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  Subjects -> CHEMISTRY (Total: 843 journals)
    - ANALYTICAL CHEMISTRY (47 journals)
    - CHEMISTRY (594 journals)
    - CRYSTALLOGRAPHY (22 journals)
    - ELECTROCHEMISTRY (26 journals)
    - INORGANIC CHEMISTRY (42 journals)
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CHEMISTRY (594 journals)                  1 2 3 4 5 6 | Last

2D Materials     Hybrid Journal   (Followers: 7)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 27)
ACS Catalysis     Full-text available via subscription   (Followers: 28)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 16)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 17)
ACS Macro Letters     Full-text available via subscription   (Followers: 24)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 26)
ACS Nano     Full-text available via subscription   (Followers: 179)
ACS Photonics     Full-text available via subscription   (Followers: 5)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 18)
Acta Chemica Iasi     Open Access  
Acta Chimica Sinica     Full-text available via subscription  
Acta Chimica Slovaca     Open Access   (Followers: 5)
Acta Chromatographica     Full-text available via subscription   (Followers: 8)
Acta Facultatis Medicae Naissensis     Open Access   (Followers: 1)
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 7)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 5)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 10)
Advanced Functional Materials     Hybrid Journal   (Followers: 48)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 26)
Advances in Chemical Science     Open Access   (Followers: 10)
Advances in Chemistry     Open Access   (Followers: 4)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 14)
Advances in Drug Research     Full-text available via subscription   (Followers: 19)
Advances in Environmental Chemistry     Open Access   (Followers: 1)
Advances in Enzyme Research     Open Access   (Followers: 2)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 13)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 9)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 15)
Advances in Nanoparticles     Open Access   (Followers: 11)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 11)
Advances in Polymer Science     Hybrid Journal   (Followers: 38)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 12)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Science and Technology     Full-text available via subscription  
African Journal of Chemical Education     Open Access   (Followers: 1)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 5)
Afrique Science : Revue Internationale des Sciences et Technologie     Open Access   (Followers: 1)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 1)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 4)
AMB Express     Open Access  
Ambix     Hybrid Journal   (Followers: 2)
American Journal of Applied Sciences     Open Access   (Followers: 33)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 72)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 11)
American Journal of Chemistry     Open Access   (Followers: 25)
American Journal of Plant Physiology     Open Access   (Followers: 11)
American Mineralogist     Full-text available via subscription   (Followers: 7)
Analyst     Full-text available via subscription   (Followers: 40)
Angewandte Chemie     Hybrid Journal   (Followers: 30)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 143)
Annales UMCS, Chemia     Open Access   (Followers: 2)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 1)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 2)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 3)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 7)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 10)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 13)
Anti-Infective Agents     Hybrid Journal   (Followers: 2)
Antiviral Chemistry and Chemotherapy     Full-text available via subscription   (Followers: 1)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 5)
Applied Spectroscopy     Full-text available via subscription   (Followers: 16)
Applied Surface Science     Hybrid Journal   (Followers: 23)
Arabian Journal of Chemistry     Full-text available via subscription   (Followers: 6)
ARKIVOC     Open Access   (Followers: 1)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 5)
Autophagy     Hybrid Journal   (Followers: 3)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 6)
Biochemistry     Full-text available via subscription   (Followers: 165)
Biochemistry Insights     Open Access   (Followers: 4)
Biochemistry Research International     Open Access   (Followers: 5)
BioChip Journal     Hybrid Journal   (Followers: 1)
Bioinorganic Chemistry and Applications     Open Access   (Followers: 6)
Bioinspired Materials     Open Access   (Followers: 2)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 1)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access  
Biomacromolecules     Full-text available via subscription   (Followers: 19)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 8)
Biomedical Chromatography     Hybrid Journal   (Followers: 7)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 2)
BioNanoScience     Partially Free   (Followers: 3)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 32)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 25)
Bioorganic Chemistry     Hybrid Journal   (Followers: 6)
Biopolymers     Hybrid Journal   (Followers: 16)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 3)
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 3)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 14)
C - Journal of Carbon Research     Open Access  
Cakra Kimia (Indonesian E-Journal of Applied Chemistry)     Open Access   (Followers: 1)
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 4)

        1 2 3 4 5 6 | Last

Journal Cover Bioorganic & Medicinal Chemistry
  [32 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [2801 journals]
  • Synthesis, molecular docking and biological evaluation of
           N,N-disubstituted 2-aminothiazolines as a new class of
           butyrylcholinesterase and carboxylesterase inhibitors
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Galina F. Makhaeva, Natalia P. Boltneva, Sofya V. Lushchekina, Olga G. Serebryakova, Tatyana S. Stupina, Alexey A. Terentiev, Igor V. Serkov, Alexey N. Proshin, Sergey O. Bachurin, Rudy J. Richardson
      A series of 31 N,N-disubstituted 2-amino-5-halomethyl-2-thiazolines was designed, synthesized, and evaluated for inhibitory potential against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carboxylesterase (CaE). The compounds did not inhibit AChE; the most active compounds inhibited BChE and CaE with IC50 values of 0.22–2.3μM. Pyridine-containing compounds were more selective toward BChE; compounds with the para-OMe substituent in one of the two dibenzyl fragments were more selective toward CaE. Iodinated derivatives were more effective BChE inhibitors than brominated ones, while there was no influence of halogen type on CaE inhibition. Inhibition kinetics for the 9 most active compounds indicated non-competitive inhibition of CaE and varied mechanisms (competitive, non-competitive, or mixed-type) for inhibition of BChE. Docking simulations predicted key binding interactions of compounds with BChE and CaE and revealed that the best docked positions in BChE were at the bottom of the gorge in close proximity to the catalytic residues in the active site. In contrast, the best binding positions for CaE were clustered rather far from the active site at the top of the gorge. Thus, the docking results provided insight into differences in kinetic mechanisms and inhibitor activities of the tested compounds. A cytotoxicity test using the MTT assay showed that within solubility limits (<30μM), none of the tested compounds significantly affected viability of human fetal mesenchymal stem cells. The results indicate that a new series of N,N-disubstituted 2-aminothiazolines could serve as BChE and CaE inhibitors for potential medicinal applications.
      Graphical abstract image

      PubDate: 2016-02-12T14:47:55Z
       
  • Incorporation of fluorophore–cholesterol conjugates into liposomal
           and mycobacterial membranes
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Ashley N. Wercholuk, Jenna M. Thuman, Jordan L. Stanley, Andrew L. Sargent, Eric S. Anderson, William E. Allen
      Fluorescently-labeled steroids that emit intense blue light in nonpolar solvent (λ em (CH2Cl2)≈440nm, Φ F =0.70) were prepared by treating cholesteryl chloroformate with 4-amino-1,8-naphthalimides. The lipid portion of the conjugates embeds into liposomal membrane bilayers in minutes, leaving the fluorophore exposed to the external aqueous environment. This causes a 40-nm red-shift in λ em and significant quenching. DFT optimizations predict the conjugates to be about 30Å long when fully extended, but rotation about the linker group can bring the compounds into an ‘L’-shape. Such a conformation would allow the cholesteryl anchor to remain parallel to the acyl chains of a membrane while the fluorescent group resides in the interfacial region, instead of extending beyond it. When incubated with Mycobacterium smegmatis mc2 155, a bacterial species known to use natural cholesterol, the labeled steroids support growth and can be found localized in the membrane fraction of the cells using HPLC. These findings demonstrate stable integration of fluorescent cholesterols into bacterial membranes in vivo, indicating that these compounds may be useful for evaluating cholesterol uptake in prokaryotic organisms.
      Graphical abstract image

      PubDate: 2016-02-12T14:47:55Z
       
  • Overcoming multidrug resistance by targeting mitochondria with NO-donating
           doxorubicins
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Elena Gazzano, Konstantin Chegaev, Barbara Rolando, Marco Blangetti, Lorenzo Annaratone, Dario Ghigo, Roberta Fruttero, Chiara Riganti
      A library of nitric oxide-donor doxorubicins (NO–DOXOs) was synthesized by linking appropriate NO-donor moieties at C-14 position through an ester bridge. Their hydrolytic stability was evaluated. The intracellular accumulation and cytotoxicity of these novel NO–DOXOs were studied in DOXO-sensitive (HT29) and DOXO-resistant (HT29/dx) tumor-cells. Hydrolytically-stable compounds accumulated in HT29 and HT29/dx cells, thanks to the nitration of plasma-membrane efflux transporters. Surprisingly, no close correlation was found between intracellular accumulation and cytotoxicity. Only compounds with high mitochondria retention (due to nitration of mitochondrial efflux transporter) exert high cytotoxicity, through the activation of a mitochondrial-dependent apoptosis.
      Graphical abstract image

