted to control cancer. This study shows evidences and potential of the cembranoid 1 as a potent angiogenesis modulator through targeting VEGFR2. In silico study suggested favorable docking scores and binding affinity of 1 at the ATP binding pocket of VEGFR2. The binding mode of 1 was parallel to the standard FDA-approved antiangiogenic drug sunitinib (4). In vitro, cembranoid 1 significantly reduced the activated VEGFR2 levels in multiple breast cancer cell lines. Intraperitoneal 40mg/kg, 3X/week treatment of 1 significantly reduced the MDA-MB-231 cells breast tumor size in mice. Immunohistochemistry and Western blotting analysis of the treated mice tumors showed significant downregulation of the vasculogenesis marker CD31 and suppressed activated VEGFR2-paxillin-FAK pathway. Matrigel study in Swiss albino mice showed similar trend. The tobacco cembranoid 1 is a potential antiangiogenic lead useful for future use to control breast malignancies.
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      PubDate: 2017-07-08T09:08:14Z
      DOI: 10.1016/j.bmc.2017.05.028
  • The synthesis and evaluation of triazolopyrimidines as anti-tubercular
    • Authors: Edison S. Zuniga; Aaron Korkegian; Steven Mullen; Erik J. Hembre; Paul L. Ornstein; Guillermo Cortez; Kallolmay Biswas; Naresh Kumar; Jeffrey Cramer; Thierry Masquelin; Philip A. Hipskind; Joshua Odingo; Tanya Parish
      Pages: 3922 - 3946
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
      Author(s): Edison S. Zuniga, Aaron Korkegian, Steven Mullen, Erik J. Hembre, Paul L. Ornstein, Guillermo Cortez, Kallolmay Biswas, Naresh Kumar, Jeffrey Cramer, Thierry Masquelin, Philip A. Hipskind, Joshua Odingo, Tanya Parish
      We identified a di-substituted triazolopyrimidine with anti-tubercular activity against Mycobacterium tuberculosis. Three segments of the scaffold were examined rationally to establish a structure-activity relationship with the goal of improving potency and maintaining good physicochemical properties. A number of compounds displayed sub-micromolar activity against Mycobacterium tuberculosis with no cytotoxicity against eukaryotic cells. Non-substituted aromatic rings at C5 and a two-carbon chain connecting a terminal aromatic at C7 were preferred features; the presence of NH at C7 and a lack of substituent at C2 were essential for potency. We identified compounds with acceptable metabolic stability in rodent and human liver microsomes. Our findings suggest that the easily-synthesized triazolopyrimidines are a promising class of potent anti-tubercular agents and warrant further investigation in our search for new drugs to fight tuberculosis.
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      PubDate: 2017-07-08T09:08:14Z
      DOI: 10.1016/j.bmc.2017.05.030
  • Design, synthesis and biological evaluation of renin inhibitors guided by
           simulated annealing of chemical potential simulations
    • Authors: Ian S. Cloudsdale; John K. Dickson; Thomas E. Barta; Brian S. Grella; Emilie D. Smith; John L. Kulp; Frank Guarnieri; John L. Kulp
      Pages: 3947 - 3963
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
      Author(s): Ian S. Cloudsdale, John K. Dickson, Thomas E. Barta, Brian S. Grella, Emilie D. Smith, John L. Kulp, Frank Guarnieri, John L. Kulp
      We have applied simulated annealing of chemical potential (SACP) to a diverse set of ∼150 very small molecules to provide insights into new interactions in the binding pocket of human renin, a historically difficult target for which to find low molecular weight (MW) inhibitors with good bioavailability. In one of its many uses in drug discovery, SACP provides an efficient, thermodynamically principled method of ranking chemotype replacements for scaffold hopping and manipulating physicochemical characteristics for drug development. We introduce the use of Constrained Fragment Analysis (CFA) to construct and analyze ligands composed of linking those fragments with predicted high affinity. This technique addresses the issue of effectively linking fragments together and provides a predictive mechanism to rank order prospective inhibitors for synthesis. The application of these techniques to the identification of novel inhibitors of human renin is described. Synthesis of a limited set of designed compounds provided potent, low MW analogs (IC50s<100nM) with good oral bioavailability (F>20–58%).
