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  Subjects -> CHEMISTRY (Total: 841 journals)
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CHEMISTRY (593 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 8)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 26)
ACS Catalysis     Full-text available via subscription   (Followers: 34)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 18)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 23)
ACS Macro Letters     Full-text available via subscription   (Followers: 23)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 39)
ACS Nano     Full-text available via subscription   (Followers: 233)
ACS Photonics     Full-text available via subscription   (Followers: 11)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 21)
Acta Chemica Iasi     Open Access   (Followers: 2)
Acta Chimica Sinica     Full-text available via subscription   (Followers: 1)
Acta Chimica Slovaca     Open Access   (Followers: 1)
Acta Chromatographica     Full-text available via subscription   (Followers: 9)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 7)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 5)
Advanced Functional Materials     Hybrid Journal   (Followers: 50)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 55)
Advances in Chemical Science     Open Access   (Followers: 13)
Advances in Chemistry     Open Access   (Followers: 14)
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Advances in Drug Research     Full-text available via subscription   (Followers: 22)
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Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 19)
Advances in Nanoparticles     Open Access   (Followers: 15)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15)
Advances in Polymer Science     Hybrid Journal   (Followers: 41)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 19)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Science and Technology     Full-text available via subscription   (Followers: 12)
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 2)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 68)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 14)
American Journal of Chemistry     Open Access   (Followers: 26)
American Journal of Plant Physiology     Open Access   (Followers: 14)
American Mineralogist     Hybrid Journal   (Followers: 14)
Analyst     Full-text available via subscription   (Followers: 40)
Angewandte Chemie     Hybrid Journal   (Followers: 219)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 212)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 2)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 4)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 8)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 12)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 15)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Hybrid Journal  
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7)
Applied Spectroscopy     Full-text available via subscription   (Followers: 23)
Applied Surface Science     Hybrid Journal   (Followers: 28)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 2)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Atomization and Sprays     Full-text available via subscription   (Followers: 4)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Biochemistry     Full-text available via subscription   (Followers: 293)
Biochemistry Insights     Open Access   (Followers: 6)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 9)
Bioinspired Materials     Open Access   (Followers: 5)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access   (Followers: 1)
Biomacromolecules     Full-text available via subscription   (Followers: 19)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 6)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 4)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 119)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 96)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 1)
Bitácora Digital     Open Access  
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 2)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 24)
Bulletin of the Korean Chemical Society     Hybrid Journal   (Followers: 1)
C - Journal of Carbon Research     Open Access   (Followers: 3)
Cakra Kimia (Indonesian E-Journal of Applied Chemistry)     Open Access  
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 3)
Canadian Journal of Chemistry     Hybrid Journal   (Followers: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 3)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 66)
Catalysis for Sustainable Energy     Open Access   (Followers: 7)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 8)
Catalysis Science and Technology     Free   (Followers: 6)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 8)
Cellulose     Hybrid Journal   (Followers: 7)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 1)
ChemCatChem     Hybrid Journal   (Followers: 8)
Chemical and Engineering News     Free   (Followers: 13)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 71)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 23)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 19)
Chemical Reviews     Full-text available via subscription   (Followers: 174)
Chemical Science     Open Access   (Followers: 22)
Chemical Technology     Open Access   (Followers: 16)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemical Week     Full-text available via subscription   (Followers: 8)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 57)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 26)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 6)
Chemistry & Biology     Full-text available via subscription   (Followers: 30)
Chemistry & Industry     Hybrid Journal   (Followers: 5)
Chemistry - A European Journal     Hybrid Journal   (Followers: 142)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 15)
Chemistry and Materials Research     Open Access   (Followers: 18)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 9)
Chemistry International     Hybrid Journal   (Followers: 2)
Chemistry Letters     Full-text available via subscription   (Followers: 45)
Chemistry of Materials     Full-text available via subscription   (Followers: 257)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 22)
Chemistry-Didactics-Ecology-Metrology     Open Access   (Followers: 1)
ChemistryOpen     Open Access   (Followers: 2)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 3)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 15)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 9)
ChemPlusChem     Hybrid Journal   (Followers: 2)
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 2)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 10)
Chromatographia     Hybrid Journal   (Followers: 24)
Clay Minerals     Full-text available via subscription   (Followers: 10)
Cogent Chemistry     Open Access  
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 10)
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 7)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
Combustion Science and Technology     Hybrid Journal   (Followers: 18)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Composite Interfaces     Hybrid Journal   (Followers: 6)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 2)
Comptes Rendus Chimie     Full-text available via subscription  
Comptes Rendus Physique     Full-text available via subscription   (Followers: 1)
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 9)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 12)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 9)
Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 2)
Copernican Letters     Open Access   (Followers: 1)
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 5)
Crystal Structure Theory and Applications     Open Access   (Followers: 3)
CrystEngComm     Full-text available via subscription   (Followers: 12)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Metabolomics     Hybrid Journal   (Followers: 5)
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Current Science     Open Access   (Followers: 58)
Dalton Transactions     Full-text available via subscription   (Followers: 22)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)
Diamond and Related Materials     Hybrid Journal   (Followers: 12)
Dislocations in Solids     Full-text available via subscription  
Doklady Chemistry     Hybrid Journal  
Drying Technology: An International Journal     Hybrid Journal   (Followers: 4)
Eclética Química     Open Access   (Followers: 1)
Ecological Chemistry and Engineering S     Open Access   (Followers: 4)
Ecotoxicology and Environmental Contamination     Open Access  
Educación Química     Open Access   (Followers: 1)
Education for Chemical Engineers     Hybrid Journal   (Followers: 5)
EJNMMI Radiopharmacy and Chemistry     Open Access  
Elements     Full-text available via subscription   (Followers: 2)
Environmental Chemistry     Hybrid Journal   (Followers: 8)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 4)
Environmental Science & Technology Letters     Full-text available via subscription   (Followers: 5)
Environmental Science : Nano     Partially Free   (Followers: 1)
Environmental Toxicology & Chemistry     Hybrid Journal   (Followers: 17)

        1 2 3 | Last

Journal Cover Bioorganic & Medicinal Chemistry Letters
  [SJR: 0.952]   [H-I: 112]   [96 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0960-894X
   Published by Elsevier Homepage  [3044 journals]
  • [11C]BCTC: Radiosynthesis and in vivo binding to transient receptor
           potential vanilloid subfamily member 1 (TRPV1) receptor in the mouse
           trigeminal nerve
    • Authors: Katsushi Kumata; Joji Yui; Yiding Zhang; Yusuke Kurihara; Masanao Ogawa; Wakana Mori; Masayuki Fujinaga; Ming-Rong Zhang
      Pages: 4521 - 4524
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 19
      Author(s): Katsushi Kumata, Joji Yui, Yiding Zhang, Yusuke Kurihara, Masanao Ogawa, Wakana Mori, Masayuki Fujinaga, Ming-Rong Zhang
      The purpose of this study was to synthesize a new positron emission tomography radiotracer, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-[11C]carboxamide ([11C]BCTC, [11C]1), and assess its in vivo binding to the transient receptor potential vanilloid subfamily member 1 (TRPV1) receptor in mice. [11C]BCTC was synthesized by reacting the hydrochloride of 4-tertiarybutylaniline (2·HCl) with [11C]phosgene ([11C]COCl2) to give isocyanate [11C]4, followed by reaction with 4-(3-chloropyridin-2-yl)tetrahydropyrazine (3). [11C]BCTC was obtained at a 16–20% radiochemical yield, based on the cyclotron-produced [11C]CO2 (decay-corrected to the end of bombardment), with >98% radiochemical purity and 65–110GBq/μmol specific activity at the end of synthesis. An ex vivo biodistribution study in mice confirmed the specific binding of [11C]BCTC to TRPV1 in the trigeminal nerve, which is a tissue with high TRPV1 expression.
      Graphical abstract image

      PubDate: 2017-09-19T02:42:27Z
      DOI: 10.1016/j.bmcl.2017.08.061
       
  • Discovery of novel steroidal histamine H3 receptor antagonists/inverse
           agonists
    • Authors: Istvan Ledneczki; Pál Tapolcsányi; Eszter Gábor; János Éles; István Greiner; Éva Schmidt; Zsolt Némethy; Rita Soukupné Kedves; Ottilia Balázs; Viktor Román; György Lévay; Sándor Mahó
      Pages: 4525 - 4530
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 19
      Author(s): Istvan Ledneczki, Pál Tapolcsányi, Eszter Gábor, János Éles, István Greiner, Éva Schmidt, Zsolt Némethy, Rita Soukupné Kedves, Ottilia Balázs, Viktor Román, György Lévay, Sándor Mahó
      Emerging from an HTS campaign, novel steroid-based histamine H3 receptor antagonists were identified and characterized. Structural moieties of the hit compounds were combined to improve binding affinities which resulted in compound 4 as lead molecule. During the lead optimization due to the versatile modifications of diamino steroid derivatives, several in vitro potent compounds with subnanomolar binding affinities to histamine H3 receptors were found. The unfavorable binding to rat muscarinic receptors was successfully reduced by tuning the basicity. Compound 20 showed significant in vivo activity in the rat dipsogenia model and could serve as a pharmacological tool in the future.
      Graphical abstract image