      PubDate: 2016-02-12T14:47:55Z
       
  • Discovery of benzenesulfonamide derivatives as potent PI3K/mTOR dual
           inhibitors with in vivo efficacies against hepatocellular carcinoma
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Ying Chen, Ling Zhang, Chao Yang, Jinsong Han, Chongqing Wang, Canhui Zheng, Youjun Zhou, Jiaguo Lv, Yunlong Song, Ju Zhu
      The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is related to cellular activities. Abnormalities of this signaling pathway were discovered in various cancers, including hepatocellular carcinoma (HCC). The PI3K/mTOR dual inhibitors were proposed to have enhanced antitumor efficacies by targeting multiple points of the signaling pathway. We synthesized a series of propynyl-substituted benzenesulfonamide derivatives as PI3K/mTOR dual inhibitors. Compound 7k (NSC781406) was identified as a highly potent dual inhibitor, which exhibited potent tumor growth inhibition in the hepatocellular carcinoma BEL-7404 xenograft model. Compound 7k may be a potential therapeutic drug candidate for HCC.
      Graphical abstract image

      PubDate: 2016-02-12T14:47:55Z
       
  • Synthesis and biological evaluation of enantiomerically pure glyceric acid
           derivatives as LpxC inhibitors
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Giovanni Tangherlini, Tullio Torregrossa, Oriana Agoglitta, Jens Köhler, Jelena Melesina, Wolfgang Sippl, Ralph Holl
      Inhibitors of the UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) represent a promising class of novel antibiotics, selectively combating Gram-negative bacteria. In order to elucidate the impact of the hydroxymethyl groups of diol (S,S)-4 on the inhibitory activity against LpxC, glyceric acid ethers (R)-7a, (S)-7a, (R)-7b, and (S)-7b, lacking the hydroxymethyl group in benzylic position, were synthesized. The compounds were obtained in enantiomerically pure form by a chiral pool synthesis and a lipase-catalyzed enantioselective desymmetrization, respectively. The enantiomeric hydroxamic acids (R)-7b (K i =230nM) and (S)-7b (K i =390nM) show promising enzyme inhibition. However, their inhibitory activities do not substantially differ from each other leading to a low eudismic ratio. Generally, the synthesized glyceric acid derivatives 7 show antibacterial activities against two Escherichia coli strains exceeding the ones of their respective regioisomes 6.
      Graphical abstract image

      PubDate: 2016-02-12T14:47:55Z
       
  • Design, synthesis, and biological evaluation of water-soluble amino acid
           prodrug conjugates derived from combretastatin, dihydronaphthalene, and
           benzosuberene-based parent vascular disrupting agents
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Laxman Devkota, Chen-Ming Lin, Tracy E. Strecker, Yifan Wang, Justin K. Tidmore, Zhi Chen, Rajsekhar Guddneppanavar, Christopher J. Jelinek, Ramona Lopez, Li Liu, Ernest Hamel, Ralph P. Mason, David J. Chaplin, Mary Lynn Trawick, Kevin G. Pinney
      Targeting tumor vasculature represents an intriguing therapeutic strategy in the treatment of cancer. In an effort to discover new vascular disrupting agents with improved water solubility and potentially greater bioavailability, various amino acid prodrug conjugates (AAPCs) of potent amino combretastatin, amino dihydronaphthalene, and amino benzosuberene analogs were synthesized along with their corresponding water-soluble hydrochloride salts. These compounds were evaluated for their ability to inhibit tubulin polymerization and for their cytotoxicity against selected human cancer cell lines. The amino-based parent anticancer agents 7, 8, 32 (also referred to as KGP05) and 33 (also referred to as KGP156) demonstrated potent cytotoxicity (GI50 =0.11–40nM) across all evaluated cell lines, and they were strong inhibitors of tubulin polymerization (IC50 =0.62–1.5μM). The various prodrug conjugates and their corresponding salts were investigated for cleavage by the enzyme leucine aminopeptidase (LAP). Four of the glycine water-soluble AAPCs (16, 18, 44 and 45) showed quantitative cleavage by LAP, resulting in the release of the highly cytotoxic parent drug, whereas partial cleavage (<10–90%) was observed for other prodrugs (15, 17, 24, 38 and 39). Eight of the nineteen AAPCs (13–16, 42–45) showed significant cytotoxicity against selected human cancer cell lines. The previously reported CA1-diamine analog and its corresponding hydrochloride salt (8 and 10, respectively) caused extensive disruption (at a concentration of 1.0μM) of human umbilical vein endothelial cells growing in a two-dimensional tubular network on matrigel. In addition, compound 10 exhibited pronounced reduction in bioluminescence (greater than 95% compared to saline control) in a tumor bearing (MDA-MB-231-luc) SCID mouse model 2h post treatment (80mg/kg), with similar results observed upon treatment (15mg/kg) with the glycine amino-dihydronaphthalene AAPC (compound 44). Collectively, these results support the further pre-clinical development of the most active members of this structurally diverse collection of water-soluble prodrugs as promising anticancer agents functioning through a mechanism involving vascular disruption.
      Graphical abstract image

      PubDate: 2016-02-12T14:47:55Z
       
  • Discovery of potent anti-tuberculosis agents targeting leucyl-tRNA
           synthetase
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Olga I. Gudzera, Andriy G. Golub, Volodymyr G. Bdzhola, Galyna P. Volynets, Sergiy S. Lukashov, Oksana P. Kovalenko, Ivan A. Kriklivyi, Anna D. Yaremchuk, Sergiy A. Starosyla, Sergiy M. Yarmoluk, Michail A. Tukalo
      Tuberculosis is a serious infectious disease caused by human pathogen bacteria Mycobacterium tuberculosis. Bacterial drug resistance is a very significant medical problem nowadays and development of novel antibiotics with different mechanisms of action is an important goal of modern medical science. Leucyl-tRNA synthetase (LeuRS) has been recently clinically validated as antimicrobial target. Here we report the discovery of small-molecule inhibitors of M. tuberculosis LeuRS. Using receptor-based virtual screening we have identified six inhibitors of M. tuberculosis LeuRS from two different chemical classes. The most active compound 4-{[4-(4-Bromo-phenyl)-thiazol-2-yl]hydrazonomethyl}-2-methoxy-6-nitro-phenol (1) inhibits LeuRS with IC50 of 6μM. A series of derivatives has been synthesized and evaluated in vitro toward M. tuberculosis LeuRS. It was revealed that the most active compound 2,6-Dibromo-4-{[4-(4-nitro-phenyl)-thiazol-2-yl]-hydrazonomethyl}-phenol inhibits LeuRS with IC50 of 2.27μM. All active compounds were tested for antimicrobial effect against M. tuberculosis H37Rv. The compound 1 seems to have the best cell permeability and inhibits growth of pathogenic bacteria with IC50 =10.01μM and IC90 =13.53μM.
      Graphical abstract image

      PubDate: 2016-02-12T14:47:55Z
       
  • Discovery of novel phenoxazinone derivatives as DKK1/LRP6 interaction
           inhibitors: Synthesis, biological evaluation and structure–activity
           relationships
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Savvas Thysiadis, Spyros Mpousis, Nicolaos Avramidis, Sotirios Katsamakas, Athanasios Balomenos, Rosaria Remelli, Spyros Efthimiopoulos, Vasiliki Sarli
      Amino derivatives of NCI8642 were synthesized and evaluated as inhibitors of DKK1/LRP6 interactions. The new inhibitors were able to activate the Wnt signaling pathway as indicated by the increased levels of β-catenin, and decrease the DKK1-induced Tau phosphorylation at serine 396.
      Graphical abstract image

      PubDate: 2016-02-12T14:47:55Z
       
  • Novel naphtho[2,1-d]oxazole-4,5-diones as NQO1 substrates with improved
           aqueous solubility: Design, synthesis, and in vivo antitumor evaluation
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Xiang Li, Jinlei Bian, Nan Wang, Xue Qian, Jing Gu, Tong Mu, Jun Fan, Xiuwen Yang, Shangzhen Li, Tingting Yang, Haopeng Sun, Qidong You, Xiaojin Zhang
      A new series of ortho-naphthoquinone analogs of β-lapachone were designed, synthesized and evaluated. The biological results indicated that most of our compounds were efficient substrates for NQO1. The new scaffold with water-soluble side chain resulted in greater solubility under acidic condition compared to β-lapachone. Thus avoiding the use of hydroxylpropyl β-cyclodextrin which would finally cause the rapid drug clearance from the blood and dose-limiting toxicity in the form of hemolytic anemia. The most soluble and promising compound in this series was 2-((4-benzylpiperazin-1-yl)methyl)naphtho[2,1-d]oxazole-4,5-dione (3k), which inhibited cancer cell (NQO1-rich A549 cell line) growth at IC50 values of 4.6±1.0μmol·L−1. Furthermore, compound 3k had in vivo antitumor activity in an A549 tumor xenografts mouse model comparable to the activity obtained with β-lapachone. The results indicated that these ortho-naphthoquinones could serve as promising leads for further optimization as novel substrates for NQO1.
      Graphical abstract image

