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  Subjects -> CHEMISTRY (Total: 848 journals)
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    - CHEMISTRY (602 journals)
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CHEMISTRY (602 journals)                  1 2 3 4 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 5)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 25)
ACS Catalysis     Full-text available via subscription   (Followers: 29)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 16)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 23)
ACS Macro Letters     Full-text available via subscription   (Followers: 21)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 37)
ACS Nano     Full-text available via subscription   (Followers: 188)
ACS Photonics     Full-text available via subscription   (Followers: 7)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 20)
Acta Chemica Iasi     Open Access   (Followers: 1)
Acta Chimica Sinica     Full-text available via subscription  
Acta Chimica Slovaca     Open Access   (Followers: 1)
Acta Chromatographica     Full-text available via subscription   (Followers: 8)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5)
Acta Scientifica Naturalis     Open Access   (Followers: 1)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 6)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 4)
Advanced Functional Materials     Hybrid Journal   (Followers: 45)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 52)
Advances in Chemical Science     Open Access   (Followers: 11)
Advances in Chemistry     Open Access   (Followers: 11)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 17)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Enzyme Research     Open Access   (Followers: 6)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 12)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 16)
Advances in Nanoparticles     Open Access   (Followers: 12)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 14)
Advances in Polymer Science     Hybrid Journal   (Followers: 39)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 17)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 16)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Science and Technology     Full-text available via subscription   (Followers: 7)
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)
Alchemy : Jurnal Penelitian Kimia     Open Access  
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: 64)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 14)
American Journal of Chemistry     Open Access   (Followers: 24)
American Journal of Plant Physiology     Open Access   (Followers: 12)
American Mineralogist     Full-text available via subscription   (Followers: 8)
Anadolu University Journal of Science and Technology     Open Access  
Analyst     Full-text available via subscription   (Followers: 42)
Angewandte Chemie     Hybrid Journal   (Followers: 138)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 188)
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: 23)
Applied Surface Science     Hybrid Journal   (Followers: 23)
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: 6)
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: 243)
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: 17)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 7)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 4)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 110)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 99)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 17)
Biosensors     Open Access   (Followers: 1)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 2)
Bitácora Digital     Open Access  
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 3)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 26)
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: 8)
Canadian Mineralogist     Full-text available via subscription   (Followers: 3)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 65)
Catalysis for Sustainable Energy     Open Access   (Followers: 5)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 7)
Catalysis Science and Technology     Free   (Followers: 6)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 6)
Cellulose     Hybrid Journal   (Followers: 5)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 1)
ChemCatChem     Hybrid Journal   (Followers: 7)
Chemical and Engineering News     Free   (Followers: 10)
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: 22)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 18)
Chemical Reviews     Full-text available via subscription   (Followers: 148)
Chemical Science     Open Access   (Followers: 19)
Chemical Technology     Open Access   (Followers: 13)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 4)
Chemical Week     Full-text available via subscription   (Followers: 7)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 53)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 25)
ChemInform     Hybrid Journal   (Followers: 7)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 5)
Chemistry & Biology     Full-text available via subscription   (Followers: 30)
Chemistry & Industry     Hybrid Journal   (Followers: 4)
Chemistry - A European Journal     Hybrid Journal   (Followers: 124)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 14)
Chemistry and Materials Research     Open Access   (Followers: 15)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 4)
Chemistry in Education     Open Access   (Followers: 3)
Chemistry International     Hybrid Journal   (Followers: 1)
Chemistry Letters     Full-text available via subscription   (Followers: 45)
Chemistry of Materials     Full-text available via subscription   (Followers: 159)
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: 1)
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 3)
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: 5)
Clay Minerals     Full-text available via subscription   (Followers: 8)
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: 1)
Composite Interfaces     Hybrid Journal   (Followers: 5)
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: 11)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 10)
Coordination Chemistry Reviews     Full-text available via subscription  
Copernican Letters     Open Access  
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 5)
Crystal Structure Theory and Applications     Open Access   (Followers: 2)
CrystEngComm     Full-text available via subscription   (Followers: 10)
Current Catalysis     Hybrid Journal   (Followers: 1)
Current Metabolomics     Hybrid Journal   (Followers: 3)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 8)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 15)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 46)
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: 2)
Ecotoxicology and Environmental Contamination     Open Access  
Educación Química     Open Access   (Followers: 1)
Education for Chemical Engineers     Hybrid Journal   (Followers: 5)
EDUSAINS     Open Access  
Elements     Full-text available via subscription   (Followers: 1)
Environmental Chemistry     Hybrid Journal   (Followers: 5)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 2)

        1 2 3 4 | 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  [3040 journals]
  • Chiral resolution of serial potent and selective σ1 ligands and
           biological evaluation of (-)-[18F]TZ3108 in rodent and the nonhuman
           primate brain
    • Abstract: Publication date: Available online 16 January 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Xuyi Yue, Hongjun Jin, Zonghua Luo, Hui Liu, Xiang Zhang, Ethan D. McSpadden, Linlin Tian, Hubert P. Flores, Joel S. Perlmutter, Stanley M. Parsons, Zhude Tu
      Twelve optically pure enantiomers were obtained using either crystallization or chiral high performance liquid chromatography (HPLC) separation methodologies to resolve six racemic sigma-1 (σ 1) receptor ligands. The in vitro binding affinities of each enantiomer for σ 1, σ 2 receptors and vesicular acetylcholine transporter (VAChT) were determined. Out of the 12 optically pure enantiomers, five displayed very high affinities for σ 1 (K i < 2 nM) and high selectivity for σ 1 versus σ 2 and VAChT (>100-fold). The minus enantiomer, (-)-14a ((-)-TZ3108)) (Ki- σ 1 = 1.8 ± 0.4 nM, Ki- σ 2 = 6960 ± 810 nM, Ki-VAChT = 980 ± 87 nM), was chosen for radiolabeling and further in vivo evaluation in rodents and nonhuman primates (NHPs). A biodistribution study in Sprague Dawley rats showed brain uptake (%ID/gram) of (-)-[18F]TZ3108 reached 1.285 ± 0.062 at 5 min and 0.802 ± 0.129 at 120 min. NHP microPET imaging studies revealed higher brain uptake of (-)-[18F]TZ3108 and more favorable pharmacokinetics compared to its racemic counterpart. Pretreatment of the animal using two structurally different σ 1 ligands significantly decreased accumulation of (-)-[18F]TZ3108 in the brain. Together, our in vivo evaluation results suggest that (-)-[18F]TZ3108 is a promising positron emission tomography (PET) tracer for quantifying σ 1 receptor in the brain.
      Graphical abstract image

      PubDate: 2017-01-18T00:53:30Z
       
  • Design, synthesis and antithrombotic evaluation of novel non-peptide
           thrombin inhibitors
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Dongxing Chen, Jinyu Shi, Jing Liu, Xueying Zhang, Xiaoying Deng, Yanyan Yang, Shuang Cui, Qihua Zhu, Guoqing Gong, Yungen Xu
      Ten derivatives of 4-((1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-1-yl)methyl)benzimida-mide (I-1∼I-2, II-1∼II-8) were designed, synthesized and evaluated for their inhibitory effect on human thrombin. Compound II-7 (IC50 =82.8nM), which showed the strongest thrombin inhibitory activity among the tested compounds, was chosen as the lead compound, and ten carbamate derivatives (II-9a∼II-13a, II-9b∼II-12b, II-14) were prepared and evaluated for their anticoagulant activity. The results indicate that most of the tested compounds exhibit a certain degree of inhibitory effect on thrombin-induced platelet aggregation, among which compounds II-11a (IC50 =8.16μM) and II-14 (IC50 =1.95μM) show better anti-platelet aggregation activity than the others. The in vivo experimental results in rat venous thrombosis model also demonstrate compounds II-11a and II-14 can significantly reduce thrombosis in a dose-response manner. It is worth pointing out that the enhanced potency of compound II-14 may be the synergetic effect of 2-hydroxymethyl-3,5,6-trimethylpyrazine (HTMP) and II-7 which are generated by hydrolysis in vivo.
      Graphical abstract image

      PubDate: 2017-01-18T00:53:30Z
       
  • Discovery of biphenyl imidazole derivatives as potent antifungal agents:
           Design, synthesis, and structure-activity relationship studies
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Dongmei Zhao, Shizhen Zhao, Liyu Zhao, Xiangqian Zhang, Peng Wei, Chunchi Liu, Chenzhou Hao, Bin Sun, Xin Su, Maosheng Cheng
      Fungal infections have became a serious medical problem due to their high incidence and mortality. We describe the discovery and structure-activity relationships studies (SARs) of a series of novel biphenyl imidazole derivatives with excellent antifungal activities against Candida albicans and Cryptococcus neoformans. The most promising compounds 12f–g and 19a–b exhibited excellent activity with minimum inhibitory concentration (MIC) values in the range of 0.03125–2μg/mL. Preliminary mechanism studies showed that the potent antifungal activity of compound 12g stemed from inhibition of CYP51 in Candida albicans. Furthermore, compounds 12g and 19b exhibited low inhibition profiles for various human cytochrome P450 isoforms. The SARs and binding mode established in this study will be useful for further lead optimization.
      Graphical abstract image