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      PubDate: 2017-07-08T09:08:14Z
      DOI: 10.1016/j.bmc.2017.05.032
  • BACE1 inhibitory activity and molecular docking analysis of meroterpenoids
           from Sargassum serratifolium
    • Authors: Su Hui Seong; Md Yousof Ali; Hyeung-Rak Kim; Hyun Ah Jung; Jae Sue Choi
      Pages: 3964 - 3970
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
      Author(s): Su Hui Seong, Md Yousof Ali, Hyeung-Rak Kim, Hyun Ah Jung, Jae Sue Choi
      A wide range of pharmacological properties of Sargassum spp. extracts and isolated components have been recognized. Although individual meroterpenoids of Sargassum species have been reported to possess strong activity against Alzheimer’s disease (AD), the active compounds of Sargassum serratifolium have not been fully explored. Therefore, we evaluated the anti-AD activity of S. serratifolium extract through enzyme inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1). Three meroterpenoids (sargahydroquinoic acid (1), sargachromenol (2) and sargaquinoic acid (3)) were isolated from S. serratifolium. These compounds showed moderate AChE inhibitory activity, but exhibited potent inhibitory activity against BChE and BACE1 (15.1, 9.4, and 10.4µM for BChE; 4.3, 6.9, and 12.5µM for BACE1, respectively). Kinetic study and molecular docking simulation of these compounds demonstrated that 1 and 3 interacted with both catalytic aspartyl residues and allosteric sites of BACE1, whereas 2 interacted with the allosteric site of BACE1. The results of the present study demonstrate that meroterpenoids from S. serratifolium might be beneficial in the treatment of AD.
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      PubDate: 2017-07-08T09:08:14Z
      DOI: 10.1016/j.bmc.2017.05.033
  • Novel pyridyl nitrofuranyl isoxazolines show antibacterial activity
           against multiple drug resistant Staphylococcus species
    • Authors: Pietro Picconi; Priya Prabaharan; Jennifer L. Auer; Stephanie Sandiford; Francesco Cascio; Madiha Chowdhury; Charlotte Hind; Matthew E. Wand; J. Mark Sutton; Khondaker M. Rahman
      Pages: 3971 - 3979
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
      Author(s): Pietro Picconi, Priya Prabaharan, Jennifer L. Auer, Stephanie Sandiford, Francesco Cascio, Madiha Chowdhury, Charlotte Hind, Matthew E. Wand, J. Mark Sutton, Khondaker M. Rahman
      A novel series of pyridyl nitrofuranyl isoxazolines were synthesized and evaluated for their antibacterial activity against multiple drug resistant (MDR) Staphylococcus strains. Compounds with piperazine linker between the pyridyl group and isoxazoline ring showed better activity when compared to compounds without the piperazine linker. 3-Pyridyl nitrofuranyl isoxazoline with a piperazine linker was found to be more active than corresponding 2-and 4-pyridyl analogues with MICs in the range of 4–32µg/mL against MDR Staphylococcus strains. The eukaryotic toxicity of the compounds was tested by MTT assay and were found to be non-toxic against both non-tumour lung fibroblast WI-38 and cervical cancer cell line HeLa. The most active pyridyl nitrofuranyl isoxazoline compound showed improved activity against a panel of Staphylococcus strains compared to nitrofuran group containing antibiotic nitrofurantoin.