      PubDate: 2016-02-12T14:47:55Z
       
  • Anionic surfactants enhance click reaction-mediated protein conjugation
           with ubiquitin
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Daniel Schneider, Tatjana Schneider, Joos Aschenbrenner, Franziska Mortensen, Martin Scheffner, Andreas Marx
      The Cu(I)-catalyzed alkyne–azide cycloaddition (CuAAC) has become increasingly important in the conjugation chemistry of biomolecules. For example, it is an efficient and convenient method to generate defined ubiquitin–protein conjugates. Here, we investigate the effect of surfactants on the efficiency of CuAAC for chemical protein ubiquitylation. We found that anionic surfactants enhance conjugate formation by up to 10-fold resulting in high yields even at low (i.e., micromolar) concentrations of the reactants. Notably, the herein investigated conjugates are functional and thus properly folded.
      Graphical abstract image

      PubDate: 2016-02-12T14:47:55Z
       
  • In vitro interactions between anidulafungin and nonsteroidal
           anti-inflammatory drugs on biofilms of Candida spp.
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Antonio Rosato, Alessia Catalano, Alessia Carocci, Antonio Carrieri, Addolorata Carone, Giuseppina Caggiano, Carlo Franchini, Filomena Corbo, Maria Teresa Montagna
      Candida spp. are responsible for many biomaterial-related infections; they give rise to infective pathologies typically associated with biofilm formation. We recently reported that the echinocandin anidulafungin (ANF) showed a strong in vitro activity against both planktonic and biofilms cells. Herein, we report the antifungal activities of ANF alone and in association with some non-steroidal anti-inflammatory drugs (NSAIDs) against nine Candida strain biofilms: four Candida albicans, two Candida glabrata and three Candida guilliermondii. The activity of ANF was assessed using an in vitro microbiological model relevant for clinical practice. ANF proved oneself to be active against biofilms cells, and a clear-cut synergism was found against Candida species biofilms when ANF was used in combination with three NSAIDs: aspirin, diclofenac, ibuprofen. The positive synergism against Candida spp. of ANF in association with aspirin or the other NSAIDs proved to be a very effective antifungal treatment (FICI<0.5). These results may provide the starting point for new combination therapies of ANF with NSAIDs against Candida biofilm pathologies.
      Graphical abstract image

      PubDate: 2016-02-12T14:47:55Z
       
  • Insight to the binding mode of triazole RGD-peptidomimetics to
           integrin-rich cancer cells by NMR and molecular modeling
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Francesca Vasile, Gloria Menchi, Elena Lenci, Antonio Guarna, Donatella Potenza, Andrea Trabocchi
      The binding features of a novel class of ‘click chemistry’-derived RGD mimics with integrin ligand capability were studied toward αvβ3 integrin using STD-NMR techniques on intact integrin-rich ECV340 bladder cancer cell line. STD is useful to identify which moieties of the ligand are closest to the receptor in the bound state. The NMR data were integrated with competitive binding assays to the purified αvβ3 receptor and were interpreted with the aid of docking calculations. The involvement of the triazole hydrogen atom in the interaction with the receptor was evinced for all compounds but 2, in agreement with docking studies showing a certain proximity between triazole and Tyr178. Moreover, the interaction of the hydroxylated ligands with the receptor was not as extended as in the compounds belonging to the corresponding series, with the exception of compound 4 having 2-aminobenzimidazole as the arginine bioisostere, in agreement with biological assay results showing reduced binding capability for the hydroxylated peptidomimetics.
      Graphical abstract image

      PubDate: 2016-02-12T14:47:55Z
       
  • Synthesis of 4-sulfamoylphenyl-benzylamine derivatives with inhibitory
           activity against human carbonic anhydrase isoforms I, II, IX and XII
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Mustafa Durgun, Hasan Turkmen, Mariangela Ceruso, Claudiu T. Supuran
      Imine derivatives were obtained by condensation of sulfanilamide with substituted aromatic aldehydes. The Schiff bases were thereafter reduced with sodium borohydride, leading to the corresponding amines, derivatives of 4-sulfamoylphenyl-benzylamine. These sulfonamides were investigated as inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isozymes), as well as hCA IX and XII (transmembrane, tumor-associated enzymes). We noted that the compounds incorporating secondary amine moieties showed a better inhibitory activity against all CA isozymes compared to the corresponding Schiff bases. Low nanomolar CA II, IX and XII inhibitors were detected, whereas the activity against hCA I was less potent. The secondary amines incorporating sulfonamide or similar zinc-binding groups, poorly investigated chemotypes for designing metalloenzyme inhibitors, may offer interesting opportunities in the field due to the facile preparation and possibility to explore a vast chemical space.
      Graphical abstract image

      PubDate: 2016-02-12T14:47:55Z
       
  • Kinetic and X-ray crystallographic investigations on carbonic anhydrase
           isoforms I, II, IX and XII of a thioureido analog of SLC-0111
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Carrie L. Lomelino, Brian P. Mahon, Robert McKenna, Fabrizio Carta, Claudiu T. Supuran
      SLC-0111 (4-(4-fluorophenylureido)-benzenesulfonamide) is the first carbonic anhydrase (CA, EC 4.2.1.1) IX inhibitor to reach phase I clinical trials as an antitumor/antimetastatic agent. Here we report a kinetic and X-ray crystallographic study of a congener of SLC-0111 which incorporates a thioureido instead of ureido linker between the two aromatic rings as inhibitor of four physiologically relevant CA isoforms. Similar to SLC-0111, the thioureido derivative was a weak hCA I and II inhibitor and a potent one against hCA IX and XII. X-ray crystallography of its adduct with hCA II and comparison of the structure with that of other five hCA II—sulfonamide adducts belonging to the SLC-0111 series, afforded us to understand the particular inhibition profile of the new sulfonamide. Similar to SLC-0111, the thioureido sulfonamide primarily interacted with the hydrophobic side of the hCA II active site, with the tail participating in van der Waals interactions with Phe131 and Pro202, in addition to the coordination of the deprotonated sulfonamide to the active site metal ion. On the contrary, the tail of other sulfonamides belonging to the SLC-0111 series (2-isopropyl-phenyl; 3-nitrophenyl) were orientated towards the hydrophilic half of the active site, which was correlated with orders of magnitude better inhibitory activity against hCA II, and a loss of selectivity for the inhibition of the tumor-associated CAs.
      Graphical abstract image

      PubDate: 2016-02-12T14:47:55Z
       
  • Editorial board
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5




      PubDate: 2016-02-12T14:47:55Z
       
  • A spectroscopic study of substituted anthranilic acids as sensitive
           environmental probes for detecting cancer cells
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Adrian S. Culf, Huimin Yin, Susan Monro, Anirban Ghosh, David A. Barnett, Rodney J. Ouellette, Miroslava Čuperlović-Culf, Sherri A. McFarland
      Small-molecule fluorescent reporters of disease states are highly sought after, yet they remain elusive. Anthranilic acids are extremely sensitive environmental probes, and hold promise as general but selective agents for cancer-cell detection if they can be equipped with the appropriate targeting groups. The optical properties of a small library of N-isopropyl invariant anthranilic acids were investigated in methanol and chloroform. Points of variation included: fluoro, trifluoromethyl, or cyano substitution on the aromatic ring, and derivitization of the parent carboxylic acid as esters or secondary carboxamides. Phenylboronic acid conjugation at the carboxylic acid alongside un-, mono-, and dimethylated 2-amino groups was also explored. The boron-containing anthranilic acids were also evaluated as sensitive fluorescent probes for cancer cells using laser scanning confocal microscopy. In general, the compounds produced blue fluorescence that was strongly influenced by substitution and environment. 4-Trifluoromethyl and 4-cyano esters proved to be the most sensitive environmental probes with quantum yields as large as 100% in chloroform, and enhancements of up to 30-fold on going from methanol to chloroform. Stokes shifts ranged from 63 to 120nm, generally increasing with ortho-substitution and environmental polarity. It was demonstrated that phenylboronic acid conjugation was an attractive method for cancer cell detection via boronate ester formation with overexpressed glycoproteins (with no interference from normal, healthy cells), presumably due to favorable boron-sialic acid interactions.
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      PubDate: 2016-02-12T14:47:55Z
       