      PubDate: 2017-01-18T00:53:30Z
       
  • Design, synthesis, molecular modeling and anti-hyperglycemic evaluation of
           novel quinoxaline derivatives as potential PPARγ and SURs agonists
    • Abstract: Publication date: Available online 16 January 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Mohamed.K. Ibrahim, Ibrahim H. Eissa, AbdallahE. Abdallah, Ahmed M. Metwaly, M.M. and M.A. Radwan ElSohly
      In our effort to develop potent anti-hyperglycemic agents with potential agonistic activities toward PPARγ and SURs, three novel series of quinoxaline derivatives bearing sulfonylurea or sulfonylthiourea moieties with different linkers were designed and synthesized. Some of the newly synthesized compounds were evaluated in vivo for their anti-hyperglycemic activities in STZ-induced hyperglycemic rats. Compounds 15a , 15e, 19b and 24a exhibited the highest anti-hyperglycemic activities with% reduction in blood glucose level of (50.58, 43.84, 45.10 and 49.62, respectively). Additionally, eight compounds revealed potent anti-hyperglycemic activities were further evaluated in vitro for their PPARγ binding affinity and insulin-secreting ability as potential mechanisms for anti-hyperglycemic activity. Four compounds (15a , 15b , 15d and 15e ) significantly bound to PPARγ with IC50 values of 0.482, 0.491, 0.350 and 0.369 μM, respectively. Moreover, Compounds 15a and 15b have demonstrated induction of insulin-secretion with EC50 values of 0.92 and 0.98 μM, respectively. Furthermore, molecular docking and pharmacophore generation techniques were carried out to investigate binding patterns and fit values of the designed compounds with PPARγ and SUR, respectively.
      Graphical abstract image

      PubDate: 2017-01-18T00:53:30Z
       
  • Coating lanthanide nanoparticles with carbohydrate ligands elicits
           affinity for HeLa and RAW264.7 cells, enhancing their photodamaging effect
           
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Takashi Kanamori, Takashi Sawamura, Tatsumi Tanaka, Izumi Sotokawa, Ryota Mori, Kotaro Inada, Akihiro Ohkubo, Shun-Ichiro Ogura, Yasutoshi Murayama, Eigo Otsuji, Hideya Yuasa
      Lanthanide nanoparticles (LNPs) conjugated with monosaccharides were synthesized as a photon energy-upconverting nanodevice with affinity to cancer cells. The conjugates were designed to selectively damage the cancer cells containing protoporphyrin IX, a photosensitizer endogenously synthesized from priorly administrated 5-aminolevlunic acid (ALA), by a highly tissue-penetrative near-infrared (NIR) irradiation. First of all, the affinities of monosaccharides toward cells (HeLa, RAW264.7, and MKN45) were assessed by a novel cell aggregation assay with trivalent monosaccharide-citric acid conjugates. As a result, HeLa exhibited high affinity for glucose, while RAW264.7 for glucose, galactose, mannose, and fucose. A similar cell-monosaccharide affinity was microscopically observed when the cells were mixed with monosaccharide-LNP conjugates and rinsed, in which the high affinity LNP probes luminesced on the cells. The high affinity monosaccharide-LNPs showed greater photodamaging effects than the unmodified LNP toward the corresponding cells, when the cells were pretreated with ALA and irradiated by NIR. This study demonstrates that carbohydrates can be used as selective ligands for cancer cells in a photodynamic therapy with LNP.
      Graphical abstract image

      PubDate: 2017-01-18T00:53:30Z
       
  • Synthesis and optimization of novel α-phenylglycinamides as selective
           TRPM8 antagonists
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Jun-ichi Kobayashi, Hideaki Hirasawa, Tetsuji Ozawa, Tomonaga Ozawa, Hiroo Takeda, Yoshikazu Fujimori, Osamu Nakanishi, Noboru Kamada, Tetsuya Ikeda
      Transient receptor potential melastatin 8 (TRPM8) is activated by innocuous cold and chemical substances, and antagonists of this channel have been considered to be effective for pain and urinary diseases. N-(3-aminopropyl)-2-{[(3-methylphenyl)methyl]oxy}-N-(2-thienylmethyl)benzamide hydrochloride (AMTB), a TRPM8 antagonist, was proposed to be effective for overactive bladder and painful bladder syndrome; however, there is a potential risk of low blood pressure. We report herein the synthesis and structure–activity relationships of novel phenylglycine derivatives that led to the identification of KPR-2579 (20l), a TRPM8 selective antagonist. KPR-2579 reduced the number of icilin-induced wet-dog shakes and rhythmic bladder contraction in rats, with no negative cardiovascular effects at the effective dose.
      Graphical abstract image

      PubDate: 2017-01-18T00:53:30Z
       
  • Multitarget drug design strategy against Alzheimer’s disease:
           Homoisoflavonoid Mannich base derivatives serve as acetylcholinesterase
           and monoamine oxidase B dual inhibitors with multifunctional properties
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Yan Li, Xiaoming Qiang, Li Luo, Xia Yang, Ganyuan Xiao, Yunxiaozhu Zheng, Zhongcheng Cao, Zhipei Sang, Fu Su, Yong Deng
      A series of homoisoflavonoid Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents against Alzheimer’s disease. It demonstrated that most of the derivatives were selective AChE and MAO-B dual inhibitors with good multifunctional properties. Among them, compound 10d displayed the comprehensive advantages, with excellent AChE and MAO-B inhibitory activities (IC50 =2.49±0.08nM and 1.74±0.0581μM, respectively), good self- and Cu2+-induced Aβ 1-42 aggregation inhibitory potency, antioxidant activity, biometal chelating ability and high BBB permeability. These multifunctional properties make 10d as an excellent candidate for the development of efficient drugs against AD.
      Graphical abstract image

      PubDate: 2017-01-18T00:53:30Z
       
  • Cellular uptake of glucoheptoamidated poly(amidoamine) PAMAM G3 dendrimer
           with amide-conjugated biotin, a potential carrier of anticancer drugs
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Łukasz Uram, Magdalena Szuster, Aleksandra Filipowicz, Magdalena Zaręba, Elżbieta Wałajtys-Rode, Stanisław Wołowiec
      In search for soluble derivatives of PAMAM dendrimers as potential carriers for hydrophobic drugs, the conjugates of PAMAM G3 with biotin, further converted into glycodendrimer with d-glucoheptono-1,4-lactone, were prepared. Polyamidoamine dendrimer (PAMAM) of third generation, G3 was functionalized with four biotin equivalents covalently attached to terminal amine nitrogens via amide bond G34B. The remaining 28 amine groups were blocked by glucoheptoamide substituents (gh) to give G34B28gh or with one fluorescein equivalent (attached by reaction of G34B with fluorescein isothiocyanate, FITC) via thiourea bond as FITC followed by exhaustive glucoheptoamidation to get G34B27gh1F. As a control the G3 substituted totally with 32 glucoheptoamide residues, G3gh and its fluorescein labeled analogue G331gh1F were synthesized. The glucoheptoamidation of PAMAM G0 dendrimer with glucoheptono-1,4-lactone was performed in order to fully characterize the 1H NMR spectra of glucoheptoamidated PAMAM dendrimers and to control the derivatization of G3 with glucoheptono-1,4-lactone. Another two derivatives of G3, namely G34B28gh1F′ and G332ghF′, with ester bonded fluorescein were also obtained. Biological properties of obtained dendrimer conjugates were estimated in vitro with human cell lines: normal fibroblast (BJ) and two cancer glioblastoma (U-118 MG) and squamous carcinoma (SCC-15), including cytotoxicity by reduction of XTT and neutral red (NR) assays. Cellular uptake of dendrimer conjugates was evaluated with confocal microscopy. Obtained results confirmed, that biotinylated bioconjugates have always lower cytotoxicity and 3–4 times higher cellular uptake than non-biotinylated dendrimer conjugates in all cell lines. Comparison of various cell lines revealed different dose-dependent cell responses and the lower cytotoxicity of examined dendrimer conjugates for normal fibroblasts and squamous carcinoma, as compared with much higher cytotoxic effects seen in glioblastoma cell line. Synthetized multi-functional conjugate (G34B27gh1F) is a promising candidate as biocompatible vehicle for hydrophobic molecules used in anticancer therapy.
      Graphical abstract image

      PubDate: 2017-01-18T00:53:30Z
       
  • Synthesis and immunological evaluation of a low molecular weight
           saccharide with TLR-4 agonist activity
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Vikram Basava, Heather Romlein, Constantine Bitsaktsis, Cecilia H. Marzabadi
      The paucity of FDA approved adjuvants renders the synthesis, characterization, and use of new compounds as vaccine adjuvants, a necessity. For this purpose, a novel saccharide analog has been synthesized from glucosamine, pyruvylated galactose and 1,4-cyclohexanediol and its biological efficacy was determined in innate immune cells. More specifically, we assessed the production of pro-inflammatory cytokines from the murine monocyte cell line, Raw 264.7 and from C57 BL/6 mouse peritoneal macrophages following exposure to the saccharide analog. Our data conclude that the novel saccharide has immunostimulatory activity on mouse macrophages as indicated by the elevated levels of IL-6 and TNF-α in culture supernatants. This effect was TLR-4-dependent but TLR-2-independent. Our data, suggest TLR-4 agonism; a key feature of vaccine adjuvants.
      Graphical abstract image