      PubDate: 2017-09-19T02:42:27Z
      DOI: 10.1016/j.bmcl.2017.08.060
       
  • Anti-influenza activity of diazaadamantanes combined with monoterpene
           moieties
    • Authors: Evgeniy Suslov; Vladimir V. Zarubaev; Alexander V. Slita; Konstantin Ponomarev; Dina Korchagina; Daniel M. Ayine-Tora; Jóhannes Reynisson; Konstantin Volcho; Nariman Salakhutdinov
      Pages: 4531 - 4535
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 19
      Author(s): Evgeniy Suslov, Vladimir V. Zarubaev, Alexander V. Slita, Konstantin Ponomarev, Dina Korchagina, Daniel M. Ayine-Tora, Jóhannes Reynisson, Konstantin Volcho, Nariman Salakhutdinov
      The antiviral activity of several diaza-adamantanes containing monoterpenoid moieties against a rimantadine-resistant strain of the influenza A/Puerto Rico/8/34 (H1N1) virus was studied. Hetero-adamantanes containing monoterpene moieties at the aminal position of the heterocycle were found to exhibit lower activity compared to compounds with a diaza-adamantane fragment and a monoterpene moiety linked via an amino group at the 6-position of the hetero-adamantane ring. The highest selectivity index (a ratio of the 50% cytotoxic concentration to the 50% inhibitory concentration) out of 30 was observed for compound 8d, which contains a citronellal monoterpenoid moiety. Diaza-adamantane 8d was superior to its adamantane-containing analog 5 both in its anti-influenza activity and selectivity. Furthermore, 8d has more balanced physicochemical properties than 5, making the former a more promising drug candidate. Modelling these compounds against an influenza virus M2 ion channel predicted plausible binding modes to both the wild-type and the mutant (S31N).
      Graphical abstract image

      PubDate: 2017-09-19T02:42:27Z
      DOI: 10.1016/j.bmcl.2017.08.062
       
  • Synthesis and evaluation of biological activities of vibsanin A analogs
    • Authors: Wataru Matsuki; So Miyazaki; Keisuke Yoshida; Akihiro Ogura; Yukiko Sasazawa; Ken-ichi Takao; Siro Simizu
      Pages: 4536 - 4539
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 19
      Author(s): Wataru Matsuki, So Miyazaki, Keisuke Yoshida, Akihiro Ogura, Yukiko Sasazawa, Ken-ichi Takao, Siro Simizu
      Vibsanin A is an 11-membered vibsane diterpenoid and is reported to induce myeloid cell differentiation via activation of protein kinase C (PKC) without tumor-promoting activity. Therefore, vibsanin A is thought to be an attractive compound for acute myeloid leukemia (AML) therapy. In this study, we synthesized vibsanin A analogs and compared the activity of these compounds for PKC activation and myeloid cell differentiation. We found that the hydroxymethyl group in vibsanin A is an important substituent to induce differentiation of AML cells. Collectively, our results showed the biochemical features of vibsanin A and provided new insights into the development of new antileukemic drugs.
      Graphical abstract image

      PubDate: 2017-09-19T02:42:27Z
      DOI: 10.1016/j.bmcl.2017.08.059
       
  • Synthesis and anti-enterovirus activity of new analogues of MDL-860
    • Authors: Georgi M. Dobrikov; Ivaylo Slavchev; Ivanka Nikolova; Adelina Stoyanova; Nadya Nikolova; Lucia Mukova; Rosica Nikolova; Boris Shivachev; Angel S. Galabov
      Pages: 4540 - 4543
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 19
      Author(s): Georgi M. Dobrikov, Ivaylo Slavchev, Ivanka Nikolova, Adelina Stoyanova, Nadya Nikolova, Lucia Mukova, Rosica Nikolova, Boris Shivachev, Angel S. Galabov
      A series of twelve novel compounds, analogues of antiviral agent MDL-860 were synthesized and their antiviral activity was evaluated in vitro against enteroviruses poliovirus 1 (PV1), Coxsackieviruses B1 (CVB1) and Coxsackieviruses B3 (CVB3). Compounds 14, 24 and 25 manifested strong antiviral effects against CVB1 and PV1 (SI values of 405 and 118 for CVB1 and PV1 respectively). In contrast to the wide anti-enteroviral activity of MDL-860, these three compounds were inactive against CVB3. Compounds 14, 24 and 25 along with MDL-860 were tested in vivo in mice infected with CVB1. Marked protective effects of compounds 14 and 24 were established, PI values of 50% and 33.3%, respectively. In addition, almost all of the tested compounds manifested very low toxicity.
      Graphical abstract image

      PubDate: 2017-09-19T02:42:27Z
      DOI: 10.1016/j.bmcl.2017.08.056
       
  • Ester-prodrugs of ethambutol control its antibacterial activity and
           provide rapid screening for mycobacterial hydrolase activity
    • Authors: Erik M. Larsen; Dominique C. Stephens; Nathan H. Clarke; R. Jeremy Johnson
      Pages: 4544 - 4547
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 19
      Author(s): Erik M. Larsen, Dominique C. Stephens, Nathan H. Clarke, R. Jeremy Johnson
      M. tuberculosis contains an unusually high number of serine hydrolases by proteome percentage compared to other common bacteria or humans. This letter describes a method to probe the global substrate specificity of mycobacterial serine hydrolases with ester-protected prodrugs of ethambutol, a first-line antibiotic treatment for TB. These compounds were synthesized directly from ethambutol using a selective o-acylation to yield products in high yield and purity with minimal workup. A library of derivatives was screened against M. smegmatis, a non-infectious model for M. tuberculosis, which displayed significantly lowered biological activity compared to ethambutol. Incubation with a general serine hydrolase reactivated each derivative to near-ethambutol levels, demonstrating that esterification of ethambutol should provide a simple screen for mycobacterial hydrolase activity.
      Graphical abstract image

      PubDate: 2017-09-19T02:42:27Z
      DOI: 10.1016/j.bmcl.2017.08.057
       
  • Synergistic antiproliferative effect of chemo-phototherapy: Synthesis and
           photodynamic activity evaluation of novel Chlorin e6-artesunate conjugates
           as antiproliferative agents
    • Authors: Xiuhan Guo; Liu Wang; Shisheng Wang; Yueqing Li; Lei Cao; Rui Cai; Weijie Zhao
      Pages: 4548 - 4551
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 19
      Author(s): Xiuhan Guo, Liu Wang, Shisheng Wang, Yueqing Li, Lei Cao, Rui Cai, Weijie Zhao
      In order to increase the photodynamic effect of Chlorin e6, four Chlorin e6-artesunate conjugates were designed and synthesized. Among them, three conjugates (3, 6, 9) contained single artesunate side chain at 152, 173 and 131 of Chlorin e6, respectively, and one conjugate (11) contained three artesunate side chains. In the in vitro evaluation of photodynamic effect, the four conjugates showed more potent phototoxicity against HepG2 cells than Chlorin e6. The introduction of artesunate side chain significantly increased the intracellular ROS production, although the production of singlet oxygen was not improved. Compound 11 exhibited much more potent phototoxicity than the other conjugates because the three artesunate side chains greatly enhanced the ROS production and cellular uptake. The results demonstrated that the conjugation of Chlorin e6 and artesunate could accomplish synergistic effects of chemo-phototherapy, and finally enhanced their antiproliferative effects.
      Graphical abstract image

      PubDate: 2017-09-19T02:42:27Z
      DOI: 10.1016/j.bmcl.2017.08.055
       
  • 68Ga labeled Erlotinib: A novel PET probe for imaging EGFR over-expressing
           tumors
    • Authors: Akanksha Jain; Mythili Kameswaran; Usha Pandey; Kumar Prabhash; Haladhar Dev Sarma; Ashutosh Dash
      Pages: 4552 - 4557
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 19
      Author(s): Akanksha Jain, Mythili Kameswaran, Usha Pandey, Kumar Prabhash, Haladhar Dev Sarma, Ashutosh Dash
      Molecular imaging using radiolabeled Tyrosine Kinase Inhibitors (TKI) is a promising strategy for detection and staging of EGFR-positive cancers. A novel analogue of one such TKI, Erlotinib has been developed for PET imaging by derivatizing the parent Erlotinib molecule for conjugation with the bifunctional chelator p-SCN-Bn-NOTA towards radiolabeling with 68Ga. NOTA-Erlotinib conjugate was synthesized and characterized by NMR and ESI-MS techniques. The conjugate was radiolabeled with 68Ga in 95±2% yield, as evidenced by HPLC characterization. The logP value of 68Ga-NOTA-Erlotinib was – (0.6±0.1). The 68Ga-NOTA-Erlotinib conjugate was characterized using its natGa-NOTA-Erlotinib surrogate. Cell viability studies showed that the NOTA-Erlotinib conjugate retained the biological efficacy of the parent Erlotinib molecule. Further, 68Ga-NOTA-Erlotinib exhibited an uptake of 9.8±0.4% in A431 cells which was inhibited by 55.1±0.2% on addition of cold Erlotinib (10µg) confirming the specificity of the radioconjugate for EGFR expressing cells. In the biodistribution studies carried out in tumor bearing SCID mice, 68Ga-NOTA-Erlotinib conjugate showed moderate tumor accumulation (1.5±0.1% ID/g at 30minp.i.; 0.7±0.2% ID/g at 1hp.i.). Hepatobiliary clearance of the radioconjugate was observed. The 68Ga-NOTA-Erlotinib conjugate was found to have high in vivo stability as determined by the metabolite analysis study using urine sample of the Swiss mice injected with the preparation. The overall properties of 68Ga-NOTA-Erlotinib are promising and merit further exploration. To the best of our knowledge, this is the first report on the design of a 68Ga labeled Erlotinib for PET imaging of EGFR and opens avenues for the successful development of 68Ga labeled TKI for imaging of EGFR over-expressing tumors.
      Graphical abstract image