  • Pyrazole antagonists of the CB1 receptor with reduced brain penetration
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Alan Fulp, Yanan Zhang, Katherine Bortoff, Herbert Seltzman, Rodney Snyder, Robert Wiethe, George Amato, Rangan Maitra
      Type 1 cannabinoid receptor (CB1) antagonists might be useful for treating obesity, liver disease, metabolic syndrome, and dyslipidemias. Unfortunately, inhibition of CB1 in the central nervous system (CNS) produces adverse effects, including depression, anxiety and suicidal ideation in some patients, which led to withdrawal of the pyrazole inverse agonist rimonabant (SR141716A) from European markets. Efforts are underway to produce peripherally selective CB1 antagonists to circumvent CNS-associated adverse effects. In this study, novel analogs of rimonabant (1) were explored in which the 1-aminopiperidine group was switched to a 4-aminopiperidine, attached at the 4-amino position (5). The piperidine nitrogen was functionalized with carbamates, amides, and sulfonamides, providing compounds that are potent inverse agonists of hCB1 with good selectivity for hCB1 over hCB2. Select compounds were further studied using in vitro models of brain penetration, oral absorption and metabolic stability. Several compounds were identified with predicted minimal brain penetration and good metabolic stability. In vivo pharmacokinetic testing revealed that inverse agonist 8c is orally bioavailable and has vastly reduced brain penetration compared to rimonabant.
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      PubDate: 2016-02-12T14:47:55Z
       
  • A clickable psoralen to directly quantify DNA interstrand crosslinking and
           repair
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Benjamin J. Evison, Marcelo L. Actis, Naoaki Fujii
      DNA interstrand crosslinks (ICLs) represent physical obstacles to advancing replication forks and transcription complexes. A range of ICL-inducing agents have successfully been incorporated into cancer therapeutics. While studies have adopted UVA-activated psoralens as model ICL-inducing agents for investigating ICL repair, direct detection of the lesion has often been tempered by tagging the psoralen scaffold with a relatively large reporter group that may perturb the biological activity of the parent psoralen. Here a minimally-modified psoralen probe was prepared featuring a small alkyne handle suitable for click chemistry. The psoralen probe, designated 8-propargyloxypsoralen (8-POP), can be activated by UVA in vitro to generate ICLs that are susceptible to post-labeling with an azide-tagged fluorescent reporter via a copper-catalyzed reaction. A modified alkaline comet assay demonstrated that UVA-activated 8-POP proficiently generated ICLs in cells. Cellular 8-POP–DNA lesions were amenable to click-mediated ligation to fluorescent reporters in situ, which permitted their detection and quantitation by fluorescence microscopy and flow cytometry. Small molecule DNA repair inhibitors to 8-POP-treated cells attenuated the removal of 8-POP–DNA lesions, validating 8-POP as an appropriate probe for investigating cellular ICL repair. The post-labeling strategy applied in this study is inexpensive, rapid and highly modular in nature with the potential for multiple applications in DNA repair studies.
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      PubDate: 2016-02-12T14:47:55Z
       
  • Synthesis and pharmacological evaluation of trifluoromethyl containing
           
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Minhang Xin, Liandi Zhang, Jun Wen, Han Shen, Zhaoyu Liu, Xinge Zhao, Qiu Jin, Mengyu Wang, Lingfei Cheng, Wei Huang, Feng Tang
      In present study, a series of novel containing trifluoromethyl 4-(2-pyrimidinylamino)benzamide derivatives were designed by the fluorine scan strategy. Their Hh signaling inhibitory activities were evaluated by Gli-luciferase reporter method. The comprehensive SAR was discussed and several derivatives were found to display more potent Hh signaling inhibitory activity than positive drug vismodegib. Compound 13d was the most potent compound with IC50 of 1.44nM against Hh signaling pathway and also exhibited optimal PK properties in the in vivo PK properties study, deserved as an ideal lead compound for further study in future.
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      PubDate: 2016-02-12T14:47:55Z
       
  • Symmetric 4,4′-(piperidin-4-ylidenemethylene)bisphenol derivatives
           as novel tunable estrogen receptor (ER) modulators
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Manabu Sato, Kiminori Ohta, Asako Kaise, Sayaka Aoto, Yasuyuki Endo
      We designed and synthesized 4,4′-(piperidin-4-ylidenemethylene)bisphenol derivatives as novel tunable estrogen receptor (ER) modulators. The introduction of hydrophobic substituents on the nitrogen atom of the piperidine ring enhanced ERα binding affinity. In addition, the introduction of four methyl groups adjacent to the piperidine ring nitrogen atom remarkably enhanced ERα binding affinity. N-Acetyl-2,2,6,6-tetramethylpiperidine derivative 3b showed high ERα binding affinity, high MCF-7 cell proliferation inducing activity, and high metabolic stability in rat liver S9 fractions.
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      PubDate: 2016-02-12T14:47:55Z
       
  • A novel library of saccharin and acesulfame derivatives as potent and
           selective inhibitors of carbonic anhydrase IX and XII isoforms
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Simone Carradori, Daniela Secci, Celeste De Monte, Adriano Mollica, Mariangela Ceruso, Atilla Akdemir, Anatoly P. Sobolev, Rossella Codispoti, Federica De Cosmi, Paolo Guglielmi, Claudiu T. Supuran
      Small libraries of N-substituted saccharin and N-/O-substituted acesulfame derivatives were synthesized and tested as atypical and selective inhibitors of four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). Most of them inhibited hCA XII in the low nanomolar range, hCA IX with K Is ranging between 19 and 2482nM, whereas they were poorly active against hCA II (K Is >10μM) and hCA I (K Is ranging between 318nM and 50μM). Since hCA I and II are ubiquitous off-target isoforms, whereas the cancer-related isoforms hCA IX and XII were recently validated as drug targets, these results represent an encouraging achievement in the development of new anticancer candidates. Moreover, the lack of a classical zinc binding group in the structure of these inhibitors opens innovative, yet unexplored scenarios for different mechanisms of inhibition that could explain the high inhibitory selectivity. A computational approach has been carried out to further rationalize the biological data and to characterize the binding mode of some of these inhibitors.
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      PubDate: 2016-02-12T14:47:55Z
       
  • Heptapeptide ligands against receptor-binding sites of influenza
           hemagglutinin toward anti-influenza therapy
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Teruhiko Matsubara, Ai Onishi, Daisuke Yamaguchi, Toshinori Sato
      The initial attachment of influenza virus to cells is the binding of hemagglutinin (HA) to the sialyloligosaccharide receptor; therefore, the small molecules that inhibit the sugar–protein interaction are promising as HA inhibitors to prevent the infection. We herein demonstrate that sialic acid-mimic heptapeptides are identified through a selection from a primary library against influenza virus HA. In order to obtain lead peptides, an affinity selection from a phage-displayed random heptapeptide library was performed with the HAs of the H1 and H3 strains, and two kinds of the HA-binding peptides were identified. The binding of the peptides to HAs was inhibited in the presence of sialic acid, and plaque assays indicated that the corresponding N-stearoyl peptide strongly inhibited infections by the A/Aichi/2/68 (H3N2) strain of the virus. Alanine scanning of the peptides indicated that arginine and proline were responsible for binding. The affinities of several mutant peptides with single-amino-acid substitutions against H3 HA were determined, and corresponding docking studies were performed. A Spearman analysis revealed a correlation between the affinity of the peptides and the docking study. These results provide a practicable method to design of peptide-based HA inhibitors that are promising as anti-influenza drugs.
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      PubDate: 2016-02-12T14:47:55Z
       
  • Sulfonamide inhibition studies of the β-carbonic anhydrase from the
           pathogenic bacterium Vibrio cholerae
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Sonia Del Prete, Daniela Vullo, Viviana De Luca, Vincenzo Carginale, Marta Ferraroni, Sameh M. Osman, Zeid AlOthman, Claudiu T. Supuran, Clemente Capasso
      The genome of the pathogenic bacterium Vibrio cholerae encodes for three carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the α-, β- and γ-classes. VchCA, the α-CA from this species was investigated earlier, whereas the β-class enzyme, VchCAβ was recently cloned, characterized kinetically and its X-ray crystal structure reported by this group. Here we report an inhibition study with sulfonamides and one sulfamate of this enzyme. The best VchCAβ inhibitors were deacetylated acetazolamide and methazolamide and hydrochlorothiazide, which showed inhibition constants of 68.2–87.0nM. Other compounds, with medium potency against VchCAβ, (K Is in the range of 275–463nM), were sulfanilamide, metanilamide, sulthiame and saccharin whereas the clinically used agents such as acetazolamide, methazolamide, ethoxzolamide, dorzolamide, zonisamide and celecoxib were micromolar inhibitors (K Is in the range of 4.51–8.57μM). Identification of potent and possibly selective inhibitors of VchCA and VchCAβ over the human CA isoforms, may lead to pharmacological tools useful for understanding the physiological role(s) of this under-investigated enzymes.
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      PubDate: 2016-02-12T14:47:55Z
       