      PubDate: 2017-01-18T00:53:30Z
       
  • Synthesis of new spirooxindole-pyrrolothiazoles derivatives: Anti-cancer
           activity and molecular docking
    • Abstract: Publication date: Available online 16 January 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Gehad Lotfy, Mohamed M. Said, El Sayed H. El Ashry, El Sayed H. El Tamany, Abdullah Al-Dhfyan, Yasmine M. Abdel Aziz, Assem Barakat
      The 1,3-dipolar cycloadditions of an azomethine ylide generated from isatin and thiazolidinecarboxylic acid to a series of 2,6-bis[(E)-arylmethylidene]cyclohexanones afforded new di-spiro heterocycles incorporating pyrrolidine and oxindole rings in quantitative yields and chemo-, regio-, and stereoselectively. The newly synthesized compounds were characterized using spectroscopic techniques. Furthermore, the molecular structures of 4a, 4e, and 4n were confirmed by X-ray crystallography. These newly synthesized compounds were screened for their in vitro activity against breast cancer cell line MCF-7 and K562-leukemia. 4k was found to be the most potent compound of this series in targeting MCF-7 breast cancer cells and K562-leukemia, with IC50 values of 15.32 ± 0.02 and 14.74 ± 0.7 μM, respectively. The molecular studies of the synthesized compounds were investigated.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Identification of Novel Inverse Agonists of Estrogen-Related Receptors
           ERRγ and ERRβ
    • Abstract: Publication date: Available online 16 January 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Donna D. Yu, Janice M. Huss, Hongzhi Li, Barry M. Forman
      Estrogen-related receptors (ERRs, α, β, and γ) are orphan nuclear receptors most closely related in sequence to estrogen receptors (ERα and ERβ). Much attention has been paid recently to the functions of ERRs for their potential roles as new therapeutic targets implicated in the etiology of metabolic disorders. While no endogenous ligand has been identified for any of the ERR isoforms to date, the potential for using synthetic small molecules to modulate their activity has been demonstrated. In the present study, a series of novel inverse agonists of ERRγ and ERRβ were synthesized using regio- and stereo-specific direct substitution of triarylethylenes. These compounds were evaluated for their ability to modulate the activities of ERRs. The rational directed substitution approach and extensive SAR studies resulted in the discovery of compound 4a (DY40) as the most potent ERRγ inverse agonist described to date with mixed ERRγ/ERRβ functional activities, which potently suppressed the transcriptional functions of ERRγ with IC50 = 0.01 μM in a cell-based reporter gene assay and antagonized ERRγ with a potency approximately 60 times greater than its analog Z-4-OHT (Z-4-hydroxytamoxifen). In addition, compound 3h (DY181) was identified as the most potent synthetic inverse agonist for the ERRβ that exhibited excellent selectivity over ERRα/γ in functional assays. This selectivity was also supported by computational docking models that suggest DY181 forms more extensive hydrogen bound network with ERRβ which should result in higher binding affinity on ERRβ over ERRγ.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Identification of allosteric binding sites for PI3Kα oncogenic mutant
           specific inhibitor design
    • Abstract: Publication date: Available online 16 January 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Michelle S. Miller, Sweta Maheshwari, Fiona M. McRobb, Kenneth W. Kinzler, L. Mario Amzel, Bert Vogelstein, Sandra B. Gabelli
      PIK3CA, the gene that encodes the catalytic subunit of phosphatidylinositol 3-kinase α (PI3Kα), is frequently mutated in breast and other types of cancer. A specific inhibitor that targets the mutant forms of PI3Kα could maximize treatment efficiency while minimizing side-effects. Herein we describe the identification of novel binding pockets that may provide an opportunity for the design of mutant selective inhibitors. Using a fragment-based approach, we screened a library of 352 fragments (MW <300 Da) for binding to PI3Kα by X-ray crystallography. Five novel binding pockets were identified, each providing potential opportunities for inhibitor design. Of particular interest was a binding pocket near Glu542, which is located in one of the two most frequently mutated domains.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Synthesis and evaluation of a 68Ga-labeled bradykinin B1 receptor agonist
           for imaging with positron emission tomography
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Guillaume Amouroux, Zhengxing Zhang, Jinhe Pan, Silvia Jenni, Chengcheng Zhang, Navjit Hundal-Jabal, Nadine Colpo, Jutta Zeisler, Kuo-Shyan Lin, François Bénard
      A novel 68Ga-labeled bradykinin B1 receptor (B1R) agonist, 68Ga-Z01115, was synthesized and evaluated for imaging with positron emission tomography (PET). Z01115 exhibited good binding affinity (Ki =25.4±5.1nM) to hB1R. 68Ga-Z01115 was prepared in 74±5 decay-corrected radiochemical yield with >99% radiochemical purity and 155±89GBq/µmol (4.2±2.4Ci/μmol) specific activity. 68Ga-Z01115 was stable in vitro in mouse plasma (93% remaining intact after 60min incubation), and relatively stable in vivo (51±5% remaining intact at 5min post-injection). PET imaging and biodistribution studies in mice showed that 68Ga-Z01115 cleared rapidly from nontarget tissues/organs, and generated high target-to-nontarget contrast images. The uptake of 68Ga-Z01115 in B1R-positive (B1R+) tumor was 5.65±0.59%ID/g at 1h post-injection. Average contrast ratios of B1R+ tumor-to-B1R− tumor, -to-blood and -to-muscle were 24.3, 24.4 and 82.9, respectively. Uptake of 68Ga-Z01115 in B1R+ tumors was reduced by ∼90% with co-injection of cold standard, confirming it was mediated by B1R. Our data suggest that 68Ga-Z01115 is a promising tracer for imaging the expression of B1R that is overexpressed in a variety of cancers.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Synthesis and biological evaluation of phosphate isosters of fosmidomycin
           and analogs as inhibitors of Escherichia coli and Mycobacterium smegmatis
           1-deoxyxylulose 5-phosphate reductoisomerases
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Mathilde Munier, Denis Tritsch, Fanny Krebs, Jérémy Esque, Andréa Hemmerlin, Michel Rohmer, Roland H. Stote, Catherine Grosdemange-Billiard
      Hydroxamate analogs of fosfoxacin, the phosphate homolog of fosmidomycin, have been synthesized and their activity tested on Escherichia coli and Mycobacterium smegmatis DXRs. Except for compound 4b, the IC50 values of phosphate derivatives are approximately 10-fold higher than those of the corresponding phosphonates. Although their inhibitory activity on Escherichia coli DXR is less efficient than their phosphonate analogs, we report the ability of phosphate compounds to inhibit the growth of Escherichia coli. This work points out that the uptake of fosfoxacin and its analogs is taking place via the GlpT and UhpT transporters. As expected, these compounds are inefficient to inhibit the growth of M. smegmatis growth inhibition probably due to a lack of uptake.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Coumarins and other fused bicyclic heterocycles with selective
           tumor-associated carbonic anhydrase isoforms inhibitory activity
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Murat Bozdag, Ahmed Mahmoud Alafeefy, Abdul Malik Altamimi, Daniela Vullo, Fabrizio Carta, Claudiu T. Supuran
      Herein we report for the first time a series of 2-benzamido-N-(2-oxo-4-(methyl/trifluoromethyl)-2H-chromen-7-yl) benzamide 3a–f and substituted quinazolin-4(3H)-ones and 2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxides (5, 6, 8 and 10a–c) as selective inhibitors of the tumor associated hCA IX and XII isoforms. Among the compounds reported the trifluoromethyl derivative 3d resulted the most potent against these CA isoforms with KIs of 10.9 and 6.7nM.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Design, synthesis and analgesic/anti-inflammatory evaluation of novel
           diarylthiazole and diarylimidazole derivatives towards selective COX-1
           inhibitors with better gastric profile
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Ahmed H. Abdelazeem, Mohammed T. El-Saadi, Asmaa G. Safi El-Din, Hany A. Omar, Samir M. El-Moghazy
      The inhibition of gastric cyclooxygenase 1 (COX-1) enzyme was believed to be the major cause of non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastric ulcer. Recent studies disproved this belief and showed that the gastric tissues vulnerability is not solely connected to COX-1 inhibition. This work aimed at exploring and rationalizing the differential analgesic and anti-inflammatory activities of novel selective COX-1 inhibitors with improved gastric profile. Two novel series of 4,5-diarylthiazole and diarylimidazole were designed, synthesized in analogy to selective COX-1 inhibitors (mofezolac and FR122047) which lack gastric damaging effects. The new compounds were evaluated in vitro for their COXs inhibitory activity and in vivo for their anti-inflammatory and analgesic potentials. Four compounds; diphenylthiazole glycine derivatives (15a, 15b) and diphenylimidazolo acetic acid derivatives (19a, 19b), which possess carboxylic acid group exhibited significant activity and selectivity against COX-1 over COX-2. Of these compounds, (4,5-bis(4-methoxyphenyl)thiazol-2-yl)glycine 15b was the most potent compound against COX-1 with an inhibitory half maximal concentration (IC50) of 0.32μM and a selectivity index (COX-2 IC50/COX-1 IC50) of 28.84. Furthermore, an ulcerogenicity study was performed where the tested compounds demonstrated a significant gastric tolerance. Interestingly, the most selective COX-1 inhibitor showed higher analgesic activity in vivo as expected compared to their moderate anti-inflammatory activity. This study underscores the need for further design and development of novel analgesic agents with low tendency to cause gastric damage based on improving their COX-1 affinity and selectivity profile.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Influence of chain length on the activity of tripeptidomimetic antagonists
           for CXC chemokine receptor 4 (CXCR4)
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Markus Baumann, Mohammad Musarraf Hussain, Nina Henne, Daniel Moya Garrote, Stefanie Karlshøj, Torgils Fossen, Mette M. Rosenkilde, Jon Våbenø, Bengt Erik Haug
      Here we report a series of close analogues of our recently published scaffold-based tripeptidomimetic CXCR4 antagonists, containing positively charged guanidino groups in R1 and R2, and an aromatic group in R3. While contraction/elongation of the guanidine carrying side chains (R1 and R2) resulted in loss of activity, introduction of bromine in position 1 on the naphth-2-ylmethyl moiety (R3) resulted in an EC50 of 61μM (mixture of diastereoisomers) against wild-type CXCR4; thus, the antagonistic activity of these tripeptidomimetics seems to be amenable to optimization of the aromatic moiety. Moreover, for analogues carrying a naphth-2-ylmethyl substituent, we observed that a Pictet-Spengler like cyclization side reaction depended on the nature of the R1 substituent.
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      PubDate: 2017-01-18T00:53:30Z
       