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      PubDate: 2017-07-08T09:08:14Z
      DOI: 10.1016/j.bmc.2017.05.037
  • Synthesis, docking study and neuroprotective effects of some novel
           pyrano[3,2-c]chromene derivatives bearing morpholine/phenylpiperazine
    • Authors: Bilqees Sameem; Mina Saeedi; Mohammad Mahdavi; Hamid Nadri; Farshad Homayouni Moghadam; Najmeh Edraki; Muhammad Imran Khan; Mohsen Amini
      Pages: 3980 - 3988
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
      Author(s): Bilqees Sameem, Mina Saeedi, Mohammad Mahdavi, Hamid Nadri, Farshad Homayouni Moghadam, Najmeh Edraki, Muhammad Imran Khan, Mohsen Amini
      Novel pyrano[3,2-c]chromene derivatives bearing morpholine/phenylpiperazine moiety were synthesized and evaluated against acetylcholinestrase (AChE) and butylcholinestrase (BuChE). Among the synthesized compounds, N-(3-cyano-4-(4-methoxyphenyl)-5-oxo-4,5-dihydropyrano[3,2-c]chromen-2-yl)-2-(4-phenylpiperazin-1-yl)acetamide (6c) exhibited the highest acetylcholinestrase inhibitory (AChEI) activity (IC50 =1.12µM) and most of them showed moderate butylcholinestrase inhibitory activity (BChEI). Kinetic study of compound 6c confirmed mixed type of inhibition towards AChE which was in covenant with the results obtained from docking study. Also, it was evaluated against β-secretase which demonstrated low activity (inhibition percentage: 18%). It should be noted that compounds 6c, 7b, 6g, and 7d showed significant neuroprotective effects against H2O2-induced PC12 oxidative stress.
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      PubDate: 2017-07-08T09:08:14Z
      DOI: 10.1016/j.bmc.2017.05.043
  • Design, synthesis and biological evaluation of sulfonamide-substituted
           diphenylpyrimidine derivatives (Sul-DPPYs) as potent focal adhesion kinase
           (FAK) inhibitors with antitumor activity
    • Authors: Menghua Qu; Zhihao Liu; Dan Zhao; Changyuan Wang; Jianbin Zhang; Zeyao Tang; Kexin Liu; Xiaohong Shu; Hong Yuan; Xiaodong Ma
      Pages: 3989 - 3996
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
      Author(s): Menghua Qu, Zhihao Liu, Dan Zhao, Changyuan Wang, Jianbin Zhang, Zeyao Tang, Kexin Liu, Xiaohong Shu, Hong Yuan, Xiaodong Ma
      A class of sulfonamide-substituted diphenylpyrimidines (Sul-DPPYs) were synthesized to improve activity against the focal adhesion kinase (FAK). Most of these new Sul-DPPYs displayed moderate activity against the FAK enzyme with IC50 values of less than 100nM; regardless, they could effectively inhibit several classes of refractory cancer cell lines with IC50 values of less than 10µM, including the pancreatic cancer cell lines (AsPC-1, Panc-1 and BxPC-3), the NSCLC-resistant H1975 cell line, and the B lymphocyte cell line (Ramos cells). Results of flow cytometry indicated that inhibitor 7e promoted apoptosis of pancreatic cancer cells in a dose-dependent manner. In addition, it almost completely induced the apoptosis at a concentration of 10µM. Compound 7e may be selected as a potent FAK inhibitor for the treatment of pancreatic cancer.