  • Metal-based biologically active azoles and β-lactams derived from
           sulfa drugs
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Hossein Pasha Ebrahimi, Jabbar S. Hadi, Abdulelah A. Almayah, Zeinab Bolandnazar, Ali G. Swadi, Amirpasha Ebrahimi
      Metal complexes of Schiff bases derived from sulfamethoxazole (SMZ) and sulfathiazole (STZ), converted to their β-lactam derivatives have been synthesized and experimentally characterized by elemental analysis, spectral (IR, 1H NMR, 13C NMR, and EI-mass), molar conductance measurements and thermal analysis techniques. The structural and electronic properties of the studied molecules were investigated theoretically by performing density functional theory (DFT) to access reliable results to the experimental values. The spectral and thermal analysis reveals that the Schiff bases act as bidentate ligands via the coordination of azomethine nitrogen to metal ions as well as the proton displacement from the phenolic group through the metal ions; therefore, Cu complexes can attain the square planner arrangement and Zn complexes have a distorted tetrahedral structure. The thermogravimetric (TG/DTG) analyses confirm high stability for all complexes followed by thermal decomposition in different steps. In addition, the antibacterial activities of synthesized compounds have been screened in vitro against various pathogenic bacterial species. Inspection of the results revealed that all newly synthesized complexes individually exhibit varying degrees of inhibitory effects on the growth of the tested bacterial species, therefore, they may be considered as drug candidates for bacterial pathogens. The free Schiff base ligands (1–2) exhibited a broad spectrum antibacterial activity against Gram negative Escherichia coli, Pseudomonas aeruginosa, and Proteus spp., and Gram positive Staphylococcus aureus bacterial strains. The results also indicated that the β-lactam derivatives (3–4) have high antibacterial activities on Gram positive bacteria as well as the metal complexes (5–8), particularly Zn complexes, have a significant activity against all Gram negative bacterial strains. It has been shown that the metal complexes have significantly higher activity than corresponding ligands due to chelation process which reduces the polarity of metal ion by coordinating with ligands.
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      PubDate: 2016-02-12T14:47:55Z
       
  • Glycopeptide-functionalized gold nanoparticles for antibody induction
           against the tumor associated mucin-1 glycoprotein
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Hui Cai, Federica Degliangeli, Björn Palitzsch, Bastian Gerlitzki, Horst Kunz, Edgar Schmitt, Roberto Fiammengo, Ulrika Westerlind
      We report the preparation of gold nanoparticle (AuNP)-based vaccine candidates against the tumor-associated form of the mucin-1 (MUC1) glycoprotein. Chimeric peptides, consisting of a glycopeptide sequence derived from MUC1 and the T-cell epitope P30 sequence were immobilized on PEGylated AuNPs and the ability to induce selective antibodies in vivo was investigated. After immunization, mice showed significant MHC-II mediated immune responses and their antisera recognized human MCF-7 breast cancer cells. Nanoparticles designed according to this report may become key players in the development of anticancer vaccines.
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      PubDate: 2016-02-12T14:47:55Z
       
  • Structure–activity relationship study of 4-(thiazol-5-yl)benzoic
           acid derivatives as potent protein kinase CK2 inhibitors
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Hiroaki Ohno, Daiki Minamiguchi, Shinya Nakamura, Keito Shu, Shiho Okazaki, Maho Honda, Ryosuke Misu, Hirotomo Moriwaki, Shinsuke Nakanishi, Shinya Oishi, Takayoshi Kinoshita, Isao Nakanishi, Nobutaka Fujii
      Two classes of modified analogs of 4-(thiazol-5-yl)benzoic acid-type CK2 inhibitors were designed. The azabenzene analogs, pyridine- and pyridazine-carboxylic acid derivatives, showed potent protein kinase CK2 inhibitory activities [IC50 (CK2α)=0.014–0.017μM; IC50 (CK2α′)=0.0046–0.010μM]. Introduction of a 2-halo- or 2-methoxy-benzyloxy group at the 3-position of the benzoic acid moiety maintained the potent CK2 inhibitory activities [IC50 (CK2α)=0.014–0.016μM; IC50 (CK2α′)=0.0088–0.014μM] and led to antiproliferative activities [CC50 (A549)=1.5–3.3μM] three to six times higher than those of the parent compound.
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      PubDate: 2016-02-12T14:47:55Z
       
  • Synthesis and cytotoxicity of thieno[2,3-b]quinoline-2-carboxamide and
           cycloalkyl[b]thieno[3,2-e]pyridine-2-carboxamide derivatives
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Euphemia Leung, Lisa I. Pilkington, Michelle van Rensburg, Chae Yeon Jeon, Mirae Song, Homayon J. Arabshahi, Gayan Heruka De Zoysa, Vijayalekshmi Sarojini, William A. Denny, Jóhannes Reynisson, David Barker
      Seventy nine derivatives of thieno[2,3-b]quinolines, tetrahydrothieno[2,3-b]quinoline, dihydrocyclopenta[b]thieno[3,2-e]pyridine, cyclohepta[b]thieno[3,2-e]pyridine and hexahydrocycloocta[b]thieno[3,2-e]pyridine were either synthesized or obtained commercially and tested for their antiproliferative activity against HCT116, MDA-MB-468 and MDA-MB-231 human cancer cell lines. The most potent eight compounds were active against all cell lines with IC50 values in the 80–250nM range. In general hexahydrocycloocta[b]thieno[3,2-e]pyridines were most active with increasing activity observed as larger cycloalkyl rings were fused to the pyridine ring.
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      PubDate: 2016-02-12T14:47:55Z
       
  • Assemblies of ionic zinc chlorins assisted by water-soluble polypeptides
    • Abstract: Publication date: 1 March 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 5
      Author(s): Tomohiro Miyatake, Yuki Hasunuma, Yumi Mukai, Hisato Oki, Mikiya Watanabe, Shohei Yamazaki
      Artificial chlorophyll–peptide complexes were prepared by mixing ionic chlorophyll derivatives and oligopeptides in aqueous media containing a small amount of organic solvent. The pigment–peptide complexes provided chlorophyll assemblies showing a sharp red-shifted Qy absorption band concomitant with giant circular dichroism signals. The polypeptide-assisted assemblies of chlorophyllous pigments would afford a good model for photosynthetic apparatuses such as pigment–protein complexes of light-harvesting antennas.
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      PubDate: 2016-02-12T14:47:55Z
       
  • Cyclic RGD peptidomimetics containing 4- and 5-amino-cyclopropane
           pipecolic acid (CPA) templates as dual αVβ3 and α5β1
           integrin ligands
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): Lorenzo Sernissi, Andrea Trabocchi, Dina Scarpi, Francesca Bianchini, Ernesto G. Occhiato
      4-Amino- and 5-amino-cyclopropane pipecolic acids (CPAs) with cis relative stereochemistry between the carboxylic and amino groups were used as templates to prepare cyclic peptidomimetics containing the RGD sequence as possible integrin binders. The peptidomimetic c(RGD8) built on the 5-amino-CPA displayed an inhibition activity (IC50 =2.4nM) toward the αvβ3 integrin receptor (expressed in M21 human melanoma cell line) comparable to that of the most potent antagonists reported so far and it was ten times more active than the corresponding antagonist c(RGD7) derived from the isomeric 4-amino-CPA. Both compounds were also nanomolar ligands of the α5β1 integrin (expressed in human erythroleukemia cell line K562). These results suggest that the CPA-derived templates are suitable for the preparation of dual αvβ3 and α5β1 ligands to suppress integrin-mediated events as well as for targeted drug delivery in cancer therapy.
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      PubDate: 2016-02-08T17:00:51Z
       
  • Synthesis and anti-tuberculosis activity of glycitylamines
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): Hilary M. Corkran, Emma M. Dangerfield, Gregory W. Haslett, Bridget L. Stocker, Mattie S.M. Timmer
      A series of glycitylamines, which were prepared in few steps from readily available carbohydrates, were tested for their ability to inhibit tuberculosis growth in an Alamar Blue BCG colourimetric assay. Several derivatives, including (2R,3R)-1-(hexadecylamine)pent-4-ene-2,3-diol, (2R,3R)-1-(hexadecylmethylamino)pent-4-ene-2,3-diol and 5-deoxy-5-hexadecylmethylamino-d-arabinitol, were prepared in good to excellent (44–90%) overall yield and exhibited micromolar (20–41μM) inhibitory activity that was similar to the first line tuberculosis (TB) drug ethambutol (39μM) in the same assay. The ease and low cost of the synthesis of the glycitylamines offers definite advantages for their use as potential TB drugs.
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      PubDate: 2016-02-08T17:00:51Z
       