  • 3-Amino-thieno[2,3-b]pyridines as microtubule-destabilising agents:
           Molecular modelling and biological evaluation in the sea urchin embryo and
           human cancer cells
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Chatchakorn Eurtivong, Victor Semenov, Marina Semenova, Leonid Konyushkin, Olga Atamanenko, Jóhannes Reynisson, Alex Kiselyov
      A series of 3-amino-thieno[2,3-b]pyridines was prepared and tested in a phenotypic sea urchin embryo assay to identify potent and specific molecules that affect tubulin dynamics. The most active compounds featured a tricyclic core ring system with a fused cycloheptyl or cyclohexyl substituent and unsubstituted or alkyl-substituted phenyl moiety tethered via a carboxamide. Low nano-molar potency was observed in the sea urchin embryos for the most active compounds (1–5) suggestive of a microtubule-destabilising effect. The molecular modelling studies indicated that the tubulin colchicine site is inhibited, which often leads to microtubule-destabilisation in line with the sea urchin embryo results. Finally, the identified hits displayed a robust growth inhibition (GI50 of 50–250nM) of multidrug-resistant melanoma MDA-MB-435 and breast MDA-MB-468 human cancer cell lines. This work demonstrates that for the thieno[2,3-b]pyridines the most effective mechanism of action is microtubule-destabilisation initiated by binding to the colchicine pocket.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Structure-activity relationship study of a small cyclic peptide
           H-c[Lys-Pro-Glu]-Arg-OH: a potent inhibitor of Vascular Endothelial Growth
           Factor interaction with Neuropilin-1
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Karolina Grabowska, Anna K. Puszko, Piotr F.J. Lipiński, Anna K. Laskowska, Beata Wileńska, Ewa Witkowska, Gerard Y. Perret, Aleksandra Misicka
      Inhibition of angiogenesis is one of the most promising approaches in anticancer therapy. It was recently suggested that Neuropilin-1 (NRP-1) in tumour cells may serve as a separate receptor for Vascular Endothelial Growth Factor-165 (VEGF165) which is one of the main pro-angiogenic agents in the organism. Therefore molecules inhibiting VEGF165 binding to NRP-1 could be potential candidates for new antiangiogenic and anticancer drugs. Here we present a structure-activity relationship study of the peptide H-c[Lys-Pro-Glu]-Arg-OH which showed high inhibitory effect on VEGF165/NRP-1 binding (IC50 =0.18μM) in our previous study. We report the design, synthesis, in vitro assays and docking analysis of four small cyclic peptides (14-,15-membered ring) and one bigger cyclic compound (30-membered ring). Our study shows that both the ring size and configuration of amino acid residues present in the structure are crucial for high inhibitory effect.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Synthesis of a biological active β-hairpin peptide by addition of two
           structural motifs
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Sabrina Fischer, Matthias Lamping, Maike Gold, Yvonne Röttger, Dörte Brödje, Richard Dodel, Renate Frantz, Mobarak Abu Mraheil, Trinad Chakraborty, Armin Geyer
      The idea of privileged scaffolds – that there seem to be more bioactive compounds found around some structures than others – is well established for small drug molecules, but has little significance for standalone peptide secondary structures whose adaptable shapes escape the definition of a 3D motif in the absence of a protein scaffold. Here, we joined two independent biological functions in a single highly restricted peptide to support the hypothesis that the β-hairpin shape is the common basis of two otherwise unrelated biological recognition processes. To achieve this, the hydrophobic cluster HWX4LV from the decapeptide cyclic hairpin model peptide C1-C10 cyclo-CHWEGNKLVC was included in the bicyclic peptide 2. The designed β-hairpin peptide C4-C17, C8-C13 bicyclo-KHQCHWECTZGRCRLVCGRSGS (2, Z=citrulline), serves, on the one hand, as a specific epitope for rheumatoid autoantibodies and, on the other hand, shows a not negligible antibiotic effect against the bacterial strain E. coli AS19.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Anion inhibition profiles of the γ-carbonic anhydrase from the pathogenic
           bacterium Burkholderia pseudomallei responsible of melioidosis and highly
           drug resistant to common antibiotics
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Sonia Del Prete, Daniela Vullo, Pietro Di Fonzo, Sameh M. Osman, Zeid AlOthman, Claudiu T. Supuran, Clemente Capasso
      Burkholderia pseudomallei is a Gram-negative saprophytic bacterium responsible of melioidosis, an endemic disease of tropical and sub-tropical regions of the world. A recombinant γ-CA (BpsγCA) identified in the genome of this bacterium was cloned and purified. Its catalytic activity and anion inhibition profiles were investigated. The enzyme was an efficient catalyst for the CO2 hydration showing a kcat of 5.3×105 s−1 and kcat/Km of 2.5×107 M−1 ×s−1. The best BpsγCA inhibitors were sulfamide, sulfamic acid, phenylboronic acid and phenylarsonic acid, which showed KI in the range of 49–83μM (these inhibitors showed millimolar inhibition constant against hCA II), followed by diethyldithiocarbamate, selenate, tellurate, perrhenate, selenocyanate, trithiocarbonate, tetraborato, pyrophosphate, stannate, carbonate, bicarbonate, azide, cyanide, thiocyanate and cyanate with KIs in the range of 0.55–9.1mM. In our laboratories, work is in progress to resolve the X-ray crystal structures of BpsγCA, which may allow the development of small molecule inhibitors with desired properties for targeting and inhibiting specifically the bacterial over the human CAs, considering the fact that B. pseudomallei is involved in a serious bacterial disease.
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      PubDate: 2017-01-18T00:53:30Z
       
