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  Subjects -> CHEMISTRY (Total: 846 journals)
    - ANALYTICAL CHEMISTRY (50 journals)
    - CHEMISTRY (597 journals)
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CHEMISTRY (597 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 7)
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: 31)
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: 22)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 39)
ACS Nano     Full-text available via subscription   (Followers: 217)
ACS Photonics     Full-text available via subscription   (Followers: 10)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 20)
Acta Chemica Iasi     Open Access   (Followers: 2)
Acta Chimica Sinica     Full-text available via subscription  
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: 48)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 53)
Advances in Chemical Science     Open Access   (Followers: 12)
Advances in Chemistry     Open Access   (Followers: 12)
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: 10)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 14)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 18)
Advances in Nanoparticles     Open Access   (Followers: 12)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15)
Advances in Polymer Science     Hybrid Journal   (Followers: 40)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 18)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Science and Technology     Full-text available via subscription   (Followers: 10)
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: 65)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 14)
American Journal of Chemistry     Open Access   (Followers: 25)
American Journal of Plant Physiology     Open Access   (Followers: 13)
American Mineralogist     Full-text available via subscription   (Followers: 12)
Analyst     Full-text available via subscription   (Followers: 38)
Angewandte Chemie     Hybrid Journal   (Followers: 153)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 203)
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: 7)
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: 6)
Applied Spectroscopy     Full-text available via subscription   (Followers: 22)
Applied Surface Science     Hybrid Journal   (Followers: 26)
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: 9)
Biochemistry     Full-text available via subscription   (Followers: 278)
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: 3)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access  
Biomacromolecules     Full-text available via subscription   (Followers: 18)
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: 107)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 99)
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: 2)
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 2)
Canadian Journal of Chemistry     Full-text available via subscription   (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: 69)
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: 165)
Chemical Science     Open Access   (Followers: 21)
Chemical Technology     Open Access   (Followers: 15)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 4)
Chemical Week     Full-text available via subscription   (Followers: 7)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 55)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 25)
ChemInform     Hybrid Journal   (Followers: 7)
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: 136)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 15)
Chemistry and Materials Research     Open Access   (Followers: 17)
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: 43)
Chemistry of Materials     Full-text available via subscription   (Followers: 190)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
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: 8)
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: 23)
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: 10)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Metabolomics     Hybrid Journal   (Followers: 4)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 48)
Dalton Transactions     Full-text available via subscription   (Followers: 18)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)
Diamond and Related Materials     Hybrid Journal   (Followers: 11)
Dislocations in Solids     Full-text available via subscription  
Doklady Chemistry     Hybrid Journal  
Drying Technology: An International Journal     Hybrid Journal   (Followers: 3)
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: 8)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 4)
Environmental Science & Technology Letters     Full-text available via subscription   (Followers: 5)
Environmental Science : Nano     Partially Free   (Followers: 1)
Environmental Toxicology & Chemistry     Hybrid Journal   (Followers: 19)

        1 2 3 | Last

Journal Cover Bioorganic & Medicinal Chemistry
  [SJR: 1.064]   [H-I: 119]   [107 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [3031 journals]
  • Medicinal chemistry of antischistosomal drugs: Praziquantel and
           oxamniquine
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Vinícius Barros Ribeiro da Silva, Bruna Rafaella Koresch Leiva Campos, Jamerson Ferreira de Oliveira, Jean-Luc Decout, Maria do Carmo Alves de Lima
      Neglected tropical diseases (NTDs) are a group of diseases that, besides prevailing in poverty conditions, contribute to the maintenance of social inequality, being a strong barrier to a country development. Schistosomiasis, a NTD, is a tropical and subtropical disease caused by the trematode Schistosoma mansoni (Africa, Middle East, Caribbean, Brazil, Venezuela, Suriname), japonicum (China, Indonesia, the Philippines), mekongi (several districts of Cambodia and the Lao People's Democratic Republic), intercalatum and guianensis (areas of tropical rainforests in Central Africa) and hematobium (Middle East Africa, Corsica, France) whose adult forms inhabit the mesenteric vessels of the host, while the intermediate forms are found in the aquatic gastropod snails of the genus Biomphalaria. Currently, praziquantel (PZQ) is the first line drug chosen for the treatment of schistosomiasis according to the World Health Organization (WHO) Model List of Essential Medicines, 2015. PZQ chemotherapy is considered to be the most important development for decades in the treatment of schistosomiasis. Beside the PZQ, oxamniquine (OXA) has been first described in 1969 and launched in Brazil by Pfizer under the name of Mansil® for oral administration. It has a lower cost when compared to PZQ, being active in the intestinal and hepatosplenic infections caused exclusively by S. mansoni, single species in Brazil. Both PZQ and OXA have limitations, as low efficacy in the treatment of acute schistosomiasis, low activity against S. mansoni in immature stages and resistance or tolerance, which is the reason why further research are still necessary for the development of a second generation of antischistosomal drugs. For the development of new PZQ analogs, three main strategies can be adopted: (a) synthesis and evaluation of PZQ analogues; (b) rational design of new pharmacophores; (c) discovery of new active compounds from screening programs on a large scale. Such (b) approach is difficult as the target of PZQ still unknown, the synthesis of new active analogues is possible from delineation of structure-activity relationships for PZQ. Thus, we proposed for a review article an accurate analysis of PZQ and OXA medicinal properties and uses, focusing on the pharmacochemical aspects of both drugs through 178 bibliographic references. The mechanisms of action will be discussed, with the latest information available in the literature (for the first time in the case of the oxamniquine). Cases of resistance are also discussed. As both drugs are available as a racemic mixture the biological impact of their stereochemistry to activity and side effects are reviewed. The results obtained for the combination of PZQ and artemisinin derivatives against immature worms are also introduced in the discussion. Using the information about more than 200 PZQ new derivatives synthetized during almost 35years since its discovery, a deep structure-activity relationship (SAR) is also proposed in this study.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
  • Lathyrol and epoxylathyrol derivatives: Modulation of Cdr1p and Mdr1p
           drug-efflux transporters of Candida albicans in Saccharomyces cerevisiae
           model
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Andreia Mónico, Shweta Nim, Noélia Duarte, Manpreet Kaur Rawal, Rajendra Prasad, Attilio Di Pietro, Maria-José U. Ferreira