  • Design and synthesis of an activity-based protein profiling probe derived
           from cinnamic hydroxamic acid
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): Teng Ai, Li Qiu, Jiashu Xie, Robert J. Geraghty, Liqiang Chen
      In our continued effort to discover new anti-hepatitis C virus (HCV) agents, we validated the anti-replicon activity of compound 1, a potent and selective anti-HCV hydroxamic acid recently reported by us. Generally favorable physicochemical and in vitro absorption, distribution, metabolism, and excretion (ADME) properties exhibited by 1 made it an ideal parent compound from which activity-based protein profiling (ABPP) probe 3 was designed and synthesized. Evaluation of probe 3 revealed that it possessed necessary anti-HCV activity and selectivity. Therefore, we have successfully obtained compound 3 as a suitable ABPP probe to identify potential molecular targets of compound 1. Probe 3 and its improved analogs are expected to join a growing list of ABPP probes that have made important contributions to not only the studies of biochemical and cellular functions but also discovery of selective inhibitors of protein targets.
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      PubDate: 2016-02-08T17:00:51Z
       
  • A new chromanone derivative isolated from Hypericum lissophloeus
           (Hypericaceae) potentiates GABAA receptor currents in a subunit specific
           fashion
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): Sara Crockett, Roland Baur, Olaf Kunert, Ferdinand Belaj, Erwin Sigel
      A phytochemical investigation of the lipophilic extract of Hypericum lissophloeus (smoothbark St. John’s wort, Hypericaceae) was conducted, resulting in the isolation and identification of a new chromanone derivative: 5,7-dihydroxy-2,3-dimethyl-6-(3-methyl-but-2-enyl)-chroman-4-one (1). This compound was demonstrated to act as a potent stimulator of currents elicited by GABA in recombinant α1β2γ2 GABAA receptors, with a half-maximal potentiation observed at a concentration of about 4μM and a maximal potentiation of >4000%. Significant potentiation was already evident at a concentration as low as 0.1μM. Extent of potentiation strongly depends on the type of α subunit, the type of β subunit and the presence of the γ subunit.
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      PubDate: 2016-02-08T17:00:51Z
       
  • Design, synthesis and evaluation of novel 7-aminoalkyl-substituted
           flavonoid derivatives with improved cholinesterase inhibitory activities
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): Wen Luo, Ying Chen, Ting Wang, Chen Hong, Li-Ping Chang, Cong-Cong Chang, Ya-Cheng Yang, Song-Qiang Xie, Chao-Jie Wang
      A novel series of 7-aminoalkyl-substituted flavonoid derivatives 5a–5r were designed, synthesized and evaluated as potential cholinesterase inhibitors. The results showed that most of the synthesized compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities at the micromolar range. Compound 2-(naphthalen-1-yl)-7-(8-(pyrrolidin-1-yl)octyloxy)-4H-chromen-4-one (5q) showed the best inhibitory activity (IC50, 0.64μM for AChE and 0.42μM for BChE) which were better than our previously reported compounds and the commercially available cholinergic agent Rivastigmine. The results from a Lineweaver–Burk plot indicated a mixed-type inhibition for compound 5q with AChE and BChE. Furthermore, molecular modeling study showed that 5q targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds (5a–5r) did not affect PC12 and HepG2 cell viability at the concentration of 10μM. Consequently, these flavonoid derivatives should be further investigated as multipotent agents for the treatment of Alzheimer’s disease.
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      PubDate: 2016-02-08T17:00:51Z
       
  • Illuminating the binding interactions of galactonoamidines during the
           inhibition of β-galactosidase (E. coli)
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): Qiu-Hua Fan, Jessica B. Pickens, Susanne Striegler, Cédric D. Gervaise
      Several galactonoamidines were previously identified as very potent competitive inhibitors that exhibit stabilizing hydrophobic interactions of the aglycon in the active site of β-galactosidase (Aspergillus oryzae). To elucidate the contributions of the glycon to the overall inhibition ability of the compounds, three glyconoamidine derivatives with alteration in the glycon at C-2 and C-4 were synthesized and evaluated herein. All amidines are competitive inhibitors of β-galactosidase (Escherichia coli) and show significantly reduced inhibition ability when compared to the parent. The results highlight strong hydrogen-bonding interactions between the hydroxyl group at C-2 of the amidine glycon and the active site of the enzyme. Slightly weaker H-bonds are promoted through the hydroxyl group at C-4. The inhibition constants were determined to be picomolar for the parent galactonoamidine, and nanomolar for the designed derivatives rendering all glyconoamidines very potent inhibitors of glycosidases albeit the derivatized amidines show up to 700-fold lower inhibition activity than the parent.
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      PubDate: 2016-02-08T17:00:51Z
       
  • Synthesis and biological activity of ferrocenyl indeno[1,2-c]isoquinolines
           as topoisomerase II inhibitors
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): Nathalie Wambang, Nadège Schifano-Faux, Alexandre Aillerie, Brigitte Baldeyrou, Camille Jacquet, Christine Bal-Mahieu, Till Bousquet, Sylvain Pellegrini, Peter T. Ndifon, Samuel Meignan, Jean-François Goossens, Amélie Lansiaux, Lydie Pélinski
      Three series of indeno[1,2-c]isoquinolines bearing a ferrocenyl entity were synthesized and evaluated for DNA interaction, topoisomerase I and II inhibition, and cytotoxicity against breast human cancer cell lines. In the first and second series, the ferrocenyl scaffold was inserted as a linker between the two nitrogen atoms. In the last series, it was introduced at the end of the carbon chain. The present study showed that the ferrocenyl entity enhanced the topoisomerase II inhibition. Most compounds showed a potent growth inhibitory effect on MDA-MB-231 cell line with the IC50 in μM range.
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      PubDate: 2016-02-08T17:00:51Z
       
  • Synthesis and biological evaluation of novel 5-hydroxylaminoisoxazole
           derivatives as lipoxygenase inhibitors and metabolism enhancing agents
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): Elena B. Averina, Dmitry A. Vasilenko, Yulia A. Gracheva, Yuri K. Grishin, Eugene V. Radchenko, Vladimir V. Burmistrov, Gennady M. Butov, Margarita E. Neganova, Tatyana P. Serkova, Olga M. Redkozubova, Elena F. Shevtsova, Elena R. Milaeva, Tamara S. Kuznetsova, Nikolay S. Zefirov
      A versatile synthesis of novel 5-hydroxylaminoisoxazoles bearing adamantane moieties has been accomplished using the heterocyclization reactions of readily available unsaturated esters by the treatment with tetranitromethane in the presence of triethylamine and subsequent reduction of resulting 5-nitroisoxazoles by SnCl2 with the participation of THF. A number of obtained isoxazole derivatives were evaluated for their antioxidative activity, inhibition of lipoxygenases and impact on the rat liver mitochondria. The majority of tested compounds demonstrated moderate antiradical activity in DPPH test (up to EC50 16μM). The same compounds strongly inhibited soybean lipoxygenase (up to IC50 0.4μM) and Fe2+- and Fe3+-induced lipid peroxidation (LP) of rat brain cortex homogenate (up to IC50 0.3μM). All tested isoxazole derivatives promoted the phosphorylating respiratory activity simultaneously with maximal stimulated respiratory activity of mitochondria and do not reveal any toxicity towards the primary culture of rat cortex neurons.
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      PubDate: 2016-02-08T17:00:51Z
       
  • Synthesis, characterization and antimicrobial activities of novel
           silver(I) complexes with coumarin substituted N-heterocyclic carbene
           ligands
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): Mert Olgun Karataş, Begüm Olgundeniz, Selami Günal, İlknur Özdemir, Bülent Alıcı, Engin Çetinkaya
      Eight new coumarin substituted silver(I) N-heterocyclic carbene (NHC) complexes were synthesized by the interaction of the corresponding imidazolium or benzimidazolium chlorides and Ag2O in dichloromethane at room temperature. Structures of these complexes were established on the basis of elemental analysis, 1H NMR, 13C NMR, IR and mass spectroscopic techniques. The antimicrobial activities of carbene precursors and silver NHC complexes were tested against standard strains: Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and the fungi Candida albicans and Candida tropicalis. Results showed that all the compounds inhibited the growth of the all bacteria and fungi strains and some complexes performed good activities against different microorganisms. Among all the compounds, the most lipophilic complex bis[1-(4-methylene-6,8-dimethyl-2H-chromen-2-one)-3-(naphthalene-2-ylmethyl)benzimidazol-2-ylidene]silver(I) dichloro argentate (5e) was found out as the most active one.
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      PubDate: 2016-02-08T17:00:51Z
       
