Chemical Biology & Drug Design

Cover image for Vol. 78 Issue 5

November 2011

Volume 78, Issue 5

Pages i–iii, 739–905

  1. Issue Information

    1. Top of page
    2. Issue Information
    3. Research Articles
    4. Research Letters
    1. Issue Information (pages i–iii)

      Version of Record online: 14 OCT 2011 | DOI: 10.1111/j.1747-0285.2011.01247.x

  2. Research Articles

    1. Top of page
    2. Issue Information
    3. Research Articles
    4. Research Letters
    1. You have free access to this content
      X-Ray Crystal Structure of Bone Marrow Kinase in the X Chromosome: A Tec Family Kinase (pages 739–748)

      Jodi Muckelbauer, John S. Sack, Nazia Ahmed, James Burke, ChiehYing Y. Chang, Mian Gao, Joseph Tino, Dianlin Xie and Andrew J. Tebben

      Version of Record online: 21 SEP 2011 | DOI: 10.1111/j.1747-0285.2011.01230.x

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      The crystal structure of BMX reveals a typical kinase protein fold that includes an extended activation loop and a stabilized DFG motif rendering the kinase in an inactive conformation. Dasatinib and PP2 bind to BMX in the ATP binding pocket and display similar binding modes to that observed in other Tec and Src protein kinases. The BMX structures identify DFG-motif conformational elements that could potentially be utilized to design potent and/or selective BMX inhibitors.

    2. Phosphorylation of Enkephalins: NMR and CD Studies in Aqueous and Membrane-Mimicking Environments (pages 749–756)

      Larisa Yeomans, Dhanasekaran Muthu, John J. Lowery, Heather N. Martinez, Leif Abrell, Guanxin Lin, Kyle Strom, Brian I. Knapp, Jean M. Bidlack, Edward J. Bilsky and Robin Polt

      Version of Record online: 26 SEP 2011 | DOI: 10.1111/j.1747-0285.2011.01203.x

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      Phosphorylation of two l-serine-containing enkephalin analogues, DTLES and DAMGO, has been explored as an alternative to glycosylation in an effort to increase blood-brain barrier (BBB) permeability and CNS bioavailability. The phosphates seem to increase the water solubility of the peptide moieties, and may be useful in promoting effective biodistribution, although they are not as effective as glucosides in this respect.

    3. Characterization of d-boroAla as a Novel Broad-Spectrum Antibacterial Agent Targeting d-Ala-d-Ala Ligase (pages 757–763)

      Sandeep Putty, Aman Rai, Darshan Jamindar, Paul Pagano, Cheryl L. Quinn, Takehiko Mima, Herbert P. Schweizer and William G. Gutheil

      Version of Record online: 21 SEP 2011 | DOI: 10.1111/j.1747-0285.2011.01210.x

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      d-boroAla was identified and characterized as an antibacterial agent. d-boroAla is active against both Gram-positive and Gram-negative organisms, with MICs as low as 8 μg/mL. d-boroAla is bactericidal at 1 × MIC against Staphylococcus aureus and Bacillus subtilis, with a frequency of resistance of 8 × 10−8 at 4 × MIC in S. aureus. An LC-MS/MS assay for the early steps of bacterial cell wall biosynthesis was used to demonstrate that d-boroAla exerts its antibacterial activity in vivo by inhibition of d-Ala-d-Ala ligase (DDL).

    4. Induction of Cell Death by a Novel Naphthoquinone Containing a Modified Anthracycline Ring System (pages 764–777)

      Denisse Carvajal, Steven Kennedy, Andre Boustani, Monica Lazar, Suong Nguyen, John C. DiCesare and Robert J. Sheaff

      Version of Record online: 26 SEP 2011 | DOI: 10.1111/j.1747-0285.2011.01214.x

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      The novel naphthoquinone adduct 12,13-Dihydro-N-methyl-6,11,13-trioxo-5H-benzo[4,5]cyclohepta[1,2-b]naphthalen-5,12-imine (hereafter called TU100) was synthesized as a potential chemotherapeutic agent. TU100 arrests tissue culture cells in S and G2/M phases of the cell cycle, followed by rapid induction of apoptosis. TU100 does not intercalate into DNA despite structural similarity to anthracyclines. Cells treated with the drug do exhibit DNA damage, however, as indicated by phosphorylation of histone H2A.X. This damage and effects on cell viability are likely mediated in part by TU100-induced reactive oxygen species.

    5. Representation of Multi-Target Activity Landscapes Through Target Pair-Based Compound Encoding in Self-Organizing Maps (pages 778–786)

      Preeti Iyer and Jürgen Bajorath

      Version of Record online: 5 OCT 2011 | DOI: 10.1111/j.1747-0285.2011.01235.x

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      A new concept to visualize multi-target activity landscapes is introduced. The activity landscape model is applied to analyze compound data sets with three to five activity annotations and identify regions of high discontinuity in multi-target activity space.

    6. Design, Synthesis and Structure of Novel Para-Quinones and their Antibacterial Activity (pages 787–799)

      Komala Pandurangan, Kevin D. Murnaghan, Aurora Walshe, Helge Müller-Bunz, Francesca Paradisi and Grace G. Morgan

      Version of Record online: 15 SEP 2011 | DOI: 10.1111/j.1747-0285.2011.01187.x

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      Eight new para-quinones and one known analogue have been synthesized from p-chloranil. Five have been structurally characterized by single crystal diffraction and a range of ligand folding is observed. All nine have been tested for their potency towards Gram(+) S. aureus and Gram(−) E. coli. Quinones 3, 6, 7 and 8 have shown activity towards S. aureus and quinones 3 and 8 also show good activity towards E. coli.

    7. Synthesis, Antifungal Activity, and Docking Study of Some New 1,2,4-triazole Analogs (pages 800–809)

      Jaiprakash N. Sangshetti, Deepak K. Lokwani, Aniket P. Sarkate and Devanand B. Shinde

      Version of Record online: 26 SEP 2011 | DOI: 10.1111/j.1747-0285.2011.01178.x

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      Synthesis of new series of 1,2,4 triazole with 1,2,3 triazole and piperidine ring ZrOCl2·8H2O as a catalyst in ethanol has been described. Docking study of the newly synthesized compounds was performed and evaluated for their in vitro antifungal activities using standard agar method.

    8. Synthesis of Aryl Aldimines and Their Activity against Fungi of Clinical Interest (pages 810–815)

      Cleiton M. da Silva, Danielle L. da Silva, Cleide V.B. Martins, Maria A. de Resende, Esther S. Dias, Thais F.F. Magalhães, Letícia P. Rodrigues, Adão A. Sabino, Rosemeire B. Alves and Ângelo de Fátima

      Version of Record online: 6 SEP 2011 | DOI: 10.1111/j.1747-0285.2011.01185.x

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      Six aryl aldimines were synthesized from the condensation of aromatic amines with benzaldehydes. The antifungal activities of synthesized compounds were evaluated against nineteen fungi strains that included Candida and Aspergillus species and Cryptococcus neoformans. The aryl aldimines 2-(benzylideneamino)phenol (3) and 4-