      Macrocyclic diterpenes were previously found to be able to modulate the efflux pump activity of Candida albicans multidrug transporters. Most of these compounds were jatrophanes, but only a few number of lathyrane-type diterpenes was evaluated. Therefore, the aim of this study was to evaluate the ability of nineteen structurally-related lathyrane diterpenes (1–19) to overcome the drug-efflux activity of Cdr1p and Mdr1p transporters of C. albicans, and get some insights on their structure-activity relationships. The transport assay was performed by monitoring Nile Red (NR) efflux in a Saccharomyces cerevisiae strain overexpressing the referred efflux pumps from C. albicans. Moreover, a chemosensitization assay was performed in order to evaluate the type of interaction between the inhibitory compounds and the antifungal drug fluconazole. Compounds 1–13 were previously isolated from Euphorbia boetica or obtained by derivatization, and compounds 14–19 were prepared by chemical transformations of compound 4. In the transport assays, compounds 14–19 revealed the strongest inhibitory activity of the Cdr1p efflux pump, ranging from 65 to 85%. Concerning Mdr1p efflux pump, the most active compounds were 1, 3, 6, 8, and 12 (75–85%). When used in combination with fluconazole, epoxyboetirane K (2) and euphoboetirane N (18) revealed synergistic effects in the AD-CDR1 yeast strain, overexpressing the Cdr1p transporter, through their ability to reduce the effective concentration of the antifungal drug by 23- and 52-fold, respectively.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
  • Design and synthesis of 1,2,3-triazolo linked
           benzo[d]imidazo[2,1-b]thiazole conjugates as tubulin polymerization
           inhibitors
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Siddiq Pasha Shaik, M.V.P.S. Vishnuvardhan, Faria Sultana, A.V. Subba Rao, Chandrakant Bagul, Debanjan Bhattacharjee, Jeevak Sopanrao Kapure, Nishant Jain, Ahmed Kamal
      1,2,3-Triazolo linked benzo[d]imidazo[2,1-b]thiazole conjugates (5a–v) were designed, synthesized and evaluated for their cytotoxic potency against some human cancer cell lines like DU-145 (prostate), HeLa (cervical), MCF-7 (breast) HepG2 (liver) and A549 (lung). Preliminary results revealed that some of these conjugates like 5f and 5k exhibited significant antiproliferative effect against human breast cancer cells (MCF-7) with IC50 values of 0.60 and 0.78µM respectively. Flow cytometric analysis of the cell cycle demonstrated an increase in the percentage of cells in the G2/M phase which was further authenticated by elevation of cyclin B1 protein levels. Immunocytochemistry revealed loss of intact microtubule structure in cells treated with 5f and 5k, and western blot analysis revealed that these conjugates accumulated more tubulin in the soluble fraction. Moreover, the conjugates caused apoptosis of the cells that was confirmed by mitochondrial membrane potential and Annexin V-FITC assay. Molecular docking studies indicated that these conjugates occupy the colchicine binding site of the tubulin protein.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
  • Identification of a novel fluoropyrrole derivative as a
           potassium-competitive acid blocker with long duration of action
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Haruyuki Nishida, Yasuyoshi Arikawa, Keizo Hirase, Toshihiro Imaeda, Nobuhiro Inatomi, Yasunobu Hori, Jun Matsukawa, Yasushi Fujioka, Teruki Hamada, Motoo Iida, Mitsuyoshi Nishitani, Akio Imanishi, Hideo Fukui, Fumio Itoh, Masahiro Kajino
      With the aim to find a novel long-lasting potassium-competitive acid blocker (P-CAB) that would perfectly overcome the limitations of proton pump inhibitors (PPIs), we tried various approaches based on pyrrole derivative 1b as a lead compound. As part of a comprehensive approach to identification of a new drug, we explored excellent compounds that have low lipophilicity by introducing a polar hetero-aromatic group at position 5 of the pyrrole ring. Among the compounds synthesized, fluoropyrrole derivative 37c, which has a 2-F-3-Py group at the fifth position, lower pKa, and much lower ClogP and logD values than 1b dose, showed potent gastric-acid suppressive action resulting from gastric H+,K+-ATPase inhibition in animal models. Its maximum intragastric pH elevation effect was strong in rats, and its duration of action was much longer than that of either lansoprazole or lead compound 1b in dogs. Therefore, compound 37c can be considered a promising new P-CAB with long duration of action.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
  • Design and optimization of purine derivatives as in vivo active PDE10A
           inhibitors
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Liu Chen, Danqi Chen, Le Tang, Jing Ren, Jiaojiao Chen, Xuechu Zhen, Yu-Chih Liu, Chenhua Zhang, Haibin Luo, Jingkang Shen, Bing Xiong
      Phosphodiesterases are important enzymes regulating signal transduction mediated by second messenger molecules cAMP or cGMP. PDE10A is a unique member in the PDE family because of its selective expression in medium spiny neurons. It is recognized as anti-psychotic drug target. Based on the structural similarity between our previous chemistry work on 8-aminoimidazo[1,2-a]pyrazines and the PDE10A inhibitors reported by Bartolome-Nebreda et al., we initialized a project for developing PDE10A inhibitors. After several rounds of optimization, we were able to obtain a few compounds with good PDE10A enzymatic activity. And after further PDE enzymatic selectivity study, metabolic stability assay and in vivo pharmacological tests we identified two inhibitors as interesting lead compounds with the potential for further PDE10A lead optimizatioin.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
  • Synthesis and biological evaluation of novel selective androgen receptor
           modulators (SARMs) Part III: Discovery of
           4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2f as a clinical
           candidate
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Katsuji Aikawa, Moriteru Asano, Koji Ono, Noriyuki Habuka, Jason Yano, Keith Wilson, Hisashi Fujita, Hitoshi Kandori, Takahito Hara, Megumi Morimoto, Takashi Santou, Masuo Yamaoka, Masaharu Nakayama, Atsushi Hasuoka
      We previously reported that 4-(pyrrolidin-1-yl)benzonitrile derivative 1b was a selective androgen receptor modulator (SARM) that exhibited anabolic effects on organs such as muscles and the central nervous system (CNS), but neutral effects on the prostate. From further modification, we identified that 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2a showed strong AR binding affinity with improved metabolic stabilities. Based on these results, we tried to enhance the AR agonistic activities by modifying the substituents of the 5-oxopyrrolidine ring. As a consequence, we found that 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (2f) had ideal SARM profiles in Hershberger assay and sexual behavior induction assay. Furthermore, 2f showed good pharmacokinetic profiles in rats, dogs, monkeys, excellent nuclear selectivity and acceptable toxicological profiles. We also determined its binding mode by obtaining the co-crystal structures with AR.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
  • Alkyne-linked reduction-activated protecting groups for diverse
           functionalization on the backbone of oligonucleotides
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Hisao Saneyoshi, Kazuhiko Kondo, Koichi Iketani, Akira Ono
      A versatile conjugatable/bioreduction-responsive protecting group for phosphodiester moieties was designed, synthesized and incorporated into oligonucleotide strands. Subsequently, controlled pore glass-supported oligonucleotides were conjugated to a variety of functional molecules using a copper-catalyzed azide-alkyne cycloaddition reaction. The functionalized protecting groups were deprotected by a nitroreductase/NADH reduction system to give “naked” oligonucleotides. This method allowed the synthesis of oligonucleotide prodrugs bearing the functionalized protecting group at the desired sites and desired residues on oligodeoxyribonucleotide (ODN) backbones.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
  • Synthesis and cytotoxic activity of new artemisinin hybrid molecules
           against human leukemia cells
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Antonios S. Letis, Ean-Jeong Seo, Sotiris S. Nikolaropoulos, Thomas Efferth, Athanassios Giannis, Manolis A. Fousteris
      A series of new artemisinin-derived hybrids which incorporate cholic acid moieties have been synthesized and evaluated for their antileukemic activity against sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 cells. The new hybrids 20–28 showed IC50 values in the range of 0.019µM–0.192µM against CCRF-CEM cells and between 0.345µM and 7.159µM against CEM/ADR5000 cells. Amide hybrid 25 proved the most active compound against both CCRF-CEM and CEM/ADR5000 cells with IC50 value of 0.019±0.001µM and 0.345±0.031µM, respectively. A relatively low cross resistance to hybrids 20–28 in the range of 5.7-fold to 46.1-fold was measured. CEM/ADR5000 cells showed higher resistance than CCRF-CEM to all the tested compounds. Interestingly, the lowest cross resistance to 23 was observed (5.7-fold), whereas hybrid 25 showed 18.2-fold cross-resistant to CEM/ADR5000 cells. Hybrid 25 which proved even more potent than clinically used doxorubicin against CEM/ADR5000 cells may serve as a promising antileukemic agent against both sensitive and multidrug-resistant cells.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
  • Antioxidant and anticholinesterase potential of diterpenoid alkaloids from
           Aconitum heterophyllum
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Hanif Ahmad, Shujaat Ahmad, Syed Adnan Ali Shah, Abdul Latif, Mumtaz Ali, Farman Ali Khan, Muhammad Nawaz Tahir, Farzana Shaheen, Abdul Wadood, Manzoor Ahmad