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      PubDate: 2017-07-08T09:08:14Z
      DOI: 10.1016/j.bmc.2017.05.044
  • Synthesis, molecular docking, and biological activity of polyfluoroalkyl
           dihydroazolo[5,1-c][1,2,4]triazines as selective carboxylesterase
    • Authors: Evgeny V. Shchegol'kov; Galina F. Makhaeva; Natalia P. Boltneva; Sofya V. Lushchekina; Olga G. Serebryakova; Elena V. Rudakova; Nadezhda V. Kovaleva; Yanina V. Burgart; Victor I. Saloutin; Oleg N. Chupakhin; Sergey O. Bachurin; Rudy J. Richardson
      Pages: 3997 - 4007
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
      Author(s): Evgeny V. Shchegol'kov, Galina F. Makhaeva, Natalia P. Boltneva, Sofya V. Lushchekina, Olga G. Serebryakova, Elena V. Rudakova, Nadezhda V. Kovaleva, Yanina V. Burgart, Victor I. Saloutin, Oleg N. Chupakhin, Sergey O. Bachurin, Rudy J. Richardson
      To search for effective and selective inhibitors of carboxylesterase (CaE), a series of 7-hydroxy-7-polyfluoroalkyl-4,7-dihydroazolo[5,1-c][1,2,4]triazines has been synthesized. Their inhibitory activity against acetylcholinesterase, butyrylcholinesterase, and CaE were investigated using the methods of enzyme kinetics and molecular docking. It was shown that the tested compounds are reversible selective CaE inhibitors of mixed type. Elongation of the polyfluoroalkyl substituent and the presence of an ester, preferably the ethoxycarbonyl group, enhance inhibitory activity toward CaE. Furthermore, the compounds with a tetrazole ring are more active against CaE than their triazole analogues. The obtained kinetic data are well explained by the results of molecular docking, according to which there is a similar orientation of triazolo- and tetrazolotriazines in the active site of CaE and the opposite one for pyrazolotriazines. In the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) assay, all of the studied tetrazolotriazines and some pyrazolotriazines demonstrated good antiradical activity comparable with a standard antioxidant, Trolox. The leading compounds were nonafluorobutyl substituted tetrazolo- and 7-phenylpyrazolotriazines, which possess effective and selective CaE inhibitory activity as well as additional useful radical-scavenging properties.
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      PubDate: 2017-07-08T09:08:14Z
      DOI: 10.1016/j.bmc.2017.05.045
  • Synthesis and evaluation of symmetric acyclic nucleoside bisphosphonates
           as inhibitors of the Plasmodium falciparum, Plasmodium vivax and human
           6-oxopurine phosphoribosyltransferases and the antimalarial activity of
           their prodrugs
    • Authors: Petr Špaček; Dianne T. Keough; Marina Chavchich; Martin Dračínský; Zlatko Janeba; Lieve Naesens; Michael D. Edstein; Luke W. Guddat; Dana Hocková
      Pages: 4008 - 4030
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
      Author(s): Petr Špaček, Dianne T. Keough, Marina Chavchich, Martin Dračínský, Zlatko Janeba, Lieve Naesens, Michael D. Edstein, Luke W. Guddat, Dana Hocková
      Two new series of symmetric acyclic nucleoside bisphosphonates (ANbPs) have been synthesised as potential inhibitors of the Plasmodium falciparum (Pf) and vivax (Pv) 6-oxopurine phosphoribosyltransferases. The structural variability between these symmetric ANbPs lies in the number of atoms in the two acyclic linkers connecting the N9 atom of the purine base to each of two phosphonate groups and the branching point of the acyclic moiety relative to the purine base, which occurs at either the alpha or beta positions. Within each series, six different 6-oxopurine bases have been attached. In general, the ANbPs with either guanine or hypoxanthine have lower Ki values than for those containing either the 8-bromo or 7-deaza 6-oxopurine bases. The lowest Ki values obtained for the two parasite enzymes were 0.1μM (Pf) and 0.2μM (Pv) for this series of compounds. Two phosphoramidate prodrugs of these inhibitors exhibited antimalarial activity against Pf in infected erythrocyte cell culture with IC50 values of 0.8 and 1.5μM. These two compounds exhibited low cytotoxicity in human A549 cells having CC50 values of >300μM resulting in an excellent selectivity index.
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      PubDate: 2017-07-08T09:08:14Z
      DOI: 10.1016/j.bmc.2017.05.048
  • Synthesis and biological activity of peptide proline-boronic acids as
           proteasome inhibitors
    • Authors: Liqiang Han; Yanzhao Wen; Ridong Li; Bo Xu; Zemei Ge; Xin Wang; Tieming Cheng; Jingrong Cui; Runtao Li
      Pages: 4031 - 4044
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
      Author(s): Liqiang Han, Yanzhao Wen, Ridong Li, Bo Xu, Zemei Ge, Xin Wang, Tieming Cheng, Jingrong Cui, Runtao Li
      On the basis of the application of proline-boronic acid as pharmacophore in the kinase inhibitors and our previous research results, using proline-boronic acid as warhead, two series of peptide proline-boronic acids, dipeptide proline-boronic acids (I) and tripeptide proline-boronic acids (II), were designed and synthesized. All the synthesized compounds were first evaluated for their biological activity against MGC803 cell, and then, the best compound II-7 was selected to test its anti-tumor spectrum on six human tumor cell lines and proteasome inhibition against three subunits. The results indicated that series II have much better biological activities than series I. The compound II-7 exhibited not only excellent biological activities with IC50 values of nM level in both cell and proteasome models, but also much better subunit selectivity. Thus, proline-boronic acid as warhead is reasonable in the design of proteasome inhibitors.