      PubDate: 2017-09-19T02:42:27Z
      DOI: 10.1016/j.bmcl.2017.08.065
       
  • Synthesis and biological evaluation of the natural product komaroviquinone
           and related compounds aiming at a potential therapeutic lead compound for
           high-risk multiple myeloma
    • Authors: Yutaka Suto; Mariko Sato; Kota Fujimori; Shotaro Kitabatake; Mikio Okayama; Daiju Ichikawa; Maiko Matsushita; Noriyuki Yamagiwa; Genji Iwasaki; Fumiyuki Kiuchi; Yutaka Hattori
      Pages: 4558 - 4563
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 19
      Author(s): Yutaka Suto, Mariko Sato, Kota Fujimori, Shotaro Kitabatake, Mikio Okayama, Daiju Ichikawa, Maiko Matsushita, Noriyuki Yamagiwa, Genji Iwasaki, Fumiyuki Kiuchi, Yutaka Hattori
      Alternatives of treatments for multiple myeloma (MM) have become increasingly available with the advent of new drugs such as proteasome inhibitors, thalidomide derivatives, histone deacetylase inhibitors, and antibody drugs. However, high-risk MM cases that are refractory to novel drugs remain, and further optimization of chemotherapeutics is urgently needed. We had achieved asymmetric total synthesis of komaroviquinone, which is a natural product from the plant Dracocephalum komarovi. Similar to several leading antitumor agents that have been developed from natural compounds, we describe the antitumor activity and cytotoxicity of komaroviquinone and related compounds in bone marrow cells. Our data suggested that komaroviquinone-related agents have potential as starting compounds for anticancer drug development.
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      PubDate: 2017-09-19T02:42:27Z
      DOI: 10.1016/j.bmcl.2017.08.054
       
  • Elucidation of antimicrobial activity and mechanism of action by
           N-substituted carbazole derivatives
    • Authors: Johannes D. Clausen; Lasse Kjellerup; Karen O'Hanlon Cohrt; John Bondo Hansen; William Dalby-Brown; Anne-Marie L. Winther
      Pages: 4564 - 4570
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 19
      Author(s): Johannes D. Clausen, Lasse Kjellerup, Karen O'Hanlon Cohrt, John Bondo Hansen, William Dalby-Brown, Anne-Marie L. Winther
      Compounds belonging to a carbazole series have been identified as potent fungal plasma membrane proton adenosine triphophatase (H+-ATPase) inhibitors with a broad spectrum of antifungal activity. The carbazole compounds inhibit the adenosine triphosphate (ATP) hydrolysis activity of the essential fungal H+-ATPase, thereby functionally inhibiting the extrusion of protons and extracellular acidification, processes that are responsible for maintaining high plasma membrane potential. The compound class binds to and inhibits the H+-ATPase within minutes, leading to fungal death after 1–3h of compound exposure in vitro. The tested compounds are not selective for the fungal H+-ATPase, exhibiting an overlap of inhibitory activity with the mammalian protein family of P-type ATPases; the sarco(endo)plasmic reticulum calcium ATPase (Ca2+-ATPase) and the sodium potassium ATPase (Na+,K+-ATPase). The ion transport in the P-type ATPases is energized by the conversion of ATP to adenosine diphosphate (ADP) and phosphate and a general inhibitory mechanism mediated by the carbazole derivative could therefore be blocking of the active site. However, biochemical studies show that increased concentrations of ATP do not change the inhibitory activity of the carbazoles suggesting they act as allosteric inhibitors. Furthermore decreased levels of intracellular ATP would suggest that the compounds inhibit the H+-ATPase indirectly, but Candida albicans cells exposed to potent H+-ATPase-inhibitory carbazoles result in increased levels of intracellular ATP, indicating direct inhibition of H+-ATPase.
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      PubDate: 2017-09-19T02:42:27Z
      DOI: 10.1016/j.bmcl.2017.08.067
       
  • Design, synthesis, and SAR study of
           3-(benzo[d][1,3]dioxol-5-yl)-N-benzylpropanamide as novel potent
           synergists against fluconazole-resistant Candida albicans
    • Authors: Zhan Cai; Zichao Ding; Yumeng Hao; Tingjunhong Ni; Fei Xie; Jing Zhao; Ran Li; Shichong Yu; Ting Wang; Xiaoyun Chai; Yongsheng Jin; Yue Gao; Dazhi Zhang; Yuanying Jiang
      Pages: 4571 - 4575
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 19
      Author(s): Zhan Cai, Zichao Ding, Yumeng Hao, Tingjunhong Ni, Fei Xie, Jing Zhao, Ran Li, Shichong Yu, Ting Wang, Xiaoyun Chai, Yongsheng Jin, Yue Gao, Dazhi Zhang, Yuanying Jiang
      Based on our previous discovery and SAR study on the lead compounds 7d, 5 and berberine which can significantly enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans, a series of 3-(benzo[d][1,3]dioxol-5-yl)-N-(substituted benzyl)propanamides were designed, synthesized, and evaluated for their in vitro synergistic activity in combination with fluconazole. The series 2a–f were designed by replacing the amide moiety of the lead compound 7d with retro-amide moiety, and compounds 2a and 2b showed more activity than the lead 7d. Furthermore, introducing biphenyl moiety into series 2d–f afforded series 3a–r, most of which exhibited significantly superior activity to the series 2d–f. Especially, compound 3e, at a concentration of 1.0µg/ml, can enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans from 128.0µg/ml to 0.125–0.25µg/ml. A clear SAR of the compounds is discussed.
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      PubDate: 2017-09-19T02:42:27Z
      DOI: 10.1016/j.bmcl.2017.08.053
       
  • Antimicrobial activity of bitespiramycin, a new genetically engineered
           macrolide
    • Authors: Weiqing He; Chunping Yang; Xiaofeng Zhao; Yiguang Wang
      Pages: 4576 - 4577
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 19
      Author(s): Weiqing He, Chunping Yang, Xiaofeng Zhao, Yiguang Wang
      The antimicrobial activity of bitespiramycin (BT) against Chlamydia trachomatis (Ct), Chlamydia pneumoniae (Cp), Ureaplasma urealyticum (Uu), and Mycoplasma pneumoniae (Mp), was compared with those of azithromycin (AZM) and acetylspiramycin (AT-SP) in vitro. Furthermore, the anti-Mp activities of BT and AZM were evaluated in a hamster model. The activities of BT in vitro were similar to those of AZM but were more effective than those of AT-SP. BT effectively inhibited Mp infection at a dose of 200mg/kg in a hamster model.
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      PubDate: 2017-09-19T02:42:27Z
      DOI: 10.1016/j.bmcl.2017.08.046
       
  • Design and synthesis of 2-phenylpyrimidine coumarin derivatives as
           anticancer agents
    • Authors: Na Lv; Ming Sun; Chen Liu; Jiabin Li
      Pages: 4578 - 4581
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 19
      Author(s): Na Lv, Ming Sun, Chen Liu, Jiabin Li
      A series of 2-phenylpyrimidine coumarin derivatives with potential telomerase-inhibiting activity was designed and synthesized. All of the compounds were screened for antiproliferative activity against CNE2, KB, and Cal27 cell lines in vitro. The results showed that most of the derivatives had a favorable effect on resisting tumor cell proliferation; compound 13, 3-(4-amino-5-oxo-5H-chromeno[4,3-d]pyrimidin-2-yl)phenyl 4-(dimethylamino)benzenesulfonate, exhibited the best activity. Flow cytometry revealed that compound 13 can inhibit CNE2 proliferation. Telomerase inhibition and in vitro antitumor activity were consistent among the compounds, but compound 13 showed the best telomerase-inhibiting activity and could inhibit telomere extension. Molecular docking results indicated that compound 13 bonded with telomerase reverse transcriptase (TERT) through multiple interactions, including hydrogen bonding and hydrophobic interactions. The results of the study provide further information on 2-phenylpyrimidine coumarins, expanding the types of telomerase inhibitors as the parent structures.
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      PubDate: 2017-09-19T02:42:27Z
      DOI: 10.1016/j.bmcl.2017.08.044
       
  • Profiling of in vitro activities of urea-based inhibitors against cysteine
           synthases from Mycobacterium tuberculosis
    • Authors: Katharina Brunner; Eva Maria Steiner; Rudraraju Srilakshmi Reshma; Dharmarajan Sriram; Robert Schnell; Gunter Schneider
      Pages: 4582 - 4587
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 19
      Author(s): Katharina Brunner, Eva Maria Steiner, Rudraraju Srilakshmi Reshma, Dharmarajan Sriram, Robert Schnell, Gunter Schneider
      CysK1 and CysK2 are two members of the cysteine/S-sulfocysteine synthase family in Mycobacterium tuberculosis, responsible for the de novo biosynthesis of l-cysteine, which is subsequently used as a building block for mycothiol. This metabolite is the first line defense of this pathogen against reactive oxygen and nitrogen species released by host macrophages after phagocytosis. In a previous medicinal chemistry campaign we had developed urea-based inhibitors of the cysteine synthase CysM with bactericidal activity against dormant M. tuberculosis. In this study we extended these efforts by examination of the in vitro activities of a library consisting of 71 urea compounds against CysK1 and CysK2. Binding was established by fluorescence spectroscopy and inhibition by enzyme assays. Several of the compounds inhibited these two cysteine synthases, with the most potent inhibitor displaying an IC50 value of 2.5µM for CysK1 and 6.6µM for CysK2, respectively. Four of the identified molecules targeting CysK1 and CysK2 were also among the top ten inhibitors of CysM, suggesting that potent compounds could be developed with activity against all three enzymes.
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      PubDate: 2017-09-19T02:42:27Z
      DOI: 10.1016/j.bmcl.2017.08.039
       