      Extensive chromatographic separations performed on the basic (pH=8–10) chloroform soluble fraction of Aconitum heterophyllum resulted in the isolation of three new diterpenoid alkaloids, 6β-Methoxy, 9β-dihydroxylheteratisine (1), 1α,11,13β-trihydroxylhetisine (2), 6,15β-dihydroxylhetisine (3), and the known compounds iso-atisine (4), heteratisine (5), hetisinone (6), 19-epi-isoatisine (7), and atidine (8). Structures of the isolated compounds were established by means of mass and NMR spectroscopy as well as single crystal X-ray crystallography. Compounds 1–8 were screened for their antioxidant and enzyme inhibition activities followed by in silico studies to find out the possible inhibitory mechanism of the tested compounds. This work is the first report demonstrating significant antioxidant and anticholinesterase potentials of diterpenoid alkaloids isolated from a natural source.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
  • Inhibition of amyloid β aggregation and protective effect on SH-SY5Y
           cells by triterpenoid saponins from the cactus Polaskia chichipe
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Koji Fujihara, Shin Koike, Yuki Ogasawara, Kunio Takahashi, Kiyotaka Koyama, Kaoru Kinoshita
      Alzheimer’s disease (AD) destroys brain function, especially in the hippocampus, and is a social problem worldwide. A major pathogenesis of AD is related to the accumulation of amyloid beta (Aβ) peptides, resulting in neuronal cell death in the brain. Here, we isolated four saponins (1–4) and elucidated their structures from 1D and 2D NMR and HRFABMS spectral data. The structures of 1 and 2 were determined as new saponins which have cochalic acid as the aglycon, and 3 was determined as a new saponin with oleanolic acid as the aglycon. Compound 4 was confirmed as the known saponin chikusetsusaponin V (=ginsenoside R0). Isolated saponins (1–4) and six previously reported saponins (5–10) were tested for their inhibitory effects of Aβ aggregation and their protective effects on SH-SY5Y cells against Aβ-associated toxicity. As the results, compounds 3 and 4 showed inhibitory effect of Aβ aggregation and compounds 5–8 exerted the protective effects on SH-SY5Y cells against Aβ-associated toxicity.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Lipase-catalyzed kinetic resolution as key step in the synthesis of
           enantiomerically pure σ ligands with 2-benzopyran structure
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Inga Knappmann, Kirstin Lehmkuhl, Jens Köhler, Dirk Schepmann, Martin Giera, Franz Bracher, Bernhard Wünsch
      In order to obtain enantiomerically pure σ1 receptor ligands with a 2-benzopyran scaffold an Oxa-Pictet-Spengler reaction with the enantiomerically pure 2-phenylethanol derivatives (R)-4 and (S)-4 was envisaged. The kinetic resolution of racemic alcohol (±)-4 using Amano Lipase PS-C II and isopropenyl acetate in tert-butyl methyl ether led to the (R)-configured alcohol (R)-4 in 42% yield with an enantiomeric excess of 99.6%. The (S)-configured alcohol (S)-4 was obtained by Amano Lipase PS-C II catalyzed hydrolysis of enantiomerically enriched acetate (S)-5 (76.9% ee) and provided (S)-4 in 26% yield and 99.7% ee. The absolute configuration of alcohol (R)-4 was determined by exciton coupled CD spectroscopy of the bis(bromobenzoate) (R)-7. The next important step for the synthesis of 2-benzopyrans 2 and 3 was the Oxa-Pictet-Spengler reaction of the enantiomerically pure alcohols (R)-4 and (S)-4 with piperidone ketal 8 and chloropropionaldehyde acetal 12. The conformationally restricted spirocyclic 2-benzopyrans 2 revealed higher σ1 affinity than the more flexible aminoethyl derivatives 3. The (R)- and (R,R)-configured enantiomers (R)-2 and (R,R)-3 represent the eutomers of this class of compounds with eudismic ratios of 4.8 (2b) and 4.5 (2c). High σ1/σ2 selectivity (>49) was found for the most potent σ1 ligands (R)-2b, (R)-2c, (R)-2d, and (S)-2d (K i(σ1) 9–15nM).
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      PubDate: 2017-05-25T15:09:02Z
       
  • Synthesis and biological activity of new phthalimides as potential
           anti-inflammatory agents
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Duc-Hiep Bach, Jian-Yu Liu, Won Kyung Kim, Ji-Young Hong, So Hyun Park, Donghwa Kim, Si-Ning Qin, Thi-Thu-Trang Luu, Hyen Joo Park, Yong-Nan Xu, Sang Kook Lee
      The overproduction of nitric oxide (NO) plays an important role in a variety of pathophysiological processes, including inflammation. Therefore, the suppression of NO production is a promising target in the design of anti-inflammatory agents. In the present study, a series of phthalimide analogs was synthesized, and their anti-inflammatory activities were evaluated using lipopolysaccharide (LPS)-stimulated NO production in cultured murine macrophage RAW264.7 cells. A structure-activity relationship study showed that the free hydroxyl group at C-4 and C-6 and the bulkiness of the N-substituted alkyl chain are associated with biological activity. Among the series of phthalimide derivatives, compound IIh exhibited potent inhibitory activity, with an IC50 value of 8.7µg/mL. Further study revealed that the inhibitory activity of compound IIh was correlated with the down-regulation of the mRNA and protein expression of LPS-stimulated inducible nitric oxide synthase (iNOS). Compound IIh also suppressed the induction of the pro-inflammatory cytokines tumor necrosis factor-α and interleukin-1β in LPS-stimulated RAW 264.7 cells. The anti-inflammatory activity of compound IIh was also found to be associated with the suppression of the Toll-like receptor (TLR)4 signaling pathway by down-regulating the activation of interferon regulatory factor 3 (IRF-3) and interferon-β and signal transducer expression. These findings demonstrate that novel phthalimides might be potential candidates for the development of anti-inflammatory agents.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Identification of novel 1,2,3,6-tetrahydropyridyl-substituted
           benzo[d]thiazoles: Lead generation and optimization toward potent and
           orally active EP1 receptor antagonists
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Kentaro Umei, Yosuke Nishigaya, Kazuya Tatani, Yasushi Kohno, Nobuyuki Tanaka, Shigeki Seto
      Herein we described the design, synthesis and evaluation of a novel series of benzo[d]thiazole derivatives toward an orally active EP1 antagonist. Lead generation studies provided benzo[d]thiazole core from the four designed scaffolds. Optimization of this scaffold in terms of EP1 antagonist potency and ligand-lipophilicity efficiency (LLE; pIC50-clogP) led to a 1,2,3,6-tetrahydropyridyl-substituted benzo[d]thiazole derivative, 7r (IC50 1.1nM; LLE 4.7), which showed a good pharmacological effect when administered intraduodenally in a 17-phenyl trinor-PGE2 (17-PTP)-induced overactive bladder model in rats.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Development of the optical sensor for discriminating isomers of fatty
           acids based on emissive network polymers composed of polyhedral oligomeric
           silsesquioxane
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Hayato Narikiyo, Takahiro Kakuta, Hiroki Matsuyama, Masayuki Gon, Kazuo Tanaka, Yoshiki Chujo
      It was shown that water-soluble network polymers composed of polyhedral oligomeric silsesquioxane (POSS) had hydrophobic spaces inside the network because of strong hydrophobicity of the cubic silica cage. In this study, the water-soluble POSS network polymers connected with triphenylamine derivatives (TPA-POSS) were synthesized, and their functions as a sensor for discriminating the geometric isomers of fatty acids were investigated. Accordingly, in the photoluminescence spectra, different time-courses of intensity and peak wavelengths of the emission bands were detected from the TPA-POSS-containing solution in the presence of cis- or trans-fatty acids during incubation. Furthermore, variable time-dependent changes were obtained by changing coexisting ratios between two geometric isomers. From the mechanistic investigation, it was implied that these changes could be originated from the difference in the degree of interaction between the POSS networks and each fatty acid. Our data could be applicable for constructing a sensing material for generation and proportion of trans-fatty acids in the oil.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Synthesis and biological research of novel azaacridine derivatives as
           potent DNA-binding ligands and topoisomerase II inhibitors
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Dan Li, Zigao Yuan, Shaopeng Chen, Cunlong Zhang, Lu Song, Chunmei Gao, Yuzong Chen, Chunyan Tan, Yuyang Jiang
      DNA and DNA-related enzymes are one of the most effective and common used intracellular anticancer targets in clinic and laboratory studies, however, most of DNA-targeting drugs suffered from toxic side effects. Development of new molecules with good antitumor activity and low side effects is important. Based on computer aided design and our previous studies, a series of novel azaacridine derivatives were synthesized as DNA and topoisomerases binding agents, among which compound 9 displayed the best antiproliferative activity with an IC50 value of 0.57μM against U937 cells, which was slightly better than m-AMSA. In addition, compound 9 displayed low cytotoxicity against human normal liver cells (QSG-7701), the IC50 of which was more than 3 times lower than m-AMSA. Later study indicated that all the compounds displayed topoisomerases II inhibition activity at 50μM. The representative compound 9 could bind with DNA and induce U937 apoptosis through the exogenous pathway.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Exploration of pyrrole derivatives to find an effective