  • Synthesis, structure, and evaluation of a β-cyclodextrin-artificial
           carbohydrate conjugate for use as a doxorubicin-carrying molecule
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): Takashi Yamanoi, Yoshiki Oda, Kaname Katsuraya, Toshiyuki Inazu, Kenjiro Hattori
      This paper describes the synthesis of a β-cyclodextrin (β-CyD) derivative conjugated with a C,C-glucopyranoside containing a benzene unit. Its doxorubicin-inclusion ability and structure are also discussed. SPR analysis revealed that the β-CyD conjugate had a high inclusion association value of 3.8×106 M−1 for immobilized doxorubicin. NMR structural analysis suggested that its high doxorubicin-inclusion ability was due to the formation of the inclusion complex as a result of the π–π stacking interaction between the benzene ring of the conjugate and the A ring of doxorubicin.
      Graphical abstract image

      PubDate: 2016-02-08T17:00:51Z
       

  •        N-(3,4-Dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[11C]methylphenyl)thiazol-2-yl]-1-carboxamide:
           A promising positron emission tomography ligand for fatty acid amide
           hydrolase
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): Yoko Shimoda, Masayuki Fujinaga, Akiko Hatori, Joji Yui, Yiding Zhang, Nobuki Nengaki, Yusuke Kurihara, Tomoteru Yamasaki, Lin Xie, Katsushi Kumata, Hideki Ishii, Ming-Rong Zhang
      To visualize fatty acid amide hydrolase (FAAH) in brain in vivo, we developed a novel positron emission tomography (PET) ligand N-(3,4-dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[11C]methylphenyl)thiazol-2-yl]-1-carboxamide ([11C]DFMC, [11C]1). DFMC (1) was shown to have high binding affinity (IC50: 6.1nM) for FAAH. [11C]1 was synthesized by C–11C coupling reaction of arylboronic ester 2 with [11C]methyl iodide in the presence of Pd catalyst. At the end of synthesis, [11C]1 was obtained with a radiochemical yield of 20±10% (based on [11C]CO2, decay-corrected, n =5) and specific activity of 48–166GBq/μmol. After the injection of [11C]1 in mice, high uptake of radioactivity (>2% ID/g) was distributed in the lung, liver, kidney, and brain, organs with high FAAH expression. PET images of rat brains for [11C]1 revealed high uptakes in the cerebellar nucleus (SUV=2.4) and frontal cortex (SUV=2.0), two known brain regions with high FAAH expression. Pretreatment with the FAAH-selective inhibitor URB597 reduced the brain uptake. Higher than 90% of the total radioactivity in the rat brain was irreversible at 30min after the radioligand injection. The present results indicate that [11C]1 is a promising PET ligand for imaging of FAAH in living brain.
      Graphical abstract image

      PubDate: 2016-02-08T17:00:51Z
       
  • Synthesis and biological evaluation of disubstituted amidoxanthones as
           potential telomeric G-quadruplex DNA-binding and apoptosis-inducing agents
           
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): Rui Shen, Yujiao Chen, Ziqian Li, Hui Qi, Yitian Wang
      A series of disubstituted xanthones was obtained by cationic modification of xanthone’s C2 and C7 with amine groups of different pKa values. Modified structures by using moieties with high pKa values had good antitumor activity according to the MTT assay, AO/EB staining and flow cytometry assay, especially bis-dimethylamine derivative (5a). Further study indicated that compound 5a had good binding activity to telomeric G-quadruplex DNA, as detected by using spectroscopy methods, melting profiles, polymerase chain reaction stop assay and molecular modeling study. The results suggested that the antitumor activity of 5a might be associated with its stabilization of G-quadruplex DNA, which could be developed as new G-quadruplex DNA stabilizer and potent antitumor agents.
      Graphical abstract image

      PubDate: 2016-02-08T17:00:51Z
       
  • New hybrid molecules with anticonvulsant and antinociceptive activity
           derived from 3-methyl- or
           
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): Krzysztof Kamiński, Mirosław Zagaja, Anna Rapacz, Jarogniew J. Łuszczki, Marta Andres-Mach, Michał Abram, Jolanta Obniska
      The purpose of this study was to synthetize the focused library of 34 new piperazinamides of 3-methyl- and 3,3-dimethyl-(2,5-dioxopyrrolidin-1-yl)propanoic or butanoic acids as potential new hybrid anticonvulsants. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. Compounds 5–38 were prepared in a coupling reaction of the 3-methyl- or 3,3-dimethyl-2-(2,5-dioxopyrrolidin-1-yl)propanoic (1, 2) or butanoic acids (3, 4) with the appropriately substituted secondary amines in the presence of the N,N-carbonyldiimidazole reagent. The initial anticonvulsant screening was performed in mice (ip) using the ‘classical’ maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests as well as in the six-Hertz (6Hz) model of pharmacoresistant limbic seizures. The acute neurological toxicity was determined applying the chimney test. The broad spectra of activity across the preclinical seizure models in mice ip displayed compounds 7, 15, and 36. The most favorable anticonvulsant properties demonstrated 15 (ED50 MES=74.8mg/kg, ED50 scPTZ=51.6mg/kg, ED50 6Hz=16.8mg/kg) which showed TD50 =213.3mg/kg in the chimney test that yielded satisfying protective indexes (PI MES=2.85, PI scPTZ=4.13, PI 6Hz=12.70) at time point of 0.5h. As a result, compound 15 displayed comparable or better safety profile than clinically relevant AEDs: ethosuximide, lacosamide or valproic acid. In the in vitro assays compound 15 was observed as relatively effective binder to the neuronal voltage-sensitive sodium and L-type calcium channels. Beyond the anticonvulsant properties, 6 compounds diminished the pain responses in the formalin model of tonic pain in mice.
      Graphical abstract image

      PubDate: 2016-02-08T17:00:51Z
       
  • Identification of B. anthracis N5-carboxyaminoimidazole ribonucleotide
           mutase (PurE) active site binding compounds via fragment library screening
           
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): Hao Lei, Christopher Jones, Tian Zhu, Kavankumar Patel, Nina M. Wolf, Leslie W.-M. Fung, Hyun Lee, Michael E. Johnson
      The de novo purine biosynthesis pathway is an attractive target for antibacterial drug design, and PurE from this pathway has been identified to be crucial for Bacillus anthracis survival in serum. In this study we adopted a fragment-based hit discovery approach, using three screening methods—saturation transfer difference nucleus magnetic resonance (STD-NMR), water-ligand observed via gradient spectroscopy (WaterLOGSY) NMR, and surface plasmon resonance (SPR), against B. anthracis PurE (BaPurE) to identify active site binding fragments by initially testing 352 compounds in a Zenobia fragment library. Competition STD NMR with the BaPurE product effectively eliminated non-active site binding hits from the primary hits, selecting active site binders only. Binding affinities (dissociation constant, K D) of these compounds varied between 234 and 301μM. Based on test results from the Zenobia compounds, we subsequently developed and applied a streamlined fragment screening strategy to screen a much larger library consisting of 3000 computationally pre-selected fragments. Thirteen final fragment hits were confirmed to exhibit binding affinities varying from 14μM to 700μM, which were categorized into five different basic scaffolds. All thirteen fragment hits have ligand efficiencies higher than 0.30. We demonstrated that at least two fragments from two different scaffolds exhibit inhibitory activity against the BaPurE enzyme.
      Graphical abstract image

      PubDate: 2016-02-08T17:00:51Z
       
  • Phytochemical meanings of tetrahydro-β-carboline moiety in
           strictosidine derivatives
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): Nicole Sudžuković, Johann Schinnerl, Lothar Brecker
      Synthesis of 13 different tetrahydro-β-carbolines (THBC) was accomplished by applying the Pictet–Spengler reaction with seven aldehydes, which have been coupled with tryptamine (6) and l-tryptophan methyl ester (7), respectively. The resulting products represent analogues of strictosidine (1) and carboxystrictosidine (5). They were investigated with respect to possible effects on herbivores in feeding bioassays upon the generalist Spodoptera littoralis. Maximum inhibition averages were 42% after four and 46% after six days for the most effective product (19) at 1000ppm. Additionally, the frass of this particular bioassay was investigated via HPLC-UV for THBC digestion. All synthesized THBCs were also tested for their radical scavenger activity by monitoring their interaction with 2,2-diphenyl-1-picrylhydrazyl (DPPH). Compounds 16–20, 24 and 25 exhibited radical scavenging activity, ranging from 50% to 74% compared to that of α-tocopherol. All results were discussed with respect to possible contributions of tetrahydro-β-carboline moieties in bioactivities of strictosidine (1) and its biodegradation products.
      Graphical abstract image