  • SRC2-3 binds to vitamin D receptor with high sensitivity and strong
           affinity
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Daichi Egawa, Toshimasa Itoh, Akira Kato, Saori Kataoka, Yasuaki Anami, Keiko Yamamoto
      Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily and regulates the expression of target genes through ligand binding. To express the target gene, coactivator binding to the VDR/ligand complex is essential. Although there are many coactivators in living cells, precise interactions between coactivators and VDR have not been clarified. Here, we synthesized two coactivator peptides, DRIP205-2 and SRC2-3, evaluated their affinity for the ligand-binding domain (LBD) of VDR using 1α,25-dihydroxyvitamin D3, partial agonist 1, and antagonist 2 by surface plasmon resonance (SPR), and assessed their interaction modes with VDR-LBD using X-ray crystallographic analysis. This study showed that the SRC2-3 peptide is more sensitive to the ligands (agonist, partial agonist, and antagonist) and shows more intimate interactions with VDR-LBD than DRIP205-2 peptide.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Discovery and preclinical evaluation of
           7-benzyl-N-(substituted)-pyrrolo[3,2-d]pyrimidin-4-amines as single agents
           with microtubule targeting effects along with triple-acting angiokinase
           inhibition as antitumor agents
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Roheeth Kumar Pavana, Shruti Choudhary, Anja Bastian, Michael A. Ihnat, Ruoli Bai, Ernest Hamel, Aleem Gangjee
      The utility of cytostatic antiangiogenic agents (AA) in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of AA with microtubule targeting agents (MTAs) have been particularly successful. The discovery, synthesis and biological evaluations of a series of 7-benzyl-N-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds which inhibit proangiogenic receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor-β (PDGFR-β) and epidermal growth factor receptor (EGFR), along with microtubule targeting in single molecules are described. These compounds also inhibited blood vessel formation in the chicken chorioallantoic membrane (CAM) assay, and some potently inhibited tubulin assembly (with activity comparable to that of combretastatin A-4 (CA)). In addition, some of the analogs circumvent the most clinically relevant tumor resistance mechanisms (P-glycoprotein and β-III tubulin expression) to microtubule targeting agents (MTA). These MTAs bind at the colchicine site on tubulin. Two analogs displayed two to three digit nanomolar GI50 values across the entire NCI 60 tumor cell panel and one of these, compound 7, freely water soluble as its HCl salt, afforded excellent in vivo antitumor activity against an orthotopic triple negative 4T1 breast cancer model and was superior to doxorubicin.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Biotransformation of rutabaga phytoalexins by the fungus Alternaria
           brassicicola: Unveiling the first hybrid metabolite derived from a
           phytoalexin and a fungal polyketide
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): M. Soledade C. Pedras, Abbas Abdoli
      The biotransformations of the rutabaga phytoalexins rutalexin, brassicanate A, isalexin and rapalexin A by the plant pathogenic fungus Alternaria brassicicola are reported. While the biotransformations of rutalexin, brassicanate A, and isalexin are fast, rapalexin A is resistant to fungal transformation. Unexpectedly, biotransformation of rutalexin yields a hybrid metabolite named rutapyrone, derived from rutalexin metabolism and phomapyrone G, a fungal metabolite produced by A. brassicicola. These fungal transformations are detoxification reactions likely carried out by different enzymes. The discovery of rapalexin A resistance to detoxification suggests that this phytoalexin in combination with additional phytoalexins could protect crucifers against this pathogen. Phytoalexins resistant to degradation by A. brassicicola are expected to provide the producing plants with higher disease resistance levels.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Anti-inflammatory tetraquinane diterpenoids from a Crinipellis species
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Markus Rohr, Katharina Oleinikov, Mathias Jung, Louis P. Sandjo, Till Opatz, Gerhard Erkel
      The small pro-inflammatory 10kDa chemokine CXCL10 (Interferon-inducible protein 10, IP-10) plays an important role in mediating immune responses through the activation and recruitment of leukocytes such as T cells, eosinophils, monocytes and NK cells to the sites of inflammation. Elevated levels of CXCL10 have been associated with chronic inflammatory and infectious diseases and therefore CXCL10 represents an attractive target for the development of new anti-inflammatory drugs. In a search for anti-inflammatory compounds from fungi inhibiting the inducible CXCL10 promoter activity, four new tetraquinane diterpenoids, crinipellin E (1), crinipellin F (2), crinipellin G (3) and crinipellin H (4) were isolated from fermentations of a Crinipellis species. The structures of the compounds were elucidated by a combination of one- and two-dimensional NMR spectroscopy and mass spectrometry. Compounds 1, 2, and 3 inhibited the LPS/IFN-γ induced CXCL10 promoter activity in transiently transfected human MonoMac6 cells in a dose-dependent manner with IC50 values of 15μM, 1.5μM, and 3.15μM respectively, whereas compound 4 was devoid of any biological activity. Moreover, compounds 1, 2 and 3 reduced mRNA levels and synthesis of pro-inflammatory mediators such as cytokines and chemokines in LPS/IFN-γ stimulated MonoMac6 cells.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Triazolopyridine ethers as potent, orally active mGlu2 positive allosteric
           modulators for treating schizophrenia
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Mendi A. Higgins, Lawrence R. Marcin, F. Christopher Zusi, Robert Gentles, Min Ding, Bradley C. Pearce, Amy Easton, Walter A. Kostich, Matthew A. Seager, Clotilde Bourin, Linda J. Bristow, Kim A. Johnson, Regina Miller, John Hogan, Valerie Whiterock, Michael Gulianello, Meredith Ferrante, Yanling Huang, Adam Hendricson, Andrew Alt, John E. Macor, Joanne J. Bronson
      Triazolopyridine ethers with mGlu2 positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10mg/kg (p.o.). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mGlu2 PAMs for the treatment of schizophrenia and merit further preclinical investigation.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Structure-anticonvulsant activity studies in the group of (E)-N-cinnamoyl
           aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3
           or 2-CH3
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Agnieszka Gunia-Krzyżak, Dorota Żelaszczyk, Anna Rapacz, Ewa Żesławska, Anna M. Waszkielewicz, Katarzyna Pańczyk, Karolina Słoczyńska, Elżbieta Pękala, Wojciech Nitek, Barbara Filipek, Henryk Marona
      A series of twenty two (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3 was designed, synthesized and evaluated for anticonvulsant activity in rodent models of seizures: maximal electroshock (MES) test, subcutaneous pentylenetetrazole (scPTZ) test, and 6-Hz test. There were identified three most active compounds: S-(2E)-N-(1-hydroxypropan-2-yl)-3-(2-methylphenyl)prop-2-enamide (5) (ED50 MES=42.56, ED50 scPTZ=58.38, ED50 6-Hz 44mA=42.27mg/kg tested in mice after intraperitoneal (i.p.) administration); R,S-(2E)-3-(4-chlorophenyl)-N-(1-hydroxybutan-2-yl)prop-2-enamide (6) (ED50 MES=53.76, ED50 scPTZ=90.31, ED50 6-Hz 44mA=92.86mg/kg mice, i.p.); and R,S-(2E)-3-(4-chlorophenyl)-N-(2-hydroxypropyl)prop-2-enamide (11) (ED50 MES=55.58, ED50 scPTZ=102.15, ED50 6-Hz 44mA=51.27mg/kg mice, i.p.). Their structures and configurations were confirmed by crystal X-ray diffraction method. The structure-activity studies among the tested series showed that chlorine atom in position para or methyl group in position ortho of phenyl ring were beneficial for anticonvulsant activity. Methyl group in position para of phenyl ring decreased anticonvulsant activity in reported series of cinnamamide derivatives.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Effects of new fluorinated analogues of GABA, pregabalin bioisosters, on
           the ambient level and exocytotic release of [3H]GABA from rat brain nerve
           terminals
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): T. Borisova, N. Pozdnyakova, E. Shaitanova, I. Gerus, M. Dudarenko, G. Haufe, V. Kukhar
      Recently, we have shown that new fluorinated analogues of γ-aminobutyric acid (GABA), bioisosters of pregabalin (β-i-Bu-GABA), i.e. β-polyfluoroalkyl-GABAs (FGABAs), with substituents: β-CF3-β-OH (1), β-CF3 (2); β-CF2CF2H (3), are able to increase the initial rate of [3H]GABA uptake by isolated rat brain nerve terminals (synaptosomes), and this effect is higher than that of pregabalin. So, synthesized FGABAs are structural but not functional analogues of GABA. Herein, we assessed the effects of synthesized FGABAs (100μM) on the ambient level and exocytotic release of [3H]GABA in nerve terminals and compared with those of pregabalin (100μM). It was shown that FGABAs 1–3 did not influence the ambient level of [3H]GABA in the synaptosomal preparations, and this parameter was also not altered by pregabalin. During blockage of GABA transporters GAT1 by specific inhibitor NO-711, FGABAs and pregabalin also did not change ambient [3H]GABA in synaptosomal preparations. Exocytotic release of [3H]GABA from synaptosomes decreased in the presence of FGABAs 1–3 and pregabalin, and the effects of FGABAs 1 & 3 were more significant than those of FGABAs 2 and pregabalin. FGABAs 1–3/pregabalin-induced decrease in exocytotic release of [3H]GABA from synaptosomes was not a result of changes in the potential of the plasma membrane. Therefore, new synthesized FGABAs 1 & 3 were able to decrease exocytotic release of [3H]GABA from nerve terminals more effectively in comparison to pregabalin. Absence of unspecific side effects of FGABAs 1 & 3 on the membrane potential makes these compounds perspective for medical application.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Design and synthesis of phosphoryl-substituted diphenylpyrimidines
           (Pho-DPPYs) as potent Bruton’s tyrosine kinase (BTK) inhibitors:
           Targeted treatment of B lymphoblastic leukemia cell lines
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Yang Ge, Haijun Yang, Changyuan Wang, Qiang Meng, Lei Li, Huijun Sun, Yuhong Zhen, Kexin Liu, Yanxia Li, Xiaodong Ma
      A family of phosphoryl-substituted diphenylpyrimidine derivatives (Pho-DPPYs) were synthesized and biologically evaluated as potent BTK inhibitors in this study. Compound 7b was found to markedly inhibit BTK activity at concentrations of 0.82nmol/L, as well as to suppress the proliferations of B-cell leukemia cell lines (Ramos and Raji) expressing high levels of BTK at concentrations of 3.17μM and 6.69μM. Moreover, flow cytometry analysis results further indicated that 7b promoted cell apoptosis to a substantial degree. In a word, compound 7b is a promising BTK inhibitor for the treatment of B-cell lymphoblastic leukemia.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Synthesis and characterization of novel, conjugated, fluorescent DNJ
           derivatives for α-glucosidase recognition
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Akihiko Hatano, Yuichi Kanno, Yuya Kondo, Yuta Sunaga, Hatsumi Umezawa, Munehiro Okada, Hideshi Yamada, Ren Iwaki, Atsushi Kato, Koji Fukui
      A series of five new fluorescent deoxynojirimycin (DNJ) conjugates were synthesized and evaluated for their inhibitory effect (IC50) on several α- and β-glucosidases. Three of the conjugates showed enhanced activity. The two synthetic conjugates, DNJ-CF3 1 and DNJ-Me 2, exhibited improved α-glucosidase inhibitory effects compared to DNJ and miglitol. Interestingly, conjugates 1 and 2 showed strong inhibition of almond-derived β-glucosidase, in contrast to the inhibition tendencies of other inhibitors. Conjugate 5 strongly inhibited rat intestinal maltase, even at 0.10μM. A docking study indicated that all five conjugates bind to the active site of α-glucosidase (PDB: 3L4V, derived from Homo sapiens). The DNJ portion of the conjugate fits into the cavity of the enzyme, and the fluorescent part locates randomly on the outside surface. Thus, it is likely that these conjugates can specifically recognize intestinal cells, specifically the α-glucosidase on cell membranes.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Structure-activity relationship of the inhibitory effects of flavonoids on
           nitric oxide production in RAW264.7 cells
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Wen-Jun Jiang, Akihiro Daikonya, Mitsuyoshi Ohkawara, Takashi Nemoto, Ryusuke Noritake, Tomoko Takamiya, Susumu Kitanaka, Hiroshi Iijima
      We isolated flavonoids from herbal specimens from the Tibetan region (Sophora yunnanensis and Rhodiola sacra) that suppress nitric oxide (NO) production in macrophages stimulated by lipopolysaccharide and interferon-γ. The isolated flavonoids carry symmetric substitutions in the B ring (R3′ =R5′). We analyzed the quantitative structure-activity relationship of the inhibitory activity by comparative molecular field analysis (CoMFA) using this series of flavonoids. Use of flavonoids with symmetrical substitutions in the B ring made it simpler to align molecules because it was not necessary to consider a huge number of combinations due to the B-ring conformation. The CoMFA model, whose cross-validated q 2 value was 0.705, suggested the existence of a hydroxy group at the 5-position, the choice of the A/C-ring scaffold (chromane or chromene) and electrostatic field around the B ring are important for NO inhibitory activity. Flavonoids synthesized based on the CoMFA model exhibited significant inhibitory potential against NO production, validating the predictive capability of the CoMFA model.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Synthesis of novel C4-benzazole naphthalimide derivatives with potent
           anti-tumor properties against murine melanoma
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Yen-Ta Lu, Tien-Ling Chen, Kuo-Song Chang, Chia-Ming Chang, Tsai-Yin Wei, Jen-Wei Liu, Chih-Ang Hsiao, Tzenge-Lien Shih
      Novel C4-benzazole naphthalimide derivatives were synthesized and tested in vitro and in vivo as anti-cancer drugs. Among these synthetic molecules, compounds 9 and 10 exhibited cytotoxicity against murine B16F10 melanoma cells. In addition, the above-mentioned compounds significantly suppressed lung tumor metastasis with no visible sign of toxicity.
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      PubDate: 2017-01-18T00:53:30Z
       