           potassium-competitive acid blocker with moderately long-lasting
           suppression of gastric acid secretion
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Haruyuki Nishida, Ikuo Fujimori, Yasuyoshi Arikawa, Keizo Hirase, Koji Ono, Kazuo Nakai, Nobuhiro Inatomi, Yasunobu Hori, Jun Matsukawa, Yasushi Fujioka, Akio Imanishi, Hideo Fukui, Fumio Itoh
      With the aim to discover a novel excellent potassium-competitive acid blocker (P-CAB) that could perfectly overcome the limitations of proton pump inhibitors (PPIs), we tested various approaches based on pyrrole derivative 1 as a lead compound. As part of a comprehensive approach to identify a new effective drug, we tried to optimize the duration of action of the pyrrole derivative. Among the compounds synthesized, fluoropyrrole derivative 20j, which has a 2-F-3-Py group at position 5, fluorine atom at position 4, and a 4-Me-2-Py sulfonyl group at the first position of the pyrrole ring, showed potent gastric acid-suppressive action and moderate duration of action in animal models. On the basis of structural properties including a slightly larger ClogP value (1.95), larger logD value (0.48) at pH 7.4, and fairly similar pKa value (8.73) compared to those of the previously optimized compound 2a, compound 20j was assumed to undergo rapid transfer to the stomach and have a moderate retention time there after single administration. Therefore, compound 20j was selected as a new promising P-CAB with moderately long duration of action.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Development of nonsteroidal glucocorticoid receptor modulators based on
           N-benzyl-N-(4-phenoxyphenyl)benzenesulfonamide scaffold
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Hiromasa Yoshioka, Ayumi Yamada, Yuko Nishiyama, Hiroyuki Kagechika, Yuichi Hashimoto, Shinya Fujii
      N-Benzyl-N-(4-phenoxyphenyl)benzenesulfonamide derivatives were developed as a novel class of nonsteroidal glucocorticoid receptor (GR) modulators, which are promising drug candidates for treating immune-related disorders. Focusing on the similarity of the GR and progesterone receptor (PR) ligand-binding domain (LBD) structures, we adopted our recently developed PR antagonist 10 as a lead compound and synthesized a series of derivatives. We found that the N-(4-phenoxyphenyl)benzenesulfonamide skeleton serves as a versatile scaffold for GR antagonists. Among them, 4-cyano derivative 14m was the most potent, with an IC50 value of 1.43μM for GR. This compound showed good selectivity for GR; it retained relatively weak antagonistic activity toward PR (IC50 for PR: 8.00μM; 250-fold less potent than 10), but showed no activity toward AR, ERα or ERβ. Interestingly, the 4-amino derivative 15a exhibited transrepression activity toward NF-κB in addition to GR-antagonistic activity, whereas 14m did not. The structure-activity relationship for transrepression was different from that for GR-antagonistic activity. Computational docking simulations suggested that 15a might bind to the ligand-binding pocket of GR in a different manner from 14m. These findings open up new possibilities for developing novel nonsteroidal GR modulators with distinctive activity profiles.
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      PubDate: 2017-05-25T15:09:02Z
       
  • A fragment-based approach leading to the discovery of a novel binding site
           and the selective CK2 inhibitor CAM4066
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Claudia De Fusco, Paul Brear, Jessica Iegre, Kathy Hadje Georgiou, Hannah F. Sore, Marko Hyvönen, David R. Spring
      Recently we reported the discovery of a potent and selective CK2α inhibitor CAM4066. This compound inhibits CK2 activity by exploiting a pocket located outside the ATP binding site (αD pocket). Here we describe in detail the journey that led to the discovery of CAM4066 using the challenging fragment linking strategy. Specifically, we aimed to develop inhibitors by linking a high-affinity fragment anchored in the αD site to a weakly binding warhead fragment occupying the ATP site. Moreover, we describe the remarkable impact that molecular modelling had on the development of this novel chemical tool. The work described herein shows potential for the development of a novel class of CK2 inhibitors.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Zinc complex of tryptophan appended 1,4,7,10-tetraazacyclododecane as
           potential anticancer agent: Synthesis and evaluation
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Anupriya Adhikari, Neelam Kumari, Manish Adhikari, Nitin Kumar, Anjani K. Tiwari, Abha Shukla, Anil K. Mishra, Anupama Datta
      With the rising incidences of cancer cases, the quest for new metal based anticancer drugs has led to extensive research in cancer biology. Zinc complexes of amino acid residue side chains are well recognized for hydrolysis of phosphodiester bond in DNA at faster rate. In the presented work, a Zn(II) complex of cyclen substituted with two l-tryptophan units, Zn(II)-Cyclen-(Trp)2 has been synthesized and evaluated for antiproliferative activity. Zn(II)-Cyclen-(Trp)2 was synthesized in ∼70% yield and its DNA binding potential was evaluated through QM/MM study which suggested good binding (G=−9.426) with B-DNA. The decrease in intensity of the positive and negative bands of CT-DNA at 278nm and 240nm, respectively demonstrated an effective unwinding of the DNA helix with loss of helicity. The complex was identified as an antiproliferative agent against U-87MG cells with 5 fold increase in apoptosis with respect to control (2h post incubation, IC50 25µM). Electrophoresis and comet assay studies exhibited an increase in DNA breakage after treatment with complex while caspase-3/β-actin cleavage established a caspase-3 dependent apoptosis pathway in U-87 MG cells after triggering DNA damage. In vivo tumor specificity of the developed ligand was validated after radiocomplexation with 99mTc (>98% radiochemical yield and specific activity of 2.56GBq/µmol). Avid tumor/muscle ratio of >6 was depicted in biodistribution and SPECT imaging studies in U-87 MG xenograft model nude mice.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Development of molecular tools based on the dopamine D3 receptor ligand
           FAUC 329 showing inhibiting effects on drug and food maintained behavior
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Anne Stößel, Regine Brox, Nirupam Purkayastha, Harald Hübner, Carsten Hocke, Olaf Prante, Peter Gmeiner
      Dopamine D3 receptor-mediated networks have been associated with a wide range of neuropsychiatric diseases, drug addiction and food maintained behavior, which makes D3 a highly promising biological target. The previously described dopamine D3 receptor ligand FAUC 329 (1) showed protective effects against dopamine depletion in a MPTP mouse model of Parkinson’s disease. We used the radioligand [18F]2, a [18F]fluoroethoxy substituted analog of the lead compound 1 as a molecular tool for visualization of D3-rich brain regions including the islands of Calleja. Furthermore, structural modifications are reported leading to the pyrimidylpiperazine derivatives 3 and 9 displaying superior subtype selectivity and preference over serotonergic receptors. Evaluation of the lead compound 1 on cocaine-seeking behavior in non-human primates showed a substantial reduction in cocaine self-administration behavior and food intake.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Discovery of indolin-2-one derivatives as potent PAK4 inhibitors:
           Structure-activity relationship analysis, biological evaluation and
           molecular docking study
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Jing Guo, Mingyue Zhu, Tianxiao Wu, Chenzhou Hao, Kai Wang, Zizheng Yan, Wanxu Huang, Jian Wang, Dongmei Zhao, Maosheng Cheng
      Utilizing a pharmacophore hybridization approach, a novel series of substituted indolin-2-one derivatives were designed, synthesized and evaluated for their in vitro biological activities against p21-activated kinase 4. Compounds 11b, 12d and 12g exhibited the most potent inhibitory activity against PAK4 (IC50 =22nM, 16nM and 27nM, respectively). Among them, compound 12g showed the highest antiproliferative activity against A549 cells (IC50 =0.83μM). Apoptosis analysis in A549 cells suggested that compound 12g delayed cell cycle progression by arresting cells in the G2/M phase of the cell cycle, retarding cell growth. Further investigation demonstrated that compound 12g strongly inhibited migration and invasion of A549 cells. Western blot analysis indicated that compound 12g potently inhibited the PAK4/LIMK1/cofilin signalling pathways. Finally, the binding mode between compound 12g with PAK4 was proposed by molecular docking. A preliminary ADME profile of the compound 12g was also drawn on the basis of QikProp predictions.