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      PubDate: 2017-07-08T09:08:14Z
      DOI: 10.1016/j.bmc.2017.05.049
  • Discovery of novel quinazoline-2,4(1H,3H)-dione derivatives as potent
           PARP-2 selective inhibitors
    • Authors: Hailong Zhao; Ming Ji; Guonan Cui; Jie Zhou; Fangfang Lai; Xiaoguang Chen; Bailing Xu
      Pages: 4045 - 4054
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
      Author(s): Hailong Zhao, Ming Ji, Guonan Cui, Jie Zhou, Fangfang Lai, Xiaoguang Chen, Bailing Xu
      The PARP-2 selective inhibitor is important for clarifying specific roles of PARP-2 in the pathophysiological process and developing desired drugs with reduced off-target side effects. In this work, a series of novel quinazoline-2,4(1H,3H)-dione derivatives was designed and synthesized to explore isoform selective PARP inhibitors. As a result, compound 11a (PARP-1 IC50 =467nM, PARP-2 IC50 =11.5nM, selectivity PARP-1/PARP-2=40.6) was disclosed as the most selective PARP-2 inhibitor with high potency to date. The binding features of compound 11a within PARP-1 and PARP-2 were investigated respectively to provide useful insights for the further construction of new isoform selective inhibitors of PARP-1 and PARP-2 by using CDOCKER program.
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      PubDate: 2017-07-08T09:08:14Z
      DOI: 10.1016/j.bmc.2017.05.052
  • Synthesis, antiviral evaluation and molecular docking studies of N4-aryl
           substituted/unsubstituted thiosemicarbazones derived from 1-indanones as
           potent anti-bovine viral diarrhea virus agents
    • Authors: María C. Soraires Santacruz; Matías Fabiani; Eliana F. Castro; Lucía V. Cavallaro; Liliana M. Finkielsztein
      Pages: 4055 - 4063
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
      Author(s): María C. Soraires Santacruz, Matías Fabiani, Eliana F. Castro, Lucía V. Cavallaro, Liliana M. Finkielsztein
      A series of N 4-arylsubstituted thiosemicarbazones derived from 1-indanones and a set of compounds lacking such substitution in the N 4 position of the thiosemicarbazone moiety were synthesized and evaluated for their anti-bovine viral diarrhea virus (BVDV) activity. Among these, derivatives 2 and 15 displayed high activity (EC50 =2.7±0.4 and 0.7±0.1µM, respectively) as inhibitors of BVDV replication. Novel key structural features related to the anti-BVDV activity were identified by structure-activity relationship (SAR) analysis. In a previous study, the thiosemicarbazone of 5,6-dimethoxy-1-indanone (5,6-TSC) was characterized as a non-nucleoside inhibitor (NNI) of the BVDV RNA-dependent RNA polymerase. In the present work, cross-resistance assays were performed with the most active compounds. Such studies were carried out on 5,6-TSC resistant BVDV (BVDV-TSCr T1) carrying mutations in the viral polymerase. This BVDV mutant was also resistant to compound 15. Molecular docking studies and MM/PBSA calculations were performed to assess the most active derivatives at the 5,6-TSC viral polymerase binding site. The differences in the interaction pattern and the binding affinity of derivative 15 either to the wild type or BVDV-TSCr T1 polymerase were key factors to define the mode of action of this compound.