  • α-Pyrone derivatives, tetra/hexahydroxanthones, and cyclodepsipeptides
           from two freshwater fungi
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Tamam El-Elimat, Huzefa A. Raja, Cynthia S. Day, Hana McFeeters, Robert L. McFeeters, Nicholas H. Oberlies
      Eighteen (1–18) and seven (1, 4, 6–8, 17 and 18) compounds were isolated from organic extracts of axenic cultures of two freshwater fungi Clohesyomyces sp. and Clohesyomyces aquaticus (Dothideomycetes, Ascomycota), respectively. Compounds 1–12 belong to the α-pyrone class of natural products, compounds 13 and 14 were tetrahydroxanthones, compounds 15 and 16 were hexahydroxanthones, while compounds 17 and 18 were cyclodepsipeptides. The structures were elucidated using a set of spectroscopic and spectrometric techniques. The absolute configurations of compounds 2, 3, 6, and 7 were assigned via a modified Mosher’s ester method using 1H NMR data. The relative configurations of compounds 14–16 were determined through NOE data. Compounds 1, 2, 6, 8, 13, 14, and 15 were found to inhibit the essential enzyme bacterial peptidyl-tRNA hydrolase (Pth1), with (13; secalonic acid A) being the most potent. Compounds 1 and 4–18 were also evaluated for antimicrobial activity against an array of bacteria and fungi but were found to be inactive.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Design, synthesis and pharmacological evaluation of 4-hydroxyphenylglycine
           and 4-hydroxyphenylglycinol derivatives as GPR88 agonists
    • Abstract: Publication date: 15 January 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
      Author(s): Chunyang Jin, Ann M. Decker, Tiffany L. Langston
      The orphan receptor GPR88 is an attractive therapeutic target because of its implications in a number of basal ganglia-associated disorders. To date, pharmacological characterization of GPR88 has been limited due to the lack of potent and selective agonists and antagonists appropriate for CNS investigations. We have previously reported that GPR88 couples to Gαi proteins and modulates cAMP levels upon treatment with a small molecule agonist 2-PCCA. Recently, another chemotype of GPR88 agonist, represented by 2-AMPP [(2S)-N-((1R)-2-amino-1-(4-(2-methylpentyloxy)-phenyl)ethyl)-2-phenylpropanamide], has also been discovered. In this report, a new series of 2-AMPP structurally related 4-hydroxyphenylglycine and 4-hydroxyphenylglycinol derivatives have been designed and evaluated for agonist activity at GPR88. The structure-activity relationship (SAR) studies suggest that the amine group in 2-AMPP can be replaced by hydroxyl, ester and amide groups, resulting in analogues with good to moderate potency, whereas the phenyl group on the amide cap is essential for activity and has limited size, shape and electronic tolerance.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Novel salicylanilides from 4,5-dihalogenated salicylic acids: Synthesis,
           antimicrobial activity and cytotoxicity
    • Abstract: Publication date: Available online 14 January 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Georgios Paraskevopoulos, Sara Monteiro, Rudolf Vosátka, Martin Krátký, Lucie Navrátilová, František Trejtnar, Jiřina Stolaříková, Jarmila Vinšová
      Salicylanilides have proved their activity against tuberculosis (TB). One weak electron-withdrawing substituent is favored at the salicylic part, specially Cl or Br atoms at positions 4 or 5. On the other hand, the antimycobacterial activity of salicylanilides is negatively affected when a strong electron-withdrawing substituent (-NO2) is present at the same positions. Herein we describe the synthesis and characterization of novel salicylanilides possessing two weak electron-withdrawing groups (halogen atoms) at their salicylic part and compare their antitubercular activity with their monohalogenated analogues. All dihalogenated derivatives proved to possess antitubercular activity at a very narrow micromolar range (MIC= 1-4 μM), similar with their most active monohalogenated analogues. More importantly, the most active final molecules were further screened against multidrug resistant strains and found to inhibit their growth at the range of 0.5-4 μM.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Optical probes and Sensors as peRSpective tools In epigenetics
    • Abstract: Publication date: Available online 13 January 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Zdeněk Kejík, Robert Kaplánek, Martin Havlík, Tomáš Bříza, Milan Jakubek, Jarmila Králová, Ivan Mikula, Pavel Martásek, Vladimír Král
      Modifications of DNA cytosine bases and histone posttranslational modifications play key roles in the control of gene expression and specification of cell states. Such modifications affect many important biological processes and changes to these important regulation mechanisms can initiate or significantly contribute to the development of many serious pathological states. Therefore, recognition and determination of chromatin modifications is an important goal in basic and clinical research. Two of the most promising tools for this purpose are optical probes and sensors, especially colourimetric and fluorescence devices. The use of optical probes and sensors is simple, without highly expensive instrumentation, and with excellent sensitivity and specificity for target structural motifs. Accordingly, the application of various probes and sensors in the recognition and determination of cytosine modifications and structure of histones and histone posttranslational modifications, are discussed in detail in this review.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Synthesis of α,β-unsaturated aldehydes as potential substrates
           for bacterial luciferases
    • Abstract: Publication date: Available online 13 January 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Eveline Brodl, Jakov Ivkovic, Chaitanya R. Tabib, Rolf Breinbauer, Peter Macheroux
      Bacterial luciferase catalyzes the monooxygenation of long-chain aldehydes such as tetradecanal to the corresponding acid accompanied by light emission with a maximum at 490nm. In this study even numbered aldehydes with eight, ten, twelve and fourteen carbon atoms were compared with analogs having a double bond at the α,β-position. These α,β-unsaturated aldehydes were synthesized in three steps and were examined as potential substrates in vitro. The luciferase of Photobacterium leiognathi was found to convert these analogs and showed a reduced but significant bioluminescence activity compared to tetradecanal. This study showed the trend that aldehydes, both saturated and unsaturated, with longer chain lengths had higher activity in terms of bioluminescence than shorter chain lengths. The maximal light intensity of (E)-tetradec-2-enal was approximately half with luciferase of P. leiognathi, compared to tetradecanal. Luciferases of Vibrio harveyi and Aliivibrio fisheri accepted these newly synthesized substrates but light emission dropped drastically compared to saturated aldehydes. The onset and the decay rate of bioluminescence were much slower, when using unsaturated substrates, indicating a kinetic effect. As a result the duration of the light emission is doubled. These results suggest that the substrate scope of bacterial luciferases is broader than previously reported.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Design, synthesis and evaluation of some N-methylenebenzenamine
           derivatives as selective acetylcholinesterase (AChE) inhibitor and
           antioxidant to enhance learning and memory
    • Abstract: Publication date: Available online 11 January 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Sushant K. Shrivastava, Pavan Srivastava, T.V.R. Upendra, Prabhash Nath Tripathi, Saurabh K. Sinha
      Series of some 3,5-dimethoxy-N-methylenebenzenamine and 4-(methyleneamino)benzoic acid derivatives comprising of N-methylenebenzenamine nucleus were designed, synthesized, characterized, and assessed for their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory, and antioxidant activity thereby improving learning and memory in rats. The IC50 values of all the compound along with standard were determined on AChE and BChE enzyme. The free radical scavenging activity was also assessed by in-vitro DPPH (2, 2-diphenyl -1-picryl -hydrazyl) and hydrogen peroxide radical scavenging assay. The selective inhibitions of all compounds were observed against AChE in comparison with standard donepezil. The enzyme kinetic study of the most active compound 4 indicated uncompetitive AChE inhibition. The docking studies of compound 4 exhibited the worthy interaction on active-site gorge residues Phe330 and Trp279 responsible for its high affinity towards AChE, whereas lacking of the BChE inhibition was observed due to a wider gorge binding site and absence of important aromatic amino acids interactions. The ex vivo study confirmed AChE inhibition abilities of compound 4 at brain site. Further, a considerable decrease in escape latency period of the compound was observed in comparison with standard donepezil through in-vivo Spatial Reference Memory (SRM) and Spatial Working Memory (SWM) models which showed the cognition-enhancing potential of compound 4. The in-vivo reduced glutathione (GSH) estimation on rat brain tissue homogenate was also performed to evaluate free radical scavenging activity substantiated the antioxidant activity in learning and memory.
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      PubDate: 2017-01-18T00:53:30Z
       
  • Synthesis of isoxazole-containing sulfonamides with potent carbonic
           anhydrase II and VII inhibitory properties
    • Abstract: Publication date: Available online 11 January 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Cevher Altug, Hanife Güneş, Alessio Nocentini, Simona Maria Monti, Martina Buonanno, Claudiu T. Supuran
      Two series of benzenesulfonamide containing isoxazole compounds were prepared by using conventional and microwave (MW) methods. 5-Amino-3-aryl-N-(4-sulfamoylphenyl)isoxazole-4-carboxamide derivatives were synthesized by the reaction of hydroxymoyl chlorides with 2-cyano-N-(4-sulfamoylphenyl)acetamide in the presence of triethylamine. The synthesized 5-amino isoxazoles were reacted with various benzoyl chlorides in order to obtain 5-amidoisoxazoles. The novel compounds were screened in vitro as inhibitors of four human (h) isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1): hCA I, hCA II, hCA IV and hCA VII. The derivatives of the first series were shown to possess excellent inhibitory activity against the cytosolic isoform hCA II, an antiglaucoma drug target, with KIs in the range of 0.5–49.3 nM and hCA VII, a recently validated anti-neuropathic pain target with KIs in the range of 4.3-51.9 nM.