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      PubDate: 2017-05-25T15:09:02Z
       
  • C21-steroidal pregnane sapogenins and their derivatives as
           anti-inflammatory agents
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Lie-Jun Huang, Shao-Ru Chen, Chun-Mao Yuan, Wei Gu, Bao-Jian Guo, Yi-Tao Wang, Ying Wang, Xiao-Jiang Hao
      During the screening of natural anti-inflammatory agent, we identified some C21-steroidal pregnane sapogenins or the derivatives to inhibit TLR2, TLR3, and TLR4-initiatedinflammatory responses respectively. Treatment with active compounds 10, 2j and 3p failed to impact tumor necrosis factor-α (TNF-α) induced nucleus translocation of NF-κB p65 subunit. However, these compounds regulated distinct canonical or non-canonical NF-κB family members. Ectopic expression of TNF receptor associated factor 6 (TRAF6) abrogated the inhibitory activity of the compounds on production of pro-inflammatory cytokines downstream of TLR4. These results suggested that compounds 10, 2j, and 3p suppressed TLR-initiated innate immunity through TRAF6 with differential regulation of NF-κB family proteins.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Kinetic properties and affinities for sulfonamide inhibitors of an
           α-carbonic anhydrase (CruCA4) involved in coral biomineralization in the
           Mediterranean red coral Corallium rubrum
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Sonia Del Prete, Daniela Vullo, Didier Zoccola, Sylvie Tambutté, Clemente Capasso, Claudiu T. Supuran
      We report the kinetic properties and sulfonamide inhibition profile of an α-carbonic anhydrase (CA, EC 4.2.1.1), named CruCA4, identified in the red coral Corallium rubrum. This isoform is involved in the biomineralization process leading to the formation of a calcium carbonate skeleton. Experiments performed on the recombinant protein show that the enzyme has a “moderate activity” level. Our results are discussed compared to values obtained for other CA isoforms involved in biomineralization. This is the first study describing the biochemical characterization of an octocoral CA.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Dual functional small molecule fluorescent probes for image-guided
           estrogen receptor-specific targeting coupled potent antiproliferative
           potency for breast cancer therapy
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Lu Yang, Zhiye Hu, Junjie Luo, Chu Tang, Silong Zhang, Wentao Ning, Chune Dong, Jian Huang, Xianjun Liu, Hai-Bing Zhou
      A strategy by integrating biological imaging into early stages of the drug discovery process can improve our understanding of drug activity during preclinical and clinical study. In this article, we designed and synthesized coumarin-based nonsteroidal type fluorescence ligands for drug-target binding imaging. Among these synthesized compounds, 3e, 3f and 3h showed potent ER binding affinity and 3e (IC50 =0.012μM) exhibited excellent ERα antagonistic activity, its antiproliferative potency in breast cancer MCF-7 cells is equipotent to the approved drug tamoxifen. The fluorescence of compounds 3e and 3f depended on the solvent properties and showed significant changes when mixed with ERα or ERβ in vitro. Furthermore, target molecule 3e could cross the cell membrane, localize and image drug-target interaction in real time without cell washing. Thus, the coumarin-based platform represents a promising new ER-targeted delivery vehicle with potential imaging and therapeutic properties.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Discovery and structure-guided fragment-linking of
           4-(2,3-dichlorobenzoyl)-1-methyl-pyrrole-2-carboxamide as a pyruvate
           kinase M2 activator
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Yumi Matsui, Isao Yasumatsu, Takashi Asahi, Takahiro Kitamura, Kazuo Kanai, Osamu Ubukata, Hitoshi Hayasaka, Sachiko Takaishi, Hiroyuki Hanzawa, Shinichi Katakura
      Tumor cells switch glucose metabolism to aerobic glycolysis by expressing the pyruvate kinase M2 isoform (PKM2) in a low active form, providing glycolytic intermediates as building blocks for biosynthetic processes, and thereby supporting cell proliferation. Activation of PKM2 should invert aerobic glycolysis to an oxidative metabolism and prevent cancer growth. Thus, PKM2 has gained attention as a promising cancer therapy target. To obtain novel PKM2 activators, we conducted a high-throughput screening (HTS). Among several hit compounds, a fragment-like hit compound with low potency but high ligand efficiency was identified. Two molecules of the hit compound bound at one activator binding site, and the molecules were linked based on the crystal structure. Since this linkage succeeded in maintaining the original position of the hit compound, the obtained compound exhibited highly improved potency in an in vitro assay. The linked compound also showed PKM2 activating activity in a cell based assay, and cellular growth inhibition of the A549 cancer cell line. Discovery of this novel scaffold and binding mode of the linked compound provides a valuable platform for the structure-guided design of PKM2 activators.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Potential inhibitors of human carbonic anhydrase isozymes I and II:
           Design, synthesis and docking studies of new 1,3,4-thiadiazole derivatives
           
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Mehlika Dilek Altıntop, Belgin Sever, Ahmet Özdemir, Kaan Kucukoglu, Hicran Onem, Hayrunnisa Nadaroglu, Zafer Asım Kaplancıklı
      In the last years, inhibition of carbonic anhydrase (CA) has emerged as a promising approach for pharmacologic intervention in a variety of disorders such as glaucoma, epilepsy, obesity, and cancer. As a consequence, the design of CA inhibitors (CAIs) is a highly dynamic field of medicinal chemistry. Due to the therapeutic potential of thiadiazoles as CAIs, new 1,3,4-thiadiazole derivatives were synthesized and investigated for their inhibitory effects on hCA I and hCA II. Although the tested compounds did not carry a sulfonamide group, an important pharmacophore for CA inhibitory activity, it was a remarkable finding that most of them were more effective on hCAs than acetazolamide (AAZ), the reference agent. Among these compounds, N′-((5-(4-chlorophenyl)furan-2-yl)methylene)-2-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)thio)acetohydrazide (3) was found to be the most effective compound on hCA I with an IC50 value of 0.14nM, whereas N′-((5-(2-chlorophenyl)furan-2-yl)methylene)-2-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)thio)acetohydrazide (1) was found to be the most potent compound on hCA II with an IC50 value of 0.15nM. According to molecular docking studies, all compounds exhibited high affinity and good amino acid interactions similar to AAZ on the both active sites of hCA I and hCA II enzymes.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Sulfonamide inhibition profiles of the β-carbonic anhydrase from the
           pathogenic bacterium Francisella tularensis responsible of the febrile
           illness tularemia
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Sonia Del Prete, Daniela Vullo, Sameh M. Osman, Zeid AlOthman, Claudiu T. Supuran, Clemente Capasso
      A new β-class carbonic anhydrase (CA, EC 4.2.1.1) has been cloned, purified and characterized in the genome of the pathogenic bacterium Francisella tularensis responsible of the febrile illness tularemia. This enzyme, FtuβCA, showed a kcat of 9.8 ×105 s−1 and a kcat/KM of 8.9 ×107 M−1 s−1 for the CO2 hydration, physiological reaction, being one of the most effective β-CAs known to date, with a catalytic activity only 1.68-times lower than that of the human(h) isoform hCA II. A panel of 39 simple aromatic and heterocyclic sulfonamides, as well as clinically used drugs incorporating sulfonamide/sulfamate zinc-binding groups, was used to investigate the inhibition profile of FtuβCA with these classes of derivatives. The enzyme generally showed a weaker affinity for these inhibitors compared to other α- and β-CAs investigated earlier, with only acetazolamide and its deacetylated precursor having inhibition constant <1µM. Indeed, the two compounds acetazolamide AAZ and its deacetylated precursor 13 (KIs of 655–770nM), as well as metanilamide and methazolamide (KIs of 2.53–2.92µM), were the best FtuβCA inhibitors detected so far. As the physiological role of bacterial β-CAs is poorly understood for the virulence/life cycle of these pathogens, the present study may constitute a starting point for the design of effective pathogenic bacteria CA inhibitors with potential use as antiinfectives.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Potential anti-gout constituents as xanthine oxidase inhibitor from the
           fruits of Stauntonia brachyanthera
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Dan Liu, Dandan Wang, Wei Yang, Dali Meng
      With the aim of finding a better xanthine oxidase inhibitor with potential anti-gout properties, the studies on the fruit of Stauntonia brachyanthera were carried out, which led to the isolation of 12 glycosides, including 4 new nor-oleanane triterpenoids. Their structures were determined by comprehensive spectroscopic (NMR and HR MS) analysis. Two compounds (4 and 11) exhibited significant inhibitory activities on xanthine oxidase with IC50 values of 5.22 and 1.60µM, respectively. Another five compounds (1, 2, 3, 8 and 10) showed qualified activities. The results suggested that the existences of nor-oleanane triterpenoids and flavonoids in the fruits were responsible for the inhibitory activity on xanthine oxidase that could cut off the production of uric acid. Nor-oleanane triterpenoids, a new leading XO inhibitor, is worthy of further studies on molecular biology level for its mechanisms.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Synthesis of novel acyl selenoureido benzensulfonamides as carbonic
           anhydrase I, II, VII and IX inhibitors
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Andrea Angeli, Fabrizio Carta, Gianluca Bartolucci, Claudiu T. Supuran
      A novel series of acyl selenoureido benzensulfonamides was evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors against the human (h) isoforms hCA I, II, VII and IX, which are involved in a variety of diseases such as glaucoma, retinitis pigmentosa, epilepsy and tumors etc. These compounds showed excellent inhibitory activity for these isoforms, with several low nanomolar derivatives identified against all of them. Furthermore, the selenoureido group may provide an antioxidant activity to these enzyme inhibitors.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Design and synthesis of novel photoinduced electron transfer-based
           hybridization probes
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Chika Yokoyama, Kosuke Nakamoto, Yoshihito Ueno
      Photoinduced electron transfer (PeT)-based hybridization probe is a linear and quencher-free oligonucleotide (ON) probe for DNA or RNA detection. In this report, we designed and synthesized novel adenosine analogues for PeT-based hybridization probe. In particular, the analogue containing a piperazinomethyl moiety showed effective quenching property under physiological conditions. When the probe containing the analogue was hybridized with a complementary DNA or RNA, the fluorescence increased 3- or 4-fold, respectively, compared to the single-stranded state.