  • Recent advances in JAK3 inhibition: Isoform selectivity by covalent
           cysteine targeting
    • Authors: Michael Forster; Matthias Gehringer; Stefan A. Laufer
      Pages: 4229 - 4237
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Michael Forster, Matthias Gehringer, Stefan A. Laufer
      Janus kinases (JAKs) are a family of four cytosolic protein kinases with a high degree of structural similarity. Due to its very restricted role in immune regulation, JAK3 was promoted as an excellent target for immunosuppression for more than a decade, but clinical validation of this concept is still elusive. During the last years, speculation arose that kinase activity of JAK1, which cooperates with JAK3 in cytokine receptor signaling, may have a dominant role over the one of JAK3. Until recently, however, this issue could not be appropriately addressed due to a lack of highly isoform-selective tool compounds. With the recent resurgence of covalent drugs, targeting of a specific cysteine that distinguishes JAK3 from other JAK family members became an attractive design option. By applying this strategy, a set of JAK3 inhibitors with excellent selectivity against other JAK isoforms and the kinome was developed during the last three years and used to decipher JAK3-dependent signaling. The data obtained with these tool compounds demonstrates that selective JAK3 inhibition is sufficient to block downstream signaling. Since one of these inhibitors is currently under evaluation in phase II clinical studies against several inflammatory disorders, it will soon become apparent whether selective JAK3 inhibition translates into clinical efficacy.
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      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.07.079
       
  • Pyrrolo[2,1-f][1,2,4]triazines: From C-nucleosides to kinases and back
           again, the remarkable journey of a versatile nitrogen heterocycle
    • Authors: Gregory R. Ott; David A. Favor
      Pages: 4238 - 4246
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Gregory R. Ott, David A. Favor
      Pyrrolo[2,1-f][1,2,4]triazine, a unique NN bond-containing heterocycle with a bridgehead nitrogen, was first synthesized in the late 1970s but did not find utility until more than a decade later in the early 1990s when it was incorporated into C-nucleosides as a novel purine-like mimetic. This heterocycle remained at the fringes of medicinal chemistry until a confluence of events spurred by the explosion of the kinase inhibitor field in the early 2000s and the pressing need for novel, druggable scaffolds to occupy that exciting space led to numerous applications against diverse therapeutic targets. This digest will explore the history of this scaffold and the importance of chemistry in propelling drug discovery. The varied uses of this scaffold will be detailed as it progressed from C-nucleosides, to kinase inhibitors, to recognition as a “privileged” template, and finally reemergence in the C-nucleoside field.
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      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.07.073
       
  • Current approaches to the treatment of Parkinson’s Disease
    • Authors: J. Michael Ellis; Matthew J. Fell
      Pages: 4247 - 4255
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): J. Michael Ellis, Matthew J. Fell
      Parkinson’s Disease (PD) is the second most common neurodegenerative disorder. Clinical approaches to manage PD include symptomatic therapies, serving to compensate for the effects of dopaminergic neuronal deficits, as well as more recently a move toward disease modification, with the goal of slowing or stopping disease progression. This perspective surveys the approved therapies for PD treatment as well as provides a view of the ongoing clinical approaches aimed at improving outcomes for PD patients.
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      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.07.075
       
  • Recent progresses in biomedical applications of aptamer-functionalized
           systems
    • Authors: Fei Ding; Yangguang Gao; Xianran He
      Pages: 4256 - 4269
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Fei Ding, Yangguang Gao, Xianran He
      Aptamers, known as “chemical antibodies” are screened via a combinational technology of systematic evolution of ligands by exponential enrichment (SELEX). Due to their specific targeting ability, high binding affinity, low immunogenicity and easy modification, aptamer-functionalized systems have been extensively applied in various fields and exhibit favorable results. However, there is still a long way for them to be commercialized, and few aptamer-functionalized systems have yet successfully entered clinical and industrial use. Thus, it is necessary to overview the recent research progresses of aptamer-functionalized systems for the researchers to improve or design novel and better aptamer-functionalized systems. In this review, we first introduce the recent progresses of aptamer-functionalized systems’ applications in biosensing, targeted drug delivery, gene therapy and cancer cell imaging, followed by a discussion of the challenges faced with extensive applications of aptamer-functionalized systems and speculation of the future prospects of them.
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      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.03.032
       
  • Novel α,β-unsaturated amide derivatives bearing α-amino phosphonate
           moiety as potential antiviral agents
    • Authors: Xianmin Lan; Dandan Xie; Limin Yin; Zhenzhen Wang; Jin Chen; Awei Zhang; Baoan Song; Deyu Hu
      Pages: 4270 - 4273
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Xianmin Lan, Dandan Xie, Limin Yin, Zhenzhen Wang, Jin Chen, Awei Zhang, Baoan Song, Deyu Hu
      Based on flexible construction and broad bioactivity of ferulic acid, a series of novel α,β-unsaturated amide derivatives bearing α-aminophosphonate moiety were designed, synthesized and systematically evaluated for their antiviral activity. Bioassay results indicated that some compounds exhibited good antiviral activities against cucumber mosaic virus (CMV) and tobacco mosaic virus (TMV) in vivo. Especially, compound g18 showed excellent curative and protective activities against CMV, with half-maximal effective concentration (EC50) values of 284.67μg/mL and 216.30μg/mL, which were obviously superior to that of Ningnanmycin (352.08μg/mL and 262.53μg/mL). Preliminary structure-activity relationships (SARs) analysis revealed that the introduction of electron-withdrawing group at the 2-position or 4-position of the aromatic ring is favorable for antiviral activity. Present work provides a promising template for development of potential inhibitor of plant virus.
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      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.048
       
  • Discovery of a novel, CNS penetrant M4 PAM chemotype based on a
           6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core
    • Authors: Blake R. Bewley; Paul K. Spearing; Rebecca L. Weiner; Vincent B. Luscombe; Xiaoyan Zhan; Sichen Chang; Hyekyung P. Cho; Alice L. Rodriguez; Colleen M. Niswender; P. Jeffrey Conn; Thomas M. Bridges; Darren W. Engers; Craig W. Lindsley
      Pages: 4274 - 4279
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Blake R. Bewley, Paul K. Spearing, Rebecca L. Weiner, Vincent B. Luscombe, Xiaoyan Zhan, Sichen Chang, Hyekyung P. Cho, Alice L. Rodriguez, Colleen M. Niswender, P. Jeffrey Conn, Thomas M. Bridges, Darren W. Engers, Craig W. Lindsley
      This Letter details the discovery and subsequent optimization of a novel M4 PAM scaffold based on an 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core, which represents a distinct departure from the classical M4 PAM chemotypes. Optimized compounds in this series demonstrated improved M4 PAM potency on both human and rat M4 (4 to 5-fold relative to HTS hit), and displayed attractive physicochemical and DMPK profiles, including good CNS penetration (rat brain:plasma Kp =5.3, Kp,uu =2.4; MDCK-MDR1 (P-gp) ER=1.1).
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      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.043
       
  • Synthesis and electronic properties of ester substituted
           1,4-dicyanodibenzodioxins and evaluation of anti-proliferative activity of
           all isomeric 1,2-, 2,3- and 1,4-dicyanodibenzodioxins against HeLa cell
           line
    • Authors: Subhadeep Banerjee; Anjan Chattopadhyay; Joseph R.D. Fernandes; Arnab Banerjee; Apeksha Ashok Phadte; Akanksha Vinod Savardekar; Keisham Sarjit Singh
      Pages: 4280 - 4284
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Subhadeep Banerjee, Anjan Chattopadhyay, Joseph R.D. Fernandes, Arnab Banerjee, Apeksha Ashok Phadte, Akanksha Vinod Savardekar, Keisham Sarjit Singh
      1,4-Dicyanodibenzodioxins bearing carboxy methyl ester groups were synthesized using our established one-step SNAr coupling reaction between ortho- and meta-ester substituted catechols and perfluorinated terephthalonitrile. These are the first examples of 1,4-dicyanodibenzodioxins substituted at both the benzene moieties. Optical spectra were similar to the earlier examples reported, with a marginal blue shift for the ester dibenzodioxins. Theoretical analysis of the molecular orbitals reveals modest destabilization of the frontier molecular orbitals of one carboxy methyl ester isomer over the other and overall higher HOMO-LUMO gap for both isomers when compared to the earlier published 1,4-dicyanodibenzodioxins. In vitro cytotoxicity against human cervical cancer HeLa cell line was evaluated for these two compounds and all other previously published dibenzodioxins from our laboratory (1,4-dicyano, 1,2-dicyano and 2,3-dicyano variants). A number of derivatives showed anti-tumor activity in μM ranges and also exhibited no cytotoxicity against normal HEK 293 cell line. Mechanistic investigation of cell death pathways indicated high levels of reactive oxygen species (ROS) in the dibenzodioxin treated tumor cell lines along with cellular nuclear fragmentation, both of which are markers of the apoptotic cell death pathway.
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      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.042
       
  • Cation exchange assisted binding-elution strategy for enzymatic synthesis
           of human milk oligosaccharides (HMOs)
    • Authors: Hailiang Zhu; Zhigang Wu; Madhusudhan Reddy Gadi; Shuaishuai Wang; Yuxi Guo; Garrett Edmunds; Wanyi Guan; Junqiang Fang
      Pages: 4285 - 4287
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Hailiang Zhu, Zhigang Wu, Madhusudhan Reddy Gadi, Shuaishuai Wang, Yuxi Guo, Garrett Edmunds, Wanyi Guan, Junqiang Fang
      A cation exchange assisted binding-elution (BE) strategy for enzymatic synthesis of human milk oligosaccharides (HMOs) was developed. An amino linker was used to provide the cation ion under acidic condition which can be readily bound to cation exchange resin and then eluted off by saturated ammonium bicarbonate. Ammonium bicarbonate in the collections was easily removed by vacuum evaporation. This strategy circumvented the incompatible issue between glycosyltransferases and solid support or large polymers, and no purification was needed for intermediate products. With current approach, polyLacNAc backbones of HMOs and fucosylated HMOs were synthesized smoothly.
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      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.041
       