      PubDate: 2016-02-08T17:00:51Z
       
  • Hydroxylated chalcones with dual properties: Xanthine oxidase inhibitors
           and radical scavengers
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): Emily Hofmann, Jonathan Webster, Thuy Do, Reid Kline, Lindsey Snider, Quintin Hauser, Grace Higginbottom, Austin Campbell, Lili Ma, Stefan Paula
      In this study, we evaluated the abilities of a series of chalcones to inhibit the activity of the enzyme xanthine oxidase (XO) and to scavenge radicals. 20 mono- and polyhydroxylated chalcone derivatives were synthesized by Claisen–Schmidt condensation reactions and then tested for inhibitory potency against XO, a known generator of reactive oxygen species (ROS). In parallel, the ability of the synthesized chalcones to scavenge a stable radical was determined. Structure–activity relationship analysis in conjunction with molecular docking indicated that the most active XO inhibitors carried a minimum of three hydroxyl groups. Moreover, the most effective radical scavengers had two neighboring hydroxyl groups on at least one of the two phenyl rings. Since it has been proposed previously that XO inhibition and radical scavenging could be useful properties for reduction of ROS-levels in tissue, we determined the chalcones’ effects to rescue neurons subjected to ROS-induced stress created by the addition of β-amyloid peptide. Best protection was provided by chalcones that combined good inhibitory potency with high radical scavenging ability in a single molecule, an observation that points to a potential therapeutic value of this compound class.
      Graphical abstract image

      PubDate: 2016-02-08T17:00:51Z
       
  • Allosteric inhibitors of Coxsackie virus A24 RNA polymerase
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): Catherine H. Schein, Diane Rowold, Kyung H. Choi
      Coxsackie virus A24 (CVA24), a causative agent of acute hemorrhagic conjunctivitis, is a prototype of enterovirus (EV) species C. The RNA polymerase (3Dpol) of CVA24 can uridylylate the viral peptide linked to the genome (VPg) from distantly related EV and is thus, a good model for studying this reaction. Once UMP is bound, VPgpU primes RNA elongation. Structural and mutation data have identified a conserved binding surface for VPg on the RNA polymerase (3Dpol), located about 20Å from the active site. Here, computational docking of over 60,000 small compounds was used to select those with the lowest (best) specific binding energies (BE) for this allosteric site. Compounds with varying structures and low BE were assayed for their effect on formation of VPgU by CVA24-3Dpol. Two compounds with the lowest specific BE for the site inhibited both uridylylation and formation of VPgpolyU at 10–20μM. These small molecules can be used to probe the role of this allosteric site in polymerase function, and may be the basis for novel antiviral compounds.
      Graphical abstract image

      PubDate: 2016-02-08T17:00:51Z
       
  • Design and synthesis of calindol derivatives as potent and selective
           calcium sensing receptor agonists
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): Lionel Kiefer, Floriane Beaumard, Tatiana Gorojankina, Hélène Faure, Martial Ruat, Robert H. Dodd
      We report the first comprehensive structure–activity study of calindol (4, (R)-N-[(1H-indol-2-yl)methyl]-1-(1-naphthyl)ethanamine), a positive allosteric modulator, or calcimimetic, of the calcium sensing receptor (CaSR). While replacement of the naphthyl moiety of calindol by other aromatic groups (phenyl, biphenyl) was largely detrimental to calcimimetic activity, incorporation of substituents on the 4, 5 or 7 position of the indole portion of calindol was found to provide either equipotent derivatives compared to calindol (e.g., 4-phenyl, 4-hydroxy, 5-hydroxycalindol 44, 52, 53) or, in the case of 7-nitrocalindol (51), a 6-fold more active calcimimetic displaying an EC50 of 20nM. Unlike calindol, the more active CaSR calcimimetics were shown not to act as antagonists of the closely related GPRC6A receptor, suggesting a more selective profile for these new analogues.
      Graphical abstract image

      PubDate: 2016-02-08T17:00:51Z
       
  • Active site-directed plasmin inhibitors: Extension on the P2 residue
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): Koushi Hidaka, Keigo Gohda, Naoki Teno, Keiko Wanaka, Yuko Tsuda
      Based on the structure of YO-2 [N-(trans-4-aminomethylcyclohexanecarbonyl)-l-Tyr(O-picolyl)-NH-octyl], active site-directed plasmin (Plm) inhibitors were explored. The picolyl moiety in the Tyr(O-picolyl) residue (namely, the P2 residue) was replaced with smaller or larger groups, such as hydrogen, tert-butyl, benzyl, (2-naphthyl)methyl, and (quinolin-2-yl)methyl. Those efforts produced compound 17 {N-(trans-4-aminomethylcyclohexanecarbonyl)-l-Tyr[O-(quinolin-2-yl)methyl]-NH-octyl} [IC50 =0.22 and 77μM for Plm and urokinase (UK), respectively], which showed not only 2.4-fold greater Plm inhibition than YO-2, but also an improvement in selectivity (Plm/UK) by 35-fold. The docking experiments of the Plm-17 complexes disclosed that the amino group of the tranexamyl moiety interacted with the side-chain of Asp753 which formed S1 site.
      Graphical abstract image

      PubDate: 2016-02-08T17:00:51Z
       
  • Discovery of
           2-(1H-indol-5-ylamino)-6-(2,4-difluorophenylsulfonyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one
           (7ao) as a potent selective inhibitor of Polo like kinase 2 (PLK2)
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): M.V. Ramana Reddy, Balireddy Akula, Shashidhar Jatiani, Rodrigo Vasquez-Del Carpio, Vinay K. Billa, Muralidhar R. Mallireddigari, Stephen C. Cosenza, D.R.C. Venkata Subbaiah, E. Vijaya Bharathi, Venkat R. Pallela, Poornima Ramkumar, Rinku Jain, Aneel K. Aggarwal, E. Premkumar Reddy
      Several families of protein kinases have been shown to play a critical role in the regulation of cell cycle progression, particularly progression through mitosis. These kinase families include the Aurora kinases, the Mps1 gene product and the Polo Like family of protein kinases (PLKs). The PLK family consists of five members and of these, the role of PLK1 in human cancer is well documented. PLK2 (SNK), which is highly homologous to PLK1, has been shown to play a critical role in centriole duplication and is also believed to play a regulatory role in the survival pathway by physically stabilizing the TSC1/2 complex in tumor cells under hypoxic conditions. As a part of our research program, we have developed a library of novel ATP mimetic chemotypes that are cytotoxic against a panel of cancer cell lines. We show that one of these chemotypes, the 6-arylsulfonyl pyridopyrimidinones, induces apoptosis of human tumor cell lines in nanomolar concentrations. The most potent of these compounds, 7ao, was found to be a highly specific inhibitor of PLK2 when profiled against a panel of 288 wild type, 55 mutant and 12 lipid kinases. Here, we describe the synthesis, structure activity relationship, in vitro kinase specificity and biological activity of the lead compound, 7ao.
      Graphical abstract image

      PubDate: 2016-02-08T17:00:51Z
       
  • Editorial board
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4




      PubDate: 2016-02-08T17:00:51Z
       
  • An appraisal on recent medicinal perspective of curcumin degradant:
           Dehydrozingerone (DZG)
    • Abstract: Publication date: 15 February 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 4
      Author(s): Girish A. Hampannavar, Rajshekhar Karpoormath, Mahesh B. Palkar, Mahamadhanif S. Shaikh
      Natural products serve as a key source for the design, discovery and development of potentially novel drug like candidates for life threatening diseases. Curcumin is one such medicinally important molecule reported for an array of biological activities. However, it has major drawbacks of very poor bioavailability and solubility. Alternatively, structural analogs and degradants of curcumin have been investigated, which have emerged as promising scaffolds with diverse biological activities. Dehydrozingerone (DZG) also known as feruloylmethane, is one such recognized degradant which is a half structural analog of curcumin. It exists as a natural phenolic compound obtained from rhizomes of Zingiber officinale, which has attracted much attention of medicinal chemists. DZG is known to have a broad range of biological activities like antioxidant, anticancer, anti-inflammatory, anti-depressant, anti-malarial, antifungal, anti-platelet and many others. DZG has also been studied in resolving issues pertaining to curcumin since it shares many structural similarities with curcumin. Considering this, in the present review we have put forward an effort to revise and systematically discuss the research involving DZG with its biological diversity. From literature, it is quite clear that DZG and its structural analogs have exhibited significant potential in facilitating design and development of novel medicinally active lead compounds with improved metabolic and pharmacokinetic profiles.
      Graphical abstract image

      PubDate: 2016-02-08T17:00:51Z
       
 
 
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