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      PubDate: 2017-05-25T15:09:02Z
       
  • N-Substituted and ring opened saccharin derivatives selectively inhibit
           transmembrane, tumor-associated carbonic anhydrases IX and XII
    • Abstract: Publication date: 1 July 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
      Author(s): Jekaterīna Ivanova, Fabrizio Carta, Daniela Vullo, Janis Leitans, Andris Kazaks, Kaspars Tars, Raivis Žalubovskis, Claudiu T. Supuran
      A series of N-substituted saccharins incorporating aryl, alkyl and alkynyl moieties, as well as some ring opened derivatives were prepared and investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The widespread cytosolic isoforms CA I and II were not inhibited by these sulfonamides whereas transmembrane, tumor-associated ones were effectively inhibited, with KIs in the range of 22.1–481nM for CA IX and of 3.9–245nM for hCA XII. Although the inhibition mechanism of these tertiary/secondary sulfonamides is unknown for the moment, the good efficacy and especially selectivity for the inhibition of the tumor-associated over the cytosolic, widespread isoforms, make these derivatives of considerable interest as enzyme inhibitors with various pharmacologic applications.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Catabolism of antibody drug conjugates and characterization methods
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
      Author(s): Mohammad Shadid, Stephen Bowlin, Jayaprakasam Bolleddula
      Antibody drug conjugates (ADCs) are large molecule therapeutics in which a cytotoxic payload is conjugated to a monoclonal antibody (mAb) via a linker. The molecules are designed to selectively bind to target-expressing cells, thus delivering therapeutic agents directly to the tumor. Chemical and enzymatic stability prior to reaching the target is an important factor for ADCs since it impacts their safety, efficacy, and pharmacokinetics (PK). One of the main reasons for off-target effects of ADCs is premature release of cytotoxic agents, either in the blood stream or at non-specific sites. Once an ADC is internalized by target-expressing cells, the cytotoxic payload and/or related catabolites are released through chemical or enzymatic cleavage within the cells. In some cases, the released payload and/or catabolites are effluxed into the systemic circulation and follow a small molecule disposition path. Since doses of ADCs are low, the concentration of cytotoxic payload and related catabolites/metabolites range from ng to μg levels in systemic circulation or tumors in clinical studies. Hence, it is challenging to identify these species without prior knowledge of the pathways of catabolism. The current review summarizes the mechanism of cleavage/catabolism of various types of linkers and available in vitro, in vivo, and bioanalytical methods for evaluation of catabolism of ADCs.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
  • Design, synthesis, and evaluation of multitarget-directed ligands against
           Alzheimer’s disease based on the fusion of donepezil and curcumin
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
      Author(s): Jun Yan, Jinhui Hu, Anqiu Liu, Lin He, Xingshu Li, Hui Wei
      By fusing donepezil and curcumin, a novel series of compounds were obtained as multitarget-directed ligands against Alzheimer’s disease. Among them, compound 11b displayed potent acetylcholinesterase (AChE) inhibition (IC50 =187nM) and the highest BuChE/AChE selectivity (66.3). Compound 11b also inhibited 45.3% Aβ1–42 self-aggregation at 20μM and displayed remarkable antioxidant effects. The metal-chelating property of compound 11b was elucidated by determining the 1:1 stoichiometry for the 11b–Cu(II) complex. The excellent blood–brain barrier permeability of 11b also indicated the potential for the compound to penetrate the central nervous system.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
  • Design and synthesis of pyrazolo[3,4-d]pyrimidines: Nitric oxide releasing
           compounds targeting hepatocellular carcinoma
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
      Author(s): Yaseen A.M.M. Elshaier, Mohamed A. Shaaban, Mohammed K. Abd El Hamid, Mostafa H. Abdelrahman, Mahrous A. Abou-Salim, Sara M. Elgazwi, Fathi Halaweish
      A new series of pyrazolo[3,4-d]pyrimidines tethered with nitric oxide (NO) producing functionality was designed and synthesized. Sulforhodamine B (SRB) protein assay revealed that NO releasing moiety in the synthesized compounds significantly decreased the cell growth more than the des-NO analogues. Compounds 7C and 7G possessing N-para-substituted phenyl group, released the highest NO concentration of 4.6% and 4.7% respectively. Anti-proliferative activity of synthesized compounds on HepG2 cell line identified compounds 7h, 7p, 14a and 14b as the most cytotoxic compounds in the series of IC50 =3, 5, 3 and 5μM, respectively, compared to erlotinib as a reference drug (IC50 =25μM). Flow cytometry studies revealed that 7 h arrested the cells in G0/G1 phase of cell cycle while 7p arrested the cells in S phase. Moreover, docking study of the synthesized compounds on EGFR (PDB code: 1M17) and cytotoxicity study indicated that N-1 phenyl para substitution, pyrazole C-3 alkyl substitution and tethering the nitrate moiety through butyl group had a significant impact on the activity.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
  • Exploring the influence of indololactone structure on selectivity for
           binding to the C1 domains of PKCα, PKCε, and RasGRP
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
      Author(s): Eleonora Elhalem, Lucía Gandolfi Donadío, Xiaoling Zhou, Nancy E. Lewin, Lia C. Garcia, Christopher C. Lai, James A. Kelley, Megan L. Peach, Peter M. Blumberg, María J. Comin
      C1 domain-containing proteins, such as protein kinase C (PKC), have a central role in cellular signal transduction. Their involvement in many diseases, including cancer, cardiovascular disease, and immunological and neurological disorders has been extensively demonstrated and has prompted a search for small molecules to modulate their activity. By employing a diacylglycerol (DAG)-lactone template, we have been able to develop ultra potent analogs of diacylglycerol with nanomolar binding affinities approaching those of complex natural products such as phorbol esters and bryostatins. One current challenge is the development of selective ligands capable of discriminating between different protein family members. Recently, structure-activity relationship studies have shown that the introduction of an indole ring as a DAG-lactone substituent yielded selective Ras guanine nucleotide-releasing protein (RasGRP1) activators when compared to PKCα and PKCε. In the present work, we examine the effects of ligand selectivity relative to the orientation of the indole ring and the nature of the DAG-lactone template itself. Our results show that the indole ring must be attached to the lactone moiety through the sn-2 position in order to achieve RasGRP1 selectivity.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
  • Design, synthesis and anti-tumor activity study of novel histone
           deacetylase inhibitors containing isatin-based caps and
           o-phenylenediamine-based zinc binding groups
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
      Author(s): Shuai Gao, Jie Zang, Qianwen Gao, Xuewu Liang, Qinge Ding, Xiaoyang Li, Wenfang Xu, C. James Chou, Yingjie Zhang
      As a hot topic of epigenetic studies, histone deacetylases (HDACs) are related to lots of diseases, especially cancer. Further researches indicated that different HDAC isoforms played various roles in a wide range of tumor types. Herein a novel series of HDAC inhibitors with isatin-based caps and o-phenylenediamine-based zinc binding groups have been designed and synthesized through scaffold hopping strategy. Among these compounds, the most potent compound 9n exhibited similar if not better HDAC inhibition and antiproliferative activities against multiple tumor cell lines compared with the positive control entinostat (MS-275). Additionally, compared with MS-275 (IC50 values for HDAC1, 2 and 3 were 0.163, 0.396 and 0.605µM, respectively), compound 9n with IC50 values of 0.032, 0.256 and 0.311µM for HDAC1, 2 and 3 respectively, showed a moderate HDAC1 selectivity.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