      Graphical abstract image

      PubDate: 2017-07-08T09:08:14Z
      DOI: 10.1016/j.bmc.2017.05.056
  • 1,2,4-Triazole and 1,3,4-oxadiazole analogues: Synthesis, MO studies, in
           silico molecular docking studies, antimalarial as DHFR inhibitor and
           antimicrobial activities
    • Authors: Sampark S. Thakkar; Parth Thakor; Hiren Doshi; Arabinda Ray
      Pages: 4064 - 4075
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
      Author(s): Sampark S. Thakkar, Parth Thakor, Hiren Doshi, Arabinda Ray
      1,2,4-Triazole and 1,3,4-oxadiazole analogues are of interest due to their potential activity against microbial and malarial infections. In search of suitable antimicrobial and antimalarial compounds, we report here the synthesis, characterization and biological activities of 1,2,4-triazole and 1,3,4-oxadiazole analogues (SS 1-SS 10). The molecules were characterized by IR, mass, 1H NMR, 13C NMR and elemental analysis. The in vitro antimicrobial activity was investigated against pathogenic strains, the results were explained with the help of DFT and PM6 molecular orbital calculations. In vitro cytotoxicity and genotoxicity of the molecules were studied against S. pombe cells. In vitro antimalarial activity was studied. The active compounds were further evaluated for enzyme inhibition efficacy against the receptor Pf-DHFR computationally as well as in vitro to prove their candidature as lead dihydrofolate reductase inhibitors.
      Graphical abstract image

      PubDate: 2017-07-08T09:08:14Z
      DOI: 10.1016/j.bmc.2017.05.054
  • Synthesis, molecular modelling and CYP24A1 inhibitory activity of novel of
    • Authors: Ismail M. Taban; Jinge Zhu; Hector F. DeLuca; Claire Simons
      Pages: 4076 - 4087
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
      Author(s): Ismail M. Taban, Jinge Zhu, Hector F. DeLuca, Claire Simons
      CYP24A1 (25-hydroxyvitamin D-24-hydroxylase) is a useful enzyme target for a range of medical conditions including cancer, cardiovascular and autoimmune disease, which show elevated CYP24A1 levels and corresponding reduction of calcitriol (the biologically active form of vitamin D). A series of (E)-N-(2-(1H-imidazol-1-yl)-2-(phenylethyl)-3/4-styrylbenzamides have been synthesised using an efficient synthetic route and shown to be potent inhibitors of CYP24A1 (IC50 0.11–0.35μM) compared with the standard ketoconazole. Molecular modelling using our CYP24A1 homology model showed the inhibitors to fill the hydrophobic binding site, forming key transition metal interaction between the imidazole nitrogen and the haem Fe3+ and multiple interactions with the active site amino acid residues.
      Graphical abstract image

      PubDate: 2017-07-08T09:08:14Z
      DOI: 10.1016/j.bmc.2017.05.055
  • Synthesis, biological evaluation and molecular modeling of
           imidazo[1,2-a]pyridine derivatives as potent antitubulin agents
    • Authors: Jin Liu; Daiying Zuo; Tongfei Jing; Ming Guo; Lingyun Xing; Wenyu Zhang; Jianwen Zhao; Jiwei Shen; Ping Gong; Dajun Zhang; Xin Zhai
      Pages: 4088 - 4099
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
      Author(s): Jin Liu, Daiying Zuo, Tongfei Jing, Ming Guo, Lingyun Xing, Wenyu Zhang, Jianwen Zhao, Jiwei Shen, Ping Gong, Dajun Zhang, Xin Zhai
      Two series of novel 5,7-diarylimidazo[1,2-a]pyridine-8-carbonitrile derivatives (3a–3q and 7a–7n) were designed by modification of CA-4 pharmacophore to develop colchicine targeted antitubulin agents. All compounds were efficiently synthesized and evaluated for their cytotoxicity against five selected cancer cell lines (HT-29, H460, A549, MKN-45 and SMMC-7721) which got an insight in structure and activity relationships (SARs). Several molecules (7e, 7f, 7h–7j and 7m) were disclosed to exhibit promising antiproliferative activity with IC50 values in double-digit nanomolar degree. Optimization toward these compounds led to the discovery of a promising lead 7e, which showed noteworthy potency with IC50 value ranging from 0.01 to 3.2µM superior to CA-4 and Crolibulin. Importantly, immunofluorescence staining and colchcine competitive binding assay revealed that microtubule dynamics was disrupted by 7e by binding at the colchicine site of tubulin. Moreover, molecular docking studies suggested the binding of this mimic at colchcine-binding site is similar to Crolibulin, as was in conformity with the observed SARs for these compounds.