  • Efficacious cellular codelivery of doxorubicin and EGFP siRNA mediated by
           the composition of PLGA and PEI protected gold nanoparticles
    • Authors: Krishan Kumar; Gururaja Vulugundam; Pradeep Kumar Jaiswal; Bharti Rajesh Kumar Shyamlal; Sandeep Chaudhary
      Pages: 4288 - 4293
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Krishan Kumar, Gururaja Vulugundam, Pradeep Kumar Jaiswal, Bharti Rajesh Kumar Shyamlal, Sandeep Chaudhary
      This study reports the simultaneous delivery of EGFP siRNA and the chemotherapeutic drug, doxorubicin by means of the composition that results from the electrostatic interaction between positively charged siRNA-complexes of gold nanoparticles (AuNPs) capped with PEI, 25kDa (P25-AuNPs) and negatively charged carboxymethyl cellulose formulated PLGA nanoparticles loaded with doxorubicin. The nanoparticles and their facile interaction were studied by means of dynamic light scattering (DLS), zeta potential, transmission electron microscopic (TEM) measurements. The flow cytometric and confocal microscopic analysis evidenced the simultaneous internalization of both labelled siRNA and doxorubin into around 55% of the HeLa cancer cell population. Fluorescence microscopic studies enabled the visual analysis of EGFP expressing HeLa cells which suggested that the composition mediated codelivery resulted in a substantial downregulation of EGFP expression and intracellular accumulation of doxorubicin. Interestingly, codelivery treatment resulted in an increased cellular delivery of doxorubicin when compared to PLGA-DOX alone treatment. On the other hand, the activity of siRNA complexes of PEI-AuNPs was completely retained even when they were part of composition. The results suggest that this formulation can serve as promising tool for delivery applications in combinatorial anticancer therapy.
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      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.037
       
  • Synthesis and biological evaluation of pyridinium-functionalized carbazole
           derivatives as promising antibacterial agents
    • Authors: Pei-Yi Wang; He-Shu Fang; Wu-Bin Shao; Jian Zhou; Zhuo Chen; Bao-An Song; Song Yang
      Pages: 4294 - 4297
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Pei-Yi Wang, He-Shu Fang, Wu-Bin Shao, Jian Zhou, Zhuo Chen, Bao-An Song, Song Yang
      Various pyridinium-functionalized carbazole derivatives were constructed by coupling the key fragments of carbazole skeleton and pyridinium nucleus in a single molecular architecture. Antibacterial bioassays revealed that some of the title compounds displayed impressive bioactivities against plant pathogens such as Xanthomonas oryzae pv. oryzae, Ralstonia solanacearum, and Xanthomonas axonopodis pv. citri with minimal EC50 values of up to 0.4, 0.3, and 0.3mg/L, respectively. These bioactivities were achieved by systematically tuning and optimizing bridging linker, alkyl length of the tailor, and substituents on the carbazole scaffold. Compared with the bioactivity of the lead compound (AP-10), antibacterial efficacy dramatically increased by approximately 13-, 104- and 21-fold. This finding suggested that these compounds can serve as new lead compounds in research on antibacterial chemotherapy.
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      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.040
       
  • Synthesis and antiviral evaluation of novel
           1,3,4-oxadiazole/thiadiazole-chalcone conjugates
    • Authors: Xiuhai Gan; Deyu Hu; Zhuo Chen; Yanjiao Wang; Baoan Song
      Pages: 4298 - 4301
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Xiuhai Gan, Deyu Hu, Zhuo Chen, Yanjiao Wang, Baoan Song
      A series of novel 1,3,4-oxadiazole/thiadiazole–chalcone conjugates were synthesized and their in vitro and in vivo antiviral activities were evaluated via microscale thermophoresis method and half-leaf method, respectively. The in vitro results indicated that compounds 7g, 7l, 8h, and 8l displayed good antiviral activity against TMV, with the binding constant values of 5.93, 6.15, 6.02, and 5.04μM, respectively, which were comparable to that of Ninnanmycin (6.78μM) and even better than that of Ribavirin (99.25μM). The in vivo results demonstrated that compounds 7g, 7l, 8h, and 8l exhibited remarkable anti-TMV activity with the EC50 values of 33.66, 33.97, 33.87 and 30.57µg/mL, respectively, which were comparable to that of Ningnanmycin (36.85µg/mL) and superior to that of Ribavirin (88.52µg/mL). Interestingly, the trend of antiviral activity in vivo was consistent with the in vitro results.
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      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.038
       
  • Small molecule inhibitors of bacterial transcription complex formation
    • Authors: Daniel S. Wenholz; Ming Zeng; Cong Ma; Marcin Mielczarek; Xiao Yang; Mohan Bhadbhade; David St. C. Black; Peter J. Lewis; Renate Griffith; Naresh Kumar
      Pages: 4302 - 4308
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Daniel S. Wenholz, Ming Zeng, Cong Ma, Marcin Mielczarek, Xiao Yang, Mohan Bhadbhade, David St. C. Black, Peter J. Lewis, Renate Griffith, Naresh Kumar
      Knoevenagel condensation was employed to generate a set of molecules potentially capable of inhibiting the RNA polymerase-σ 70/σ A interaction in bacteria. Synthesis was achieved via reactions between a variety of indole-7-carbaldehydes and rhodanine, N-allylrhodanine, barbituric acid or thiobarbituric acid. A library of structurally diverse compounds was examined by enzyme-linked immunosorbent assay (ELISA) to assess the inhibition of the targeted protein–protein interaction. Inhibition of bacterial growth was also evaluated using Bacillus subtilis and Escherichia coli cultures. The structure–activity relationship studies demonstrated the significance of particular structural features of the synthesized molecules for RNA polymerase-σ 70/σ A interaction inhibition and antibacterial activity. Docking was investigated as an in silico method for the further development of the compounds.
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      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.036
       
  • Quinazoline-1-deoxynojirimycin hybrids as high active dual inhibitors of
           EGFR and α-glucosidase
    • Authors: Yaling Zhang; Hongliang Gao; Renjie Liu; Juan Liu; Li Chen; Xiabing Li; Lijun Zhao; Wei Wang; Baolin Li
      Pages: 4309 - 4313
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Yaling Zhang, Hongliang Gao, Renjie Liu, Juan Liu, Li Chen, Xiabing Li, Lijun Zhao, Wei Wang, Baolin Li
      A series of novel quinazoline-1-deoxynojirimycin hybrids were designed, synthesized and evaluated for their inhibitory activities against two drug target enzymes, epidermal growth factor receptor (EGFR) tyrosine kinase and α-glucosidase. Some synthesized compounds exhibited significantly inhibitory activities against the tested enzymes. Comparing with reference compounds gefitinib and lapatinib, compounds 7d, 8d, 9b and 9d showed higher inhibitory activities against EGFR (IC50: 1.79–10.71nM). Meanwhile the inhibitory activities of 7d, 8d and 9c against α-glucosidase (IC50 =0.14, 0.09 and 0.25µM, respectively) were obvious higher than that of miglitol (IC50 =2.43µM), a clinical using α-glucosidase inhibitor. Interestingly, compound 9d as a dual inhibitor showed high inhibitory activity to EGFRwt tyrosine kinase (IC50 =1.79nM), also to α-glucosidase (IC50 =0.39µM). The work could be very useful starting point for developing a new series of enzyme inhibitors targeting EGFR and/or α-glucosidase.
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      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.035
       
  • Synthesis of novel forskolin isoxazole derivatives with potent anti-cancer
           activity against breast cancer cell lines
    • Authors: Srinivas Burra; Vani Voora; Ch. Prasad Rao; P. Vijay Kumar; Rama Krishna Kancha; G.L. David Krupadanam
      Pages: 4314 - 4318
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Srinivas Burra, Vani Voora, Ch. Prasad Rao, P. Vijay Kumar, Rama Krishna Kancha, G.L. David Krupadanam
      Forskolin C1-isoxazole derivatives (3,5-regioisomers) (11a–e, 14, 15a–h and 15, 16a–g) were synthesized regioselectively by adopting 1,3-dipolar cycloadditions. These derivatives were tested using estrogen receptor positive breast cancer cell lines MCF-7 and BT-474. Majority of the compounds exhibited activity against the p53-positive MCF-7 breast cancer cells but not against the p53-negative BT-474 breast cancer cells. Among forskolin derivatives, compounds 11a, 11c, 14a, 14f, 14g, 14h, 15b, 16g and 17b exhibited higher anti-cancer activity against MCF-7 cell line with an IC50 ≤1µM. The derivative 14f exhibited highest activity in both p53-positive (MCF-7) and p53-negative (BT-474) breast cancer cell lines with an IC50 of 0.5µM.
      Graphical abstract image

      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.033
       
  • Evaluation of tetraether lipid-based liposomal carriers for encapsulation
           and retention of nucleoside-based drugs
    • Authors: Valentina Paolucci; Geoffray Leriche; Takaoki Koyanagi; Jerry Yang
      Pages: 4319 - 4322
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Valentina Paolucci, Geoffray Leriche, Takaoki Koyanagi, Jerry Yang
      Although liposomal nanoparticles are one of the most versatile class of drug delivery systems, stable liposomal formulation of small neutral drug molecules still constitutes a challenge due to the low drug retention of current lipid membrane technologies. In this study, we evaluate the encapsulation and retention of seven nucleoside analog-based drugs in liposomes made of archaea-inspired tetraether lipids, which are known to enhance packing and membrane robustness compared to conventional bilayer-forming lipids. Liposomes comprised of the pure tetraether lipid generally showed improved retention of drugs (up to 4-fold) compared with liposomes made from a commercially available diacyl lipid. Interestingly, we did not find a significant correlation between the liposomal leakage rates of the molecules with typical parameters used to assess lipophilicity of drugs (such logD or topological polar surface area), suggesting that specific structural elements of the drug molecules can have a dominant effect on leakage from liposomes over general lipophilic character.
      Graphical abstract image