  • Small molecules inhibit STAT3 activation, autophagy, and cancer cell
           anchorage-independent growth
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
      Author(s): Donghui Zhou, Maya Z. Springer, David Xu, Degang Liu, Andy Hudmon, Kay F. Macleod, Samy O. Meroueh
      Triple-negative breast cancers (TNBCs) lack the signature targets of other breast tumors, such as HER2, estrogen receptor, and progesterone receptor. These aggressive basal-like tumors are driven by a complex array of signaling pathways that are activated by multiple driver mutations. Here we report the discovery of 6 (KIN-281), a small molecule that inhibits multiple kinases including maternal leucine zipper kinase (MELK) and the non-receptor tyrosine kinase bone marrow X-linked (BMX) with single-digit micromolar IC50s. Several derivatives of 6 were synthesized to gain insight into the binding mode of the compound to the ATP binding pocket. Compound 6 was tested for its effect on anchorage-dependent and independent growth of MDA-MB-231 and MDA-MB-468 breast cancer cells. The effect of 6 on BMX prompted us to evaluate its effect on STAT3 phosphorylation and DNA binding. The compound’s inhibition of cell growth led to measurements of survivin, Bcl-XL, p21WAF1/CIP1, and cyclin A2 levels. Finally, LC3B-II levels were quantified following treatment of cells with 6 to determine whether the compound affected autophagy, a process that is known to be activated by STAT3. Compound 6 provides a starting point for the development of small molecules with polypharmacology that can suppress TNBC growth and metastasis.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Design, synthesis and biological evaluation of
           3,4-dihydro-2(1H)-quinoline-O-alkylamine derivatives as new multipotent
           cholinesterase/monoamine oxidase inhibitors for the treatment of
           Alzheimer’s disease
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
      Author(s): Zhipei Sang, Wanli Pan, Keren Wang, Qinge Ma, Lintao Yu, Wenmin Liu
      A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel 3,4-dihydro-2(1H)-quinoline-O-alkylamine derivatives have been designed using a conjunctive approach that combines the JMC49 and donepezil. The most promising compound TM-33 showed potent and balance inhibitory activities toward ChE and MAO (eeAChE, eqBuChE, hMAO-A and hMAO-B with IC50 values of 0.56μM, 2.3μM, 0.3μM and 1.4μM, respectively) but low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-33 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Furthermore, our investigation proved that TM-33 could cross the blood-brain barrier (BBB) in vitro, and abided by Lipinski’s rule of five. The results suggest that compound TM-33, an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer’s disease.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
  • Studies of CDK 8/19 inhibitors: Discovery of novel and selective CDK8/19
           dual inhibitors and elimination of their CYP3A4 time-dependent inhibition
           potential
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
      Author(s): Jun Fujimoto, Takaharu Hirayama, Yasuhiro Hirata, Yukiko Hikichi, Saomi Murai, Maki Hasegawa, Yuka Hasegawa, Kazuko Yonemori, Akito Hata, Kazunobu Aoyama, Douglas R. Cary
      In this article, synthetic studies around a pyridylacrylamide-based hit compound (1), utilizing structure-based drug design guided by CDK8 docking models, is discussed. Modification of the pendant 4-fluorophenyl group to various heteroaromatic rings was conducted aiming an interaction with the proximal amino acids, and then replacement of the morpholine ring was targeted for decreasing potential of time-dependent CYP3A4 inhibition. These efforts led to the compound 4k, with enhanced CDK8 inhibitory activity and no apparent potential for time-dependent CYP3A4 inhibition (CDK8 IC50: 2.5nM; CYP3A4 TDI: 99% compound remaining). Compound 4k was found to possess a highly selective kinase inhibition profile, and also showed favorable pharmacokinetic profile. Oral administration of 4k (15mg/kg, bid. for 2weeks) suppressed tumor growth (T/C 29%) in an RPMI8226 mouse xenograft model.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
  • Effect of 1,2,3-triazole salts, non-classical bioisosteres of miltefosine,
           on Leishmania amazonensis
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
      Author(s): Pedro H.F. Stroppa, Luciana M.R. Antinarelli, Arturene M.L. Carmo, Jacy Gameiro, Elaine S. Coimbra, Adilson D. da Silva
      Here, we report the effect of new non-classical bioisosteres of miltefosine on Leishmania amazonensis. Fifteen compounds were synthesized and the compound dhmtAc, containing an acetate anion, a side chain of 10 carbon atoms linked to N-1 and a methyl group linked to N-3, showed high and selective biological activity against L. amazonensis. On the intracellular amastigotes, stages of the parasite related to human disease, the IC50 values were near or similar to the 1.0μM (0.9, 0.8 and 1.0μM on L. amazonensis-WT, and two transgenic L. amazonensis expressing GFP and RFP, respectively), being more active than miltefosine. Furthermore, dhmtAc did not show toxic effects on human erythrocytes and macrophages (CC50 =115.9μM) being more destructive to the intracellular parasites (selectivity index>115). Promastigotes and intramacrophage amastigotes treated with dhmtAc showed low capacity for reversion of the effect of the compound. A study of the mechanism of action of this compound showed some features of metazoan apoptosis, including cell volume decreases, loss of mitochondrial membrane potential, ROS production, an increase in the intracellular lipid bodies, in situ labeling of DNA fragments by TUNEL labeling and phosphatidylserine exposure to the outerleaflet of the plasma membrane. In addition, the plasma membrane disruption, revealed by PI labeling, suggests cell death by necrosis. No increase in autophagic vacuoles formation in treated promastigotes was observed. Taken together, the data indicate that the bioisostere of miltefosine, dhmtAc, has promising antileishmanial activity that is mediated via apoptosis and necrosis.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Identification of selective inhibitors of sphingosine kinases 1 and 2
           through a structure–activity relationship study of 4-epi-jaspine B
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
      Author(s): Hiroaki Ohno, Maho Honda, Naoka Hamada, Jun Miyagaki, Akira Iwata, Kazuhiro Otsuki, Toru Maruyama, Shinya Nakamura, Isao Nakanishi, Shinsuke Inuki, Nobutaka Fujii, Shinya Oishi
      We recently reported that 4-epi-jaspine B exhibits potent inhibitory activity towards sphingosine kinases (SphKs). In this study, we investigated the effects of modifying the 2-alkyl group, as well as the functional groups on the THF ring of 4-epi-jaspine B using a diversity-oriented synthesis approach based on a late-stage cross metathesis reaction. The introduction of a p-phenylene tether to the alkyl group was favored in most cases, whereas the replacement of a carbon atom with an oxygen atom led to a decrease in the inhibitory activity. Furthermore, the introduction of a bulky alkyl group at the terminus led to a slight increase in the inhibitory activity of this series towards SphKs compared with 4-epi-jaspine B (the Q values of compound 13 for SphK1 and SphK2 were 0.2 and 0.4, respectively). Based on this study, we identified two isoform selective inhibitors, including the m-phenylene derivative 4 [IC50 (SphK1) ≥30μM; IC50 (SphK2)=2.2μM] and the methyl ether derivative 22 [IC50 (SphK1)=4.0μM; IC50 (SphK2) ≥30μM].