      Graphical abstract image

      PubDate: 2017-07-08T09:08:14Z
      DOI: 10.1016/j.bmc.2017.05.057
  • Olaparib hydroxamic acid derivatives as dual PARP and HDAC inhibitors for
           cancer therapy
    • Authors: Zigao Yuan; Shaopeng Chen; Qinsheng Sun; Ning Wang; Dan Li; Shuangshuang Miao; Chunmei Gao; Yuzong Chen; Chunyan Tan; Yuyang Jiang
      Pages: 4100 - 4109
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
      Author(s): Zigao Yuan, Shaopeng Chen, Qinsheng Sun, Ning Wang, Dan Li, Shuangshuang Miao, Chunmei Gao, Yuzong Chen, Chunyan Tan, Yuyang Jiang
      Olaparib was the first PARP inhibitor approved by the FDA for patients with BRCA-mutated ovarian cancer. Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of olaparib and HDAC inhibitors. Herein, based on rational drug design strategy, hydroxamic acid derivatives of olaparib were constructed as dual PARP and HDAC inhibitors. These hybrid compounds showed potent inhibitory activities against PARP1/2 and HDAC1/6 with IC50 values in the nanomolar range. Furthermore, compound P1 exhibited broad-spectrum antiproliferative activities in selected human cancer cell lines. Specially, P1 showed more potent activity than olaparib and SAHA in cancer cells MDA-MB-231, HCC1937 and Raji, and 4.1-fold less cytotoxicity compared with SAHA to normal cells MCF-10A. Further mechanism study indicated that P1 could induce the cleavage of PARP and the hyperacetylation of histones, increase the expression of DNA damage biomarker γ-H2AX, decrease the level of BRCA1 and RAD51, and regulate tumor cell growth and apoptosis through modulating both mitochondrial- and death receptor-mediated pathways. Therefore, our study suggested that compounds targeting PARP and HDAC concurrently might be a practical approach for cancer therapy.
      Graphical abstract image

      PubDate: 2017-07-08T09:08:14Z
      DOI: 10.1016/j.bmc.2017.05.058
  • Structure-activity relationship studies of G9a-like protein (GLP)
    • Authors: Yan Xiong; Fengling Nicolas Babault Hong Aiping Dong Hong Zeng
      Abstract: Publication date: 15 August 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
      Author(s): Yan Xiong, Fengling Li, Nicolas Babault, Hong Wu, Aiping Dong, Hong Zeng, Xin Chen, Cheryl H. Arrowsmith, Peter J. Brown, Jing Liu, Masoud Vedadi, Jian Jin
      Given the high homology between the protein lysine methyltransferases G9a-like protein (GLP) and G9a, it has been challenging to develop potent and selective inhibitors for either enzyme. Recently, we reported two quinazoline compounds, MS0124 and MS012, as GLP selective inhibitors. To further investigate the structure–activity relationships (SAR) of the quinazoline scaffold, we designed and synthesized a range of analogs bearing different 2-amino substitutions and evaluated their inhibition potencies against both GLP and G9a. These studies led to the identification of two new GLP selective inhibitors, 13 (MS3748) and 17 (MS3745), with 59- and 65-fold higher potency for GLP over G9a, which were confirmed by isothermal titration calorimetry (ITC). Crystal structures of GLP and G9a in complex with 13 and 17 provide insight into the interactions of the inhibitors with both proteins. In addition, we generated GLP selective inhibitors bearing a quinoline core instead of the quinazoline core.
      Graphical abstract image

      PubDate: 2017-07-20T22:26:29Z
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