      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.032
       
  • The discovery of IDX21437: Design, synthesis and antiviral evaluation of
           2′-α-chloro-2′-β-C-methyl branched uridine pronucleotides as potent
           liver-targeted HCV polymerase inhibitors
    • Authors: François-René Alexandre; Eric Badaroux; John P. Bilello; Stéphanie Bot; Tony Bouisset; Guillaume Brandt; Sylvie Cappelle; Christopher Chapron; Dominique Chaves; Thierry Convard; Clément Counor; Daniel Da Costa; David Dukhan; Marion Gay; Gilles Gosselin; Jean-François Griffon; Kusum Gupta; Brenda Hernandez-Santiago; Massimiliano La Colla; Marie-Pierre Lioure; Julien Milhau; Jean-Laurent Paparin; Jérôme Peyronnet; Christophe Parsy; Claire Pierra Rouvière; Houcine Rahali; Rachid Rahali; Aurélien Salanson; Maria Seifer; Ilaria Serra; David Standring; Dominique Surleraux; Cyril B. Dousson
      Pages: 4323 - 4330
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): François-René Alexandre, Eric Badaroux, John P. Bilello, Stéphanie Bot, Tony Bouisset, Guillaume Brandt, Sylvie Cappelle, Christopher Chapron, Dominique Chaves, Thierry Convard, Clément Counor, Daniel Da Costa, David Dukhan, Marion Gay, Gilles Gosselin, Jean-François Griffon, Kusum Gupta, Brenda Hernandez-Santiago, Massimiliano La Colla, Marie-Pierre Lioure, Julien Milhau, Jean-Laurent Paparin, Jérôme Peyronnet, Christophe Parsy, Claire Pierra Rouvière, Houcine Rahali, Rachid Rahali, Aurélien Salanson, Maria Seifer, Ilaria Serra, David Standring, Dominique Surleraux, Cyril B. Dousson
      Herein we describe the discovery of IDX21437 35b, a novel RP d-aminoacid-based phosphoramidate prodrug of 2′-α-chloro-2′-β-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes. A biochemical study revealed that the metabolism of 35b was mainly attributed to carboxyesterase 1 (CES1), an enzyme which is underexpressed in HCV Huh-7-derived replicon cells. Furthermore, due to its metabolic activation, 35b was efficiently processed in liver cells compared to other cell types, including human cardiomyocytes. The selected RP diastereoisomeric configuration of 35b was assigned by X-ray structural determination. 35b is currently in Phase II clinical trials for the treatment of HCV infection.
      Graphical abstract image

      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.029
       
  • Synthesis and optimization of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as
           potent and orally-active metabotropic glutamate receptor 5 negative
           allosteric modulators
    • Authors: Wataru Hirose; Yoshihiro Kato; Itaru Natsutani; Makoto Takata; Maiko Kitaichi; Satoki Imai; Shun Hayashi; Yukiyo Arai; Kohei Hoshino; Kohzo Yoshida
      Pages: 4331 - 4335
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Wataru Hirose, Yoshihiro Kato, Itaru Natsutani, Makoto Takata, Maiko Kitaichi, Satoki Imai, Shun Hayashi, Yukiyo Arai, Kohei Hoshino, Kohzo Yoshida
      We describe here the design, synthesis and characterization of a series of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as metabotropic glutamate receptor (mGluR) 5 negative allosteric modulators (NAMs). Optimization of the substituents led to the identification of several compounds with good pharmacokinetic profiles, including long half life and high oral bioavailability, in both rats and monkeys. The receptor occupancy test in the rat cortex revealed favorable brain penetration of these compounds. The reprsentative compound 13 produced oral antidepressant-like effect in the rat forced swimming test (MED: 0.3mg/kg, q.d.).
      Graphical abstract image

      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.030
       
  • Synthesis of some monosaccharide-related ester derivatives as insecticidal
           and acaricidal agents
    • Authors: Xiaobo Huang; Bingchuan Zhang; Hui Xu
      Pages: 4336 - 4340
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Xiaobo Huang, Bingchuan Zhang, Hui Xu
      To develop natural-product-based pesticidal agents, a series of monosaccharide-related ester derivatives (17a–q and 18a–f), glucose (xylose)-piperic acid/piperic acid-like conjugates, were synthesized. Three-dimensional structures of compounds 17b, 17g, 17h, and 17n were unambiguously determined by single-crystal X-ray diffraction. Especially compounds 18e and 18f exhibited the most potent insecticidal and acaricidal activities against Mythimna separata and Tetranychus cinnabarinus. Their structure-activity relationships were also discussed.
      Graphical abstract image

      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.031
       
  • Photodynamic inactivation of multiresistant bacteria (KPC) using
           zinc(II)phthalocyanines
    • Authors: Mariana Miretti; Romina Clementi; Tomas C. Tempesti; María T. Baumgartner
      Pages: 4341 - 4344
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Mariana Miretti, Romina Clementi, Tomas C. Tempesti, María T. Baumgartner
      The worldwide increase in antibiotic resistance has led to search of alternatives anti-microbial therapies such as photodynamic inactivation. The aim of this paper was to evaluate the photodynamic activity in vitro of a neutral and two cationic Zn phthalocyanines. Their photokilling activity was tested on Escherichia coli ATCC 25922 and Klebsiella pneumoniae Carbapenemase (KPC)-producing. After treating bacteria with phthalocyanines, the cultures were irradiated with white light. As a result, the bacteria were inactivated in presence of cationic phthalocyanines. The photoinactivation was dependent of the irradiation time and phthalocyanine concentration. The most effective photosensitizer on KPC-producing was Zinc(II)tetramethyltetrapyridino[2,3-b:2′,3′-g:2″,3″-l:2‴,3‴-q]porphyrazinium methylsulfate (ZnTM2,3PyPz). After irradiation using the water soluble ZnTM2,3PyPz (3μM) the viability of KPC (30min of irradiation) and E. coli (10min of irradiation) decreased ≈99.995%.
      Graphical abstract image

      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.028
       
  • Structural characterization of a new steroidal saponin from Agave
           angustifolia var. Marginata and a preliminary investigation of its in vivo
           antiulcerogenic activity and in vitro membrane permeability property
    • Authors: Gabriela Moysés Pereira; Marcela Gonçalves Ribeiro; Bernadete Pereira da Silva; José Paz Parente
      Pages: 4345 - 4349
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Gabriela Moysés Pereira, Marcela Gonçalves Ribeiro, Bernadete Pereira da Silva, José Paz Parente
      A new furostane steroidal saponin was isolated from the leaves of Agave angustifolia var. marginata. On the basis of chemical conversions and spectroscopic analyses, its structure was established as 3-[O-β-d-glucopyranosyl-(1→3)-O-β-d-glucopyranosyl-(1→3)-O]-[O-6-deoxy-α-l-mannopyranosyl-(1→4)-β-d-xylopyranosyl-(1→2)-O-β-d-glucopyranosyl-(1→4)-β-d-galactopyranosyl)oxy]-(3β,5α,22α,25R)-26-(β-d-glucopyranosyloxy)-22-methoxy-furostane (1). Results of preliminary biological investigations indicated that compound 1 showed significant protective effects against induced gastric ulcers using in vivo experimental models and demonstrated negligible toxicity on membrane integrity in the in vitro assays.
      Graphical abstract image

      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.026
       
  • Design, synthesis, and biological activity of
           5′-phenyl-1,2,5,6-tetrahydro-3,3′-bipyridine analogues as potential
           antagonists of nicotinic acetylcholine receptors
    • Authors: Yafei Jin; Xiaoqin Huang; Roger L. Papke; Emily M. Jutkiewicz; Hollis D. Showalter; Chang-Guo Zhan
      Pages: 4350 - 4353
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Yafei Jin, Xiaoqin Huang, Roger L. Papke, Emily M. Jutkiewicz, Hollis D. Showalter, Chang-Guo Zhan
      Starting from a known non-specific agonist (1) of nicotinic acetylcholine receptors (nAChRs), rationally guided structural-based design resulted in the discovery of a small series of 5′-phenyl-1,2,5,6-tetrahydro-3,3′-bipyridines (3a–3e) incorporating a phenyl ring off the pyridine core of 1. The compounds were synthesized via successive Suzuki couplings on a suitably functionalized pyridine starting monomer 4 to append phenyl and pyridyl substituents off the 3- and 5-positions, respectively, and then subsequent modifications were made on the flanking pyridyl ring to provide target compounds. Compound 3a is a novel antagonist, which is highly selective for α3β4 nAChR (K i =123nM) over the α4β2 and α7 receptors.
      Graphical abstract image