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      PubDate: 2017-05-25T15:09:02Z
       
  • Stereospecific cholinesterase inhibition by
           O,S-diethylphenylphosphonothioate
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
      Author(s): Ahmed Mohammed, Jennifer Sneathen, Sara Glazier Frojen, Louis Kuo, Cynthia M. Dupureur
      The inhibition kinetics and stereospecificity of the chiral nerve agent derivative O,S-diethylphenylphosphonothioate (DEPP) were examined for two forms of acetylcholinesterase (human and eel) and equine butyrylcholinesterase. Both S- and R-DEPP are poor inhibitors of eel AChE (IC50 150μM), consistent with a large, nondiscriminatory binding interaction in the active site of this enzyme. However, S-DEPP is active against human and equine AChE with low μM IC50s. DEPP stereospecificities (S/R) toward these enzymes are moderate (20) relative to other cholinesterase-organophosphate (OP) systems. Pralidoxime, a common rescue agent, affects a modest recovery of both hAChE and eqBChE from treatment with S-DEPP. This result is consistent with expected chemical modification by DEPP and indicates that a measurable amount of the enzyme-phosphonate adduct does not undergo aging. Kinetic analysis of inhibition of both hAChE and eqBChE by S-DEPP yields KI values near 8μM and k2 values of about 0.10min−1. In both cases, the reaction is practically irreversible. Second order rate constants calculated from these values are similar to those obtained previously using other thio-substituted OPs with bulky groups. Since BChE has a more accommodating acyl pocket than AChE, the similar behaviors of both enzymes toward S-DEPP is notable and is likely a reflection of the weakened potency of DEPP relative to chemical warfare agents.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
  • The synthesis and evaluation of new butadiene derivatives as tubulin
           polymerization inhibitors
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
      Author(s): Yanqing Pang, Jun Yan, Baijiao An, Ling Huang, Xingshu Li
      A series of new butadiene derivatives was synthesized and evaluated as tubulin polymerization inhibitors for the treatment of cancer. The optimal butadiene derivative, 9a, exhibited IC50 values of 0.056–0.089μM for five human cancer cell lines. This paper included a mechanistic study of the antiproliferative activity, including a tubulin polymerization assay, an examination of morphological alterations of cancer cells, an analysis of cell cycle arrest and an apoptosis assay.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
  • N-(Aroyl)-N-(arylmethyloxy)-α-alanines: Selective inhibitors of
           aldose reductase
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
      Author(s): Susanna Nencetti, Concettina La Motta, Armando Rossello, Stefania Sartini, Elisa Nuti, Lidia Ciccone, Elisabetta Orlandini
      Aldose reductase (ALR2), a NADPH-dependent reductase, is the first and rate-limiting enzyme of the polyol pathway of glucose metabolism and is implicated in the pathogenesis of secondary diabetic complications. In the last decades, this enzyme has been targeted for inhibition but despite the numerous efforts made to identify potent and safe ALR2 inhibitors, many clinical candidates have been a failure. For this reason the research of new ALR2 inhibitors highly effective, selective and with suitable pharmacokinetic properties is still of great interest. In this paper some new N-(aroyl)-N-(arylmethyloxy)alanines have been synthesized and tested for their ability to inhibit ALR2. Some of the synthesized compounds exhibit IC50 in the low micromolar range and all have proved to be highly selective towards ALR2. The N-(aroyl)-N-(arylmethyloxy)-α-alanines are a promising starting point for the development of new ALR2 selective drugs with the aim of delaying the onset of diabetic complications.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
  • Synthesis and biological evaluation of largazole zinc-binding group
           analogs
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
      Author(s): Bumki Kim, Ranjala Ratnayake, Hyunji Lee, Guqin Shi, Sabrina L. Zeller, Chenglong Li, Hendrik Luesch, Jiyong Hong
      Histone acetylation is an extensively investigated post-translational modification that plays an important role as an epigenetic regulator. It is controlled by histone acetyl transferases (HATs) and histone deacetylases (HDACs). The overexpression of HDACs and consequent hypoacetylation of histones have been observed in a variety of different diseases, leading to a recent focus of HDACs as attractive drug targets. The natural product largazole is one of the most potent natural HDAC inhibitors discovered so far and a number of largazole analogs have been prepared to define structural requirements for its HDAC inhibitory activity. However, previous structure–activity relationship studies have heavily investigated the macrocycle region of largazole, while there have been only limited efforts to probe the effect of various zinc-binding groups (ZBGs) on HDAC inhibition. Herein, we prepared a series of largazole analogs with various ZBGs and evaluated their HDAC inhibition and cytotoxicity. While none of the analogs tested were as potent or selective as largazole, the Zn2+-binding affinity of each ZBG correlated with HDAC inhibition and cytotoxicity. We expect that our findings will aid in building a deeper understanding of the role of ZBGs in HDAC inhibition as well as provide an important basis for the future development of new largazole analogs with non-thiol ZBGs as novel therapeutics for cancer.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
  • Structure of a Myeloid cell leukemia-1 (Mcl-1) inhibitor bound to drug
           site 3 of Human Serum Albumin
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
      Author(s): Bin Zhao, John Sensintaffar, Zhiguo Bian, Johannes Belmar, Taekyu Lee, Edward T. Olejniczak, Stephen W. Fesik
      Amplification of the gene encoding Myeloid cell leukemia-1 (Mcl-1) is one of the most common genetic aberrations in human cancer and is associated with high tumor grade and poor survival. Recently, we reported on the discovery of high affinity Mcl-1 inhibitors that elicit mechanism-based cell activity. These inhibitors are lipophilic and contain an acidic functionality which is a common chemical profile for compounds that bind to albumin in plasma. Indeed, these Mcl-1 inhibitors exhibited reduced in vitro cell activity in the presence of serum. Here we describe the structure of a lead Mcl-1 inhibitor when bound to Human Serum Albumin (HSA). Unlike many acidic lipophilic compounds that bind to drug site 1 or 2, we found that this Mcl-1 inhibitor binds predominantly to drug site 3. Site 3 of HSA may be able to accommodate larger, more rigid compounds that do not fit into the smaller drug site 1 or 2. Structural studies of molecules that bind to this third site may provide insight into how some higher molecular weight compounds bind to albumin and could be used to aid in the design of compounds with reduced albumin binding.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Synthesis and biological evaluation of novel aromatic and heterocyclic
           bis-sulfonamide Schiff bases as carbonic anhydrase I, II, VII and IX
           inhibitors
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
      Author(s): Suleyman Akocak, Nabih Lolak, Alessio Nocentini, Gulcin Karakoc, Anzel Tufan, Claudiu T. Supuran
      A series of sixteen novel aromatic and heterocyclic bis-sulfonamide Schiff bases were prepared by conjugation of well known aromatic and heterocyclic aminosulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor pharmacophores with aromatic and heterocyclic bis-aldehydes. The obtained bis-sulfonamide Schiff bases were investigated as inhibitors of four selected human (h) CA isoforms, hCA I, hCA II, hCA VII and hCA IX. Most of the newly synthesized compounds showed a good inhibitory profile against isoforms hCA II and hCA IX, also showing moderate selectivity against hCA I and VII. Several efficient lead compounds were identified among this bis-sulfonamide Schiff bases with low nanomolar to sub-nanomolar activity against hCA II (Kis ranging between 0.4 and 861.1nM) and IX (Kis between 0.5 and 933.6nM). Since hCA II and hCA IX are important drug targets (antiglaucoma and anti-tumor agents), these isoform-selective inhibitors may be considered of interest for various biomedical applications.
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      PubDate: 2017-05-25T15:09:02Z
       
  • Design, synthesis, and pharmacological evaluation of 4-azolyl-benzamide
           derivatives as novel GPR52 agonists
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
      Author(s): Kazuyuki Tokumaru, Yoshiteru Ito, Izumi Nomura, Takashi Nakahata, Yuji Shimizu, Emi Kurimoto, Kazunobu Aoyama, Kazuyoshi Aso
      G protein-coupled receptor 52 (GPR52) agonists are expected to improve the symptoms of psychiatric disorders. During exploration for a novel class of GPR52 agonists with good pharmacokinetic profiles, we synthesized 4-(3-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methyl-1H-1,2,4-triazol-1-yl)-2-methylbenzamide (4u; half maximal effective concentration (EC50)=75nM, maximal response (Emax)=122%) starting from a high-throughput screening hit 3 (EC50 =470nM, Emax =56%). The structural features of a reported GPR52 agonist were applied to 3, led to design 4-azolylbenzamides as novel GPR52 agonists. A structure–activity relationship study of 4-azolylbenzamide resulted in the design of the 1,2,4-triazole derivative 4u, which demonstrated excellent bioavailability in rats (F=53.8%). Oral administration of 4u (10mg/kg) significantly suppressed methamphetamine-induced hyperlocomotion in mice. Thus, 4u is a promising lead compound for drug discovery research of GPR52 agonists.
      Graphical abstract image

      PubDate: 2017-05-25T15:09:02Z
       
 
 
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