      PubDate: 2017-01-18T00:53:30Z
       
  • Design and Synthesis of Potent Substrate-based Inhibitors of the
           Trypanosoma cruzi Dihydroorotate Dehydrogenase
    • Abstract: Publication date: Available online 9 January 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Daniel Ken Inaoka, Maiko Iida, Satoshi Hashimoto, Toshiyuki Tabuchi, Takefumi Kuranaga, Emmanuel Oluwadare Balogun, Teruki Honma, Akiko Tanaka, Shigeharu Harada, Takeshi Nara, Kiyoshi Kita, Masayuki Inoue
      Chagas disease, caused by the parasitic protozoan Trypanosoma cruzi, is the leading cause of heart disease in Latin America. T. cruzi dihydroorotate dehydrogenase (DHODH), which catalyzes the production of orotate, was demonstrated to be essential for T. cruzi survival, and thus has been considered as a potential drug target to combat Chagas disease. Here we report the design and synthesis of 75 compounds based on the orotate structure. A comprehensive structure-activity relationship (SAR) study revealed two 5-substituted orotate analogues (5u and 5v) that exhibit K i app values of several ten nanomolar level and a selectivity of more than 30,000-fold over human DHODH. The information presented here will be invaluable in the search for next-generation drug leads for Chagas disease.
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      PubDate: 2017-01-18T00:53:30Z
       
  • A novel curcumin derivative which inhibits P-glycoprotein, arrests cell
           cycle and induces apoptosis in multidrug resistance cells
    • Authors: Vanessa Lopes-Rodrigues; Ana Oliveira; Marta Correia-da-Silva; Madalena Pinto; Raquel T. Lima; Emília Sousa; M. Helena Vasconcelos
      Abstract: Publication date: Available online 19 November 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Vanessa Lopes-Rodrigues, Ana Oliveira, Marta Correia-da-Silva, Madalena Pinto, Raquel T. Lima, Emília Sousa, M. Helena Vasconcelos
      Cancer multidrug resistance (MDR) is a major limitation to the success of cancer treatment and is highly associated with the overexpression of drug efflux pumps such as P-glycoprotein (P-gp). In order to achieve more effective chemotherapeutic treatments, it is important to develop P-gp inhibitors to block/decrease its activity. Curcumin (1) is a secondary metabolite isolated from the turmeric of Curcuma longa L.. Diverse biological activities have been identified for this compound, particularly, MDR modulation in various cancer cell models. However, curcumin (1) has low chemical stability, which severely limits its application. In order to improve stability and P-gp inhibitory effect, two potential more stable curcumin derivatives were synthesized as building blocks, followed by several curcumin derivatives. These compounds were then analyzed in terms of antitumor and anti-P-gp activity, in two MDR and sensitive tumour lines (from chronic myeloid leukemia and non-small cell lung cancer). We identified from a series of curcumin derivatives a novel curcumin derivative (1,7-bis(3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)hepta-1,6-diene-3,5-dione, 10) with more potent antitumor and anti-P-gp activity than curcumin (1). This compound (10) was shown to promote cell cycle arrest (at the G2/M phase) and induce apoptosis in the MDR chronic myeloid leukemia cell line. Therefore it is a really interesting P-gp inhibitor due to its ability to inhibit both P-gp function and expression.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.11.023
       
  • Discovery of 4-sulfamoyl-phenyl-β-lactams as a new class of potent
           carbonic anhydrase isoforms I, II, IV and VII inhibitors: the first
           example of subnanomolar CA IV inhibitors
    • Authors: Srinivas Angapelly; P.V. Sri Ramya; Andrea Angeli; Simona Maria Monti; Martina Buonanno; Mallika Alvala; Cladiu T. Supuran; Mohammed Arifuddin
      Abstract: Publication date: Available online 19 November 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Srinivas Angapelly, P.V. Sri Ramya, Andrea Angeli, Simona Maria Monti, Martina Buonanno, Mallika Alvala, Cladiu T. Supuran, Mohammed Arifuddin
      A series of benzenesulfonamides incorporating 1,3,4-trisubstituted-β-lactam moieties was prepared from sulfanilamide Schiff bases and in situ obtained ketenes, by using the Staudinger cycloaddition reaction. The new compounds were assayed as inhibitors of four human isoforms of the metalloenzyme carbonic anhydrase (hCA, EC 4.2.1.1) involved in various physiological/pathological conditions, hCA I, II, IV and VII. Excellent inhibitory activity was observed against all these isoforms, as follows: hCA I, involved in some eye diseases was inhibited with KIs in the range of 7.3 – 917 nM; hCA II, an antiglaucoma drug target, with KIs in the range of 0.76 – 163 nM. hCA IV, an isoform involved in several pathological conditions such as glaucoma, retinitis pigmentosa and edema was potently inhibited by the lactam-sulfonamides, with KIs in the range of 0.53 – 51.0 nM, whereas hCA VII, a recently validated anti-neuropathic pain target was the most inhibited isoform by these derivatives, with KIs in the range of 0.68 – 9.1 nM. The structure-activity relationship for inhibiting these CAs with the new lactam-sulfonamides is discussed in detail
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.11.027
       
  • Synthesis and binding monitoring of a new nanomolar PAMAM-based matrix
           metalloproteinases inhibitor (MMPIs)
    • Authors: Linda Cerofolini; Veronica Baldoneschi; Elisa Dragoni; Andrea Storai; Marianna Mamusa; Debora Berti; Marco Fragai; Barbara Richichi; Cristina Nativi
      Abstract: Publication date: Available online 19 November 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Linda Cerofolini, Veronica Baldoneschi, Elisa Dragoni, Andrea Storai, Marianna Mamusa, Debora Berti, Marco Fragai, Barbara Richichi, Cristina Nativi
      Dendrimers are efficient drug delivery systems particularly useful in ocular diseases. In particular, low generation PAMAM dendrimers are non-toxic and non-immunogenic and they provide an enhancement of the residence time of drugs in the eyes. In this context, the synthesis of the PAMAM-based matrix metalloproteinases inhibitor 5, is reported. In particular, we demonstrated that 5 strongly binds (18.0 nM ± 2.5 nM) MMP-9, the most relevant MMP responsible of ocular surface damages in induced dry eyes syndrome (DES).
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.11.028
       
  • Design, Synthesis and Biological Evaluation of Alkylamino Biphenylamides
           as Hsp90 C-Terminal Inhibitors
    • Authors: Gaurav Garg; Huiping Zhao; Brian S.J. Blagg
      Abstract: Publication date: Available online 19 November 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Gaurav Garg, Huiping Zhao, Brian S.J. Blagg
      Hsp90 is a promising therapeutic target for the development of anti-cancer agents due to its integral role in the stability and function of proteins associated with all ten hallmarks of cancer. Novobiocin, a coumarin antibiotic, was the first natural product identified that targeted the Hsp90 C-terminal domain and manifested anti-proliferative activity (SKBr3 IC50 ∼ 700 μM). Subsequent structural investigations on novobiocin led to analogues with significantly improved anti-proliferative activity against multiple cancer cell lines. In an effort to develop more efficacious and diverse analogues, it was recently found that the coumarin ring of novobiocin could be replaced with the biphenyl core without compromising activity. Based on these prior studies, a series of alkylamino biphenylamides was designed, synthesized and evaluated for anti-proliferative activity against two breast cancer cell lines. SAR studies demonstrated that the incorporation of an alkylamino side chain onto the biphenyl core improved anti-proliferative activity and resulted in compounds that exhibit sub-micromolar to mid-nanomolar activity through Hsp90 inhibition. Importantly, these studies indicate the presence of a hydrophilic region about the central core that can be exploited for the design of new inhibitors.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.11.030
       