      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.025
       
  • Design and multi-step synthesis of chalcone-polyamine conjugates as potent
           antiproliferative agents
    • Authors: Benjamin Rioux; Christelle Pouget; Chloë Fidanzi-Dugas; Aurélie Gamond; Aurélie Laurent; Josiane Semaan; Aline Pinon; Yves Champavier; David Y. Léger; Bertrand Liagre; Jean-Luc Duroux; Catherine Fagnère; Vincent Sol
      Pages: 4354 - 4357
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Benjamin Rioux, Christelle Pouget, Chloë Fidanzi-Dugas, Aurélie Gamond, Aurélie Laurent, Josiane Semaan, Aline Pinon, Yves Champavier, David Y. Léger, Bertrand Liagre, Jean-Luc Duroux, Catherine Fagnère, Vincent Sol
      The aim of this study is to synthesize chalcone-polyamine conjugates in order to enhance bioavailability and selectivity of chalcone core towards cancer cells, using polyamine-based vectors. 3-hydroxy-3′,4,4′,5′-tetramethoxychalcone (1) and 3′,4,4′,5′-tetramethoxychalcone (2) were selected as parent chalcones since they were found to be efficient anti-proliferative agents on various cancer cells. A series of ten chalcone-polyamine conjugates was obtained by reacting carboxychalcones with different polyamine tails. Chalcones 1 and 2 showed a strong cytotoxic activity against two prostatic cancer (PC-3 and DU-145) and two colorectal cancer (HT-29 and HCT-116) cell lines. Then, chalcone-spermine conjugates 7d and 8d were shown to be the most active of the series and could be considered as promising compounds for colon and prostatic cancer adjuvant therapy.
      Graphical abstract image

      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.024
       
  • Synthesis and biological evaluations of new nitric oxide-anti-inflammatory
           drug hybrids
    • Authors: Eman K.A. Abdelall; Abdou O. Abdelhamid
      Pages: 4358 - 4369
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Eman K.A. Abdelall, Abdou O. Abdelhamid
      Three novel series of nitroso derivatives (11–15), isoxazolopyrazoles (17a–c) and isoxazolo[3,4-d]pyridazines (18a–c) were prepared from the hydroxyimoyl chloride 10. In vitro COX1⧹2 inhibition activities were evaluated, both of 17b and 18a proved a promising inhibitory activity with IC50 =1.12, 0.78μM in sequent. Carrageenan induced Paw edema, ulcer liability, nitric oxide (NO ) release and histopathological study were determined. Most of the prepared compounds showed excellent activities. Reactions of 2-aminopyridine and enaminone with hydroxyimoyl chloride 10 were investigated and proved by 2D NMR. Molecular docking for most active compounds was operated giving a hint for compound–receptor interactions.
      Graphical abstract image

      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.023
       
  • Identification of an imidazopyridine scaffold to generate potent and
           selective TYK2 inhibitors that demonstrate activity in an in vivo
           psoriasis model
    • Authors: Jun Liang; Anne Van Abbema; Mercedesz Balazs; Kathy Barrett; Leo Berezhkovsky; Wade S. Blair; Christine Chang; Donnie Delarosa; Jason DeVoss; Jim Driscoll; Charles Eigenbrot; Simon Goodacre; Nico Ghilardi; Calum MacLeod; Adam Johnson; Pawan Bir Kohli; Yingjie Lai; Zhonghua Lin; Priscilla Mantik; Kapil Menghrajani; Hieu Nguyen; Ivan Peng; Amy Sambrone; Steven Shia; Jan Smith; Sue Sohn; Vickie Tsui; Mark Ultsch; Karen Williams; Lawren C. Wu; Wenqian Yang; Birong Zhang; Steven Magnuson
      Pages: 4370 - 4376
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Jun Liang, Anne Van Abbema, Mercedesz Balazs, Kathy Barrett, Leo Berezhkovsky, Wade S. Blair, Christine Chang, Donnie Delarosa, Jason DeVoss, Jim Driscoll, Charles Eigenbrot, Simon Goodacre, Nico Ghilardi, Calum MacLeod, Adam Johnson, Pawan Bir Kohli, Yingjie Lai, Zhonghua Lin, Priscilla Mantik, Kapil Menghrajani, Hieu Nguyen, Ivan Peng, Amy Sambrone, Steven Shia, Jan Smith, Sue Sohn, Vickie Tsui, Mark Ultsch, Karen Williams, Lawren C. Wu, Wenqian Yang, Birong Zhang, Steven Magnuson
      Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compound 1. Further optimization led to generation of compound 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compound 30 demonstrated dose-dependent reduction of IL-17 production in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL-17 decrease was accompanied by a reduction of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients.
      Graphical abstract image

      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.022
       
  • Design, synthesis and preliminary antiproliferative activity studies of
           new diheteroaryl thioether derivatives
    • Authors: Zhong-Hua Li; Xue-Qi Liu; Tao-Qian Zhao; Peng-Fei Geng; Ying Liu; Bing Zhao; Wen-Ge Guo; Bin Yu; Hong-Min Liu
      Pages: 4377 - 4382
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Zhong-Hua Li, Xue-Qi Liu, Tao-Qian Zhao, Peng-Fei Geng, Ying Liu, Bing Zhao, Wen-Ge Guo, Bin Yu, Hong-Min Liu
      A series of structurally new diheteroaryl thioether analogs was designed, prepared and screened toward MGC-803, MKN-45, EC-109 and H1650. Most of the target compounds displayed moderate to potent antiproliferative activities. Among them, compound 5 showed the best antiproliferative activity against the tested cell lines with the half maximal inhibitory concentration (IC50) values below 10μM. In addition, flow cytometry analysis showed that compound 5 increased Bax expression, down-regulated expression of Bcl-2, cleaved caspases-3/9, finally inducing apoptosis of MKN-45 cells as well asarrested the cell cycle at G2/M phase. This study suggests that the diheteroaryl thioethers are a class of emerging chemotypes for developing antitumor agents or biological probes, and compound 5 could serve as a good starting point to design new apoptosis inducers.
      Graphical abstract image

      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.021
       
  • Pyrazole C-region analogues of
           2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1
           antagonists
    • Authors: Sunho Lee; Changhoon Kim; Jihyae Ann; Shivaji A. Thorat; Eunhye Kim; Jongmi Park; Sun Choi; Peter M. Blumberg; Robert Frank-Foltyn; Gregor Bahrenberg; Hannelore Stockhausen; Thomas Christoph; Jeewoo Lee
      Pages: 4383 - 4388
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Sunho Lee, Changhoon Kim, Jihyae Ann, Shivaji A. Thorat, Eunhye Kim, Jongmi Park, Sun Choi, Peter M. Blumberg, Robert Frank-Foltyn, Gregor Bahrenberg, Hannelore Stockhausen, Thomas Christoph, Jeewoo Lee
      A series of 1-substituted 3-(t-butyl/trifluoromethyl)pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The structure activity relationship indicated that the 3-chlorophenyl group at the 1-position of pyrazole was the optimized hydrophobic group for antagonistic potency and the activity was stereospecific to the S-configuration, providing exceptionally potent antagonists 13S and 16S with Ki(CAP) =0.1nM. Particularly significant, 13S exhibited antagonism selective for capsaicin and NADA and not for low pH or elevated temperature. Both compounds also proved to be very potent antagonists for rTRPV1, blocking in vivo the hypothermic action of capsaicin, consistent with their in vitro mechanism. The docking study of compounds 13S and 16S in our hTRPV1 homology model indicated that the binding modes differed somewhat, with that of 13S more closely resembling that of GRT12360.
      Graphical abstract image

      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.020
       
  • Cytotoxic effect of sanguiin H-6 on MCF-7 and MDA-MB-231 human breast
           carcinoma cells
    • Authors: Eun-Ji Park; Dahae Lee; Seon-Eun Baek; Ki Hyun Kim; Ki Sung Kang; Tae Su Jang; Hye Lim Lee; Ji Hoon Song; Jeong-Eun Yoo
      Pages: 4389 - 4392
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Eun-Ji Park, Dahae Lee, Seon-Eun Baek, Ki Hyun Kim, Ki Sung Kang, Tae Su Jang, Hye Lim Lee, Ji Hoon Song, Jeong-Eun Yoo
      Sanguiin H-6 is a dimer of casuarictin linked by a bond between the gallic acid residue and one of the hexahydroxydiphenic acid units. It is an effective compound extracted from Rubus coreanus. It has an anticancer effect against several human cancer cells; however, its effect on breast cancer cells has not been clearly demonstrated. Thus, we aimed to investigate the anticancer effect and mechanism of action of sanguiin H-6 against two human breast carcinoma cell lines (MCF-7 and MDA-MB-231). We found that sanguiin H-6 significantly reduced cell viability in a concentration-dependent manner. It also increased the rates at which MCF-7 and MDA-MB-231 cells underwent apoptosis. Furthermore, sanguiin H-6 induced the cleavage of caspase-8, caspase-3, and poly(ADP-ribose) polymerase, which resulted in apoptosis. However, cleavage of caspase-9 was only detectable in MCF-7 cells. In addition, sanguiin H-6 increased the ratio of Bax to Bcl-2 in both MCF-7 and MDA-MB-231 cells. These findings suggest that sanguiin H-6 is a potent therapeutic agent against breast cancer cells. In addition, it exerts its anticancer effect in an estrogen-receptor-independent manner.
      Graphical abstract image

      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.019
       
  • Synthesis, antimicrobial activity, structure-activity relationship and
           cytotoxic studies of a new series of functionalized
           (Z)-3-(2-oxo-2-substituted
           ethylidene)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-ones
    • Authors: Ritu Sharma; Lalit Yadav; Jaggi Lal; Pradeep K. Jaiswal; Manas Mathur; Ajit K. Swami; Sandeep Chaudhary
      Pages: 4393 - 4398
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Ritu Sharma, Lalit Yadav, Jaggi Lal, Pradeep K. Jaiswal, Manas Mathur, Ajit K. Swami, Sandeep Chaudhary
      A new series of functionalized (Z)-3-(2-oxo-2-substituted ethylidene)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-ones 23–26, incorporating pharmaceutically privileged substructures such as cyclopropyl, naphthyl, biphenyl and cyclohexylphenyl were synthesized in excellent yields. All the synthesized compounds were screened for their in vitro antibacterial activity against gram-(+)ve and gram-(−)ve bacterial species i.e. S. griseus, S. aureus, B. subtillis and E. coli as well as in vitro antifungal activity against fungal species i.e. F. oxysporium, A. niger, P. funiculosum and T. reesei, respectively. In this study, compounds containing cyclopropyl and cyclohexylphenyl substructures were identified as promising antimicrobial agents than standard drugs, ampicillin and chloramphenicol as well as ketoconazole. SAR study illustrates that electron-withdrawing groups increases the antibacterial as well as antifungal activity of 2-oxo-benzo[1,4]oxazines and vice versa. Compounds 23e and 26e, the most active compounds of the series, displayed promising antibacterial activity than Ampicillin and Chloramphenicol. Moreover, compound 26d showed promising antifungal potency as compared to Ketoconazole. Cytotoxic studies of the active compounds i.e. 23c–e, 24e, 25d and 26d–e found to be non-toxic in nature in 3T3 fibroblast cell lines using MTT assay.
      Graphical abstract image

      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.017
       
  • Synthesis and biological evaluation of N9-cis-cyclobutylpurine derivatives
           for use as cyclin-dependent kinase (CDK) inhibitors
    • Authors: Sun Jun Park; Eunjin Kim; Miyoun Yoo; Joo-Youn Lee; Chi Hoon Park; Jong Yeon Hwang; Jae Du Ha
      Pages: 4399 - 4404
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Sun Jun Park, Eunjin Kim, Miyoun Yoo, Joo-Youn Lee, Chi Hoon Park, Jong Yeon Hwang, Jae Du Ha
      A novel 6-aminopurine scaffold bearing an N9-cis-cyclobutyl moiety was designed using structure-based molecular design based on two known CDK inhibitors, dinaciclib and Cmpd-27. A series of novel 6-aminopurine compounds was prepared for structure–activity relationship (SAR) studies of CDK2 and CDK5 inhibitors. Among the compounds synthesized, compound 8l displayed potent CDK2 and CDK5 inhibitory activities with low nanomolar ranges (IC50 =2.1 and 4.8nM, respectively) and showed moderate cytotoxicity in HCT116 colon cancer and MCF7 breast cancer cell lines. Here, we report the synthesis and evaluation of novel 6-aminopurine derivatives and present molecular docking models of compound 81 with CDK2 and CDK5.
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      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.018
       
  • Characterization of a highly selective inhibitor of the Aurora kinases
    • Authors: Fleur M. Ferguson; Zainab M. Doctor; Apirat Chaikuad; Taebo Sim; Nam Doo Kim; Stefan Knapp; Nathanael S. Gray
      Pages: 4405 - 4408
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Fleur M. Ferguson, Zainab M. Doctor, Apirat Chaikuad, Taebo Sim, Nam Doo Kim, Stefan Knapp, Nathanael S. Gray
      Aurora kinases play an essential role in mitosis and cell cycle regulation. In recent years Aurora kinases have proved popular cancer targets and many inhibitors have been developed. The majority of these clinical candidates are multi-targeted, rendering them inappropriate as tools for studying Aurora kinase mediated signaling. Here we report discovery of a highly selective inhibitor of Aurora kinases A, B and C, with potent cellular activity and minimal off-target activity (PLK4). The X-ray co-crystal structure of Aurora A in complex with compound 2 is reported, and provides insights into the structural determinants of ligand binding and selectivity.
      Graphical abstract image

      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.016
       
  • Design, synthesis, anti-inflammatory activity, and molecular docking
           studies of perimidine derivatives containing triazole
    • Authors: Hong-Jian Zhang; Xiu-Zhi Wang; Qi Cao; Guo-Hua Gong; Zhe-Shan Quan
      Pages: 4409 - 4414
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Hong-Jian Zhang, Xiu-Zhi Wang, Qi Cao, Guo-Hua Gong, Zhe-Shan Quan
      We report here the design, synthesis, and anti-inflammatory activities of a series of perimidine derivatives containing triazole (5a–s). The chemical structures of the synthesized compounds have been assigned on the basis of IR, 1H NMR, 13C NMR, and HRMS spectral analyses. The anti-inflammatory properties of the synthesized perimidine derivatives were evaluated in a lipopolysaccharide (LPS)-stimulated inflammation model. Among the tested compounds, compound 7-(3-methylbenzyl)-7H-[1,2,4]triazolo[4,3-a]perimidine (hereafter referred to as 5h) and compound 7-(2-fluorobenzyl)-7H-[1,2,4]triazolo[4,3-a]perimidine (hereafter referred to as 5n) caused a reduction in the levels of the pro-inflammatory cytokines—tumor necrosis factor (TNF)-α and interleukin (IL)-6—in RAW264.7 cells. The anti-inflammatory potential of compounds 5h and 5n was also evaluated in vivo in a xylene-induced ear inflammation model. Compound 5n showed the most potent anti-inflammatory activity with an inhibition of 49.26% at a dose of 50mg/kg. This activity is more potent than that of the reference drug ibuprofen (28.13%), and slightly less than that of indometacin (49.36%). To further elucidate the mechanisms underlying these inhibitory effects, LPS-induced nuclear factor-κB (NF-κB) activation and mitogen-activated protein kinase (MAPK) phosphorylation were studied. The results of western blotting showed that the extract obtained from compound 5n inhibited NF-κB (p65) activation and MAPK (extracellular signal-regulated kinase (ERK) and p38) phosphorylation in a dose-dependent manner. Moreover, the results of a docking study of compound 5n into the COX-2 binding site revealed that its mechanism was possibly similar to that of naproxen, a COX-2 inhibitor. The effect of compound 5n on COX-2 antibody was showed it could significantly inhibit COX-2 activity.
      Graphical abstract image

      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.014
       
  • Rational design, synthesis and preliminary antitumor activity evaluation
           of a chlorambucil derivative with potent DNA/HDAC dual-targeting
           inhibitory activity
    • Authors: Rui Xie; Yan Li; Pingwah Tang; Qipeng Yuan
      Pages: 4415 - 4420
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Rui Xie, Yan Li, Pingwah Tang, Qipeng Yuan
      Histone deacetylases (HDACs) play a pivotal role not only in gene expression but also in DNA repair. Herein, we report the successful design, synthesis and evaluation of a chlorambucil derivative named vorambucil with a hydroxamic acid tail as a DNA/HDAC dual-targeting inhibitor. Vorambucil obtained both potent DNA and HDACs inhibitory activities. Molecular docking results supported the initial pharmacophoric hypothesis and rationalized the potent inhibitory activity of vorambucil against HDAC1, HDAC2 and HDAC6. Vorambucil showed potent antiproliferative activity against all the test four cancer cell lines with IC50 values of as low as 3.2–6.2μM and exhibited 5.0–18.3-fold enhanced antiproliferative activity than chlorambucil. Vorambucil also significantly inhibits colony formation of A375 cancer cells. Further investigation showed that vorambucil remarkably induced apoptosis and arrested the cell cycle of A375 cells at G2/M phase. Vorambucil could be a promising candidate and a useful tool to elucidate the role of those DNA/HDAC dual-targeting inhibitors for cancer therapy.
      Graphical abstract image

      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.011
       
  • Arylamidonaphtalene sulfonate compounds as a novel class of heparanase
           inhibitors
    • Authors: Riccardo Rondanin; Sara Fochi; Riccardo Baruchello; Tatiana Bernardi; Paola Oliva; Floriana Semeraro; Daniele Simoni; Giuseppe Giannini
      Pages: 4421 - 4425
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Riccardo Rondanin, Sara Fochi, Riccardo Baruchello, Tatiana Bernardi, Paola Oliva, Floriana Semeraro, Daniele Simoni, Giuseppe Giannini
      The search for antimetastatic agents for cancer therapy may involve the ability of new compounds to maintain the tissue extracellular matrix integrity. Among known factors, heparanase, an endoglucuronidase responsible for heparan sulfate cleavage, is a promising target whose inhibition could represent a strong obstacle for metastatic cancerous mechanisms. The antimetastatic activity of some suramin derivatives reported in literature suggests a possible involvement of the heparanase enzyme. To confirm such hypothesis, we have investigated FCE27266, a molecule known for its antiangiogenic and antimetastatic properties. Other new derivatives were also synthesized and investigated. Our findings revealed that FCE27266 as well as some derivatives have a strong heparanase inhibition activity, together with no cytotoxic power. Moreover, a FCE27266 analogue (SST0546NA1; 17a) resulted also positive to lower gene expression of some proangiogenic factors.
      Graphical abstract image

      PubDate: 2017-09-12T02:51:10Z
      DOI: 10.1016/j.bmcl.2017.08.013
       
  • Antibiotic adjuvants – A strategy to unlock bacterial resistance to
           antibiotics
    • Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 18
      Author(s): Concepción González-Bello
      Resistance to available antibiotics in pathogenic bacteria is currently a global challenge since the number of strains that are resistant to multiple types of antibiotics has increased dramatically each year and has spread worldwide. To unlock this problem, the use of an ‘antibiotic adjuvant’ in combination with an antibiotic is now being exploited. This approach enables us to prolong the lifespan of these life-saving drugs. This digests review provides an overview of the main types of antibiotic adjuvants, the basis of their operation and the remaining issues to be tackled in this field. Particular emphasis is placed on those compounds that are already in clinical development, namely β-lactamase inhibitors.
      Graphical abstract image

      PubDate: 2017-09-12T02:51:10Z
       
 
 
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