  • Synthesis, antioxidant and antichagasic properties of a selected series of
           hydroxy-3-arylcoumarins
    • Authors: Natalia Robledo-O’Ryan; Maria João Matos; Saleta Vazquez-Rodriguez; Lourdes Santana; Eugenio Uriarte; Mauricio Moncada-Basualto; Francisco Mura; Michel Lapier; Juan Diego Maya; Claudio Olea-Azar
      Abstract: Publication date: Available online 19 November 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Natalia Robledo-O’Ryan, Maria João Matos, Saleta Vazquez-Rodriguez, Lourdes Santana, Eugenio Uriarte, Mauricio Moncada-Basualto, Francisco Mura, Michel Lapier, Juan Diego Maya, Claudio Olea-Azar
      Oxidative stress is involved in several parasitic diseases such as Chagas. Agents able to selectively modulate biochemical processes involved in the disease represent promising multifunctional agents for the delay or abolishment of the progression of this pathology. In the current work, differently substituted hydroxy-3-arylcoumarins are described, exerting both antioxidant and trypanocidal activity. Among the compounds synthesized, compound 8 showed the most interesting profile, presenting a moderate scavenging ability for peroxyl radicals (ORAC-FL=2.23) and a high degree of selectivity toward epimastigotes stage of the parasite T. cruzi (IC50 = 1.31 μM), higher than Nifurtimox (drug currently used for treatment of Chagas disease). Interestingly, the current study revealed that small structural changes in the hydroxy-3-arylcoumarin core allow modulating both activities, suggesting that this scaffold has desirable properties for the development of promising classes of antichagasic compounds. 2009 Elsevier Ltd. All rights reserved.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.11.033
       
  • Cyclic citrulinated MBP87-99 peptide stimulates T cell responses:
           implications in triggering disease
    • Authors: Vasso Apostolopoulos; George Deraos; Minos-Timotheos Matsoukas; Stephanie Day; Lily Stojanovska; Theodore Tselios; Maria-Eleni Androutsou; John Matsoukas
      Abstract: Publication date: Available online 19 November 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Vasso Apostolopoulos, George Deraos, Minos-Timotheos Matsoukas, Stephanie Day, Lily Stojanovska, Theodore Tselios, Maria-Eleni Androutsou, John Matsoukas
      Amino acid mutations to agonist peptide epitopes of myelin proteins have been used to modulate immune responses and experimental autoimmune encephalomyelitis (EAE, animal model of multiple sclerosis). Such amino acid alteration are termed, altered peptide ligands (APL). We have shown that the agonist myelin basic protein (MBP) 87-99 epitope (MBP87-99) with crucial T cell receptor (TCR) substitutions at positions 91 and 96 (K91,P96 (TCR contact residues) to R91,A96; [R91,A96]MBP87-99) results in altered T cell responses and inhibits EAE symptoms. In this study, the role of citrulination of arginines in [R91,A96]MBP87-99 peptide analog was determined using in vivo experiments in combination with computational studies. The immunogenicity of linear [Cit91,A96,Cit97]MBP87-99 and its cyclic analog - cyclo(87-99)[Cit91,A96,Cit97]MBP87-99 when conjugated to the carrier mannan (polysaccharide) were studied in SJL/J mice. It was found that mannocylated cyclo(87-99)[Cit91,A96,Cit97]MBP87-99 peptide induced strong T cell proliferative responses and IFN-gamma cytokine secretion compared with the linear one. Moreover, the interaction of linear and cyclic peptide analogs with the major histocompatibility complex (MHC II, H2-IAs) and TCR was analyzed using molecular dynamics simulations at the receptor level, in order to gain a better understanding of the molecular recognition mechanisms that underly the different immunological profiles of citrulinated peptides compared to its agonist native counterpart MBP87-99 epitope. The results demonstrate that the citrulination of arginine in combination with the backbone conformation of mutated linear and cyclic analogs are significant elements for the immune response triggering the induction of pro-inflammatory cytokines.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.11.029
       
  • Synthesis, Evaluation and Molecular Modelling Studies of
           2-(Carbazol-3-yl)-2-oxoacetamide Analogues as a New Class of Potential
           Pancreatic Lipase Inhibitors
    • Authors: S.N.C. Sridhar; Ginson George; P.O. Venkataramana Reddy; Mukund P. Tantak; Dalip Kumar; Atish T. Paul
      Abstract: Publication date: Available online 18 November 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): S.N.C. Sridhar, Ginson George, P.O. Venkataramana Reddy, Mukund P. Tantak, Dalip Kumar, Atish T. Paul
      A series of twenty-four 2-(carbazol-3-yl)-2-oxoacetamide analogues were synthesized, characterized and evaluated for their PL inhibitory activities. Porcine PL was used against 4-nitrophenyl butyrate and tributyrin as substrates during the PL inhibition assay. Compounds 7e, 7f and 7p exhibited potential PL inhibitory activity (IC50 values of 6.31, 8.72 and 9.58 μM, respectively in method A; and Xi50 of 21.85, 21.94 and 26.2, respectively in method B). Further, inhibition kinetics of 7e, 7f and 7p against PL revealed their competitive nature of inhibition. A comparison of the inhibition profiles of the top three compounds in method B and C, provided a preliminary idea of covalent bonding of the compounds with Ser 152 of PL. Molecular docking studies of the compounds 7a-x into the active site of human PL (PDB ID: 1LPB) was in agreement with the in vitro results, and highlighted probable covalent bond formation with Ser 152 apart from hydrophobic interactions with the lid domain. Molecular dynamics simulation of 7e complexed with PL, further confirmed the role of aromatic groups in stabilising the ligand (RMSD ⩽ 4 Å). The present study led to the identification of 2-(carbazol-3-yl)-2-oxoacetamide analogues 7a-x as a new class of potential PL inhibitors.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.11.031
       
  • Computer design, synthesis, and bioactivity analyses of drugs like
           Fingolimod used in the treatment of Multiple Sclerosis
    • Authors: Gurbet Çelik Turgut; Doğukan Doyduk; Yılmaz Yıldırır; Serkan Yavuz; Atilla Akdemir; Ali Dişli; Alaaddin Şen
      Abstract: Publication date: Available online 18 November 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Gurbet Çelik Turgut, Doğukan Doyduk, Yılmaz Yıldırır, Serkan Yavuz, Atilla Akdemir, Ali Dişli, Alaaddin Şen
      Multiple Sclerosis (MS) is a very common disease of vital importance. In the MS treatment, some drugs such as fingolimod which help to protect nerves from damage are used. The main goal of the drug therapy in MS is to take control of the inflammation which leads to the destruction of myelin and axons in nerve cell and thus prevent and stop the progression of the disease. Fingolimod (FTY720) is an orally active immunomodulatory drug that has been used for the treatment of relapsing-remitting multiple sclerosis. It is a sphingosine-1-phosphate receptor modulator which prevents lymphocytes from contributing to an autoimmune reaction by inhibiting egress of lymphocytes them from lymph nodes. In this study, we have computer designed, synthesized and characterized two novel derivatives of FTY720, F1-12h and F2-9, and have determined their underlying mechanism of their beneficial effect in SH-SY5Y, SK-N-SH, and U-118MG cell lines. For this purpose, we first determined the regulation of the cAMP response element (CRE) activity and cAMP concentration by F1-12h and F2-9 together with FTY720 using pGL4.29 luciferase reporter assay and cAMP immunoassay, respectively. Then, we have determined their effect on MS- and GPCR-related gene expression profiles using custom arrays along with FTY720 treatment at non-toxic doses (EC10). It was found that both derivatives significantly activate CRE and increase cAMP concentration in all three cell lines, indicating that they activate cAMP pathway through cell surface receptors as FTY720 does. Furthermore, F1-12h and F2-9 modulate the expression of the pathway related genes that are important in inflammatory signaling, cAMP signaling pathway, cell migration as well as diverse receptor and transcription factors. Expression of the genes involved in myelination was also increased by the treatment with F1-12h and F2-9. In summary, our data demonstrate that the two novel FTY720 derivatives act as anti-inflammatory ultimately by influencing the gene expression via the cAMP and downstream transcription factor CRE pathway. In conclusion, F1-12h and F2-9 might contribute future therapies for autoimmune diseases such as multiple sclerosis.
      Graphical abstract image

      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.11.015
       
  • N-Propargylpiperidines with Naphthalene-2-Carboxamide or
           Naphthalene-2-Sulfonamide Moieties: Potential Multifunctional
           Anti-Alzheimer’s Agents
    • Authors: Urban Košak; Damijan Knez; Nicolas Coquelle; Boris Brus; Anja Pišlar; Florian Nachon; Xavier Brazzolotto; Janko Kos; Jacques-Philippe Colletier; Stanislav Gobec
      Abstract: Publication date: Available online 19 November 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Urban Košak, Damijan Knez, Nicolas Coquelle, Boris Brus, Anja Pišlar, Florian Nachon, Xavier Brazzolotto, Janko Kos, Jacques-Philippe Colletier, Stanislav Gobec
      In the brains of patients with Alzheimer’s disease, the enzymatic activities of butyrycholinesterase (BChE) and monoamine oxidase B (MAO-B) are increased. While BChE is a viable therapeutic target for alleviation of symptoms caused by cholinergic hypofunction, MAO-B is a potential therapeutic target for prevention of neurodegeneration in Alzheimer’s disease. Starting with piperidine-based selective human (h)BChE inhibitors and propargylamine-based MAO inhibitors, we have designed, synthesized and biochemically evaluated a series of N-propargylpiperidines. All of these compounds inhibited hBChE with good selectivity over the related enzyme, acetylcholinesterase, and crossed the blood-brain barrier in a parallel artificial membrane permeation assay. The crystal structure of one of the inhibitors (compound 3) in complex with hBChE revealed its binding mode. Three compounds (4, 5, 6) showed concomitant inhibition of MAO-B. Additionally, the most potent hBChE inhibitor 7 and dual BChE and MAO-B inhibitor 6 were non-cytotoxic and protected neuronal SH-SY5Y cells from toxic amyloid β-peptide species.
      Graphical abstract image

      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.11.032
       
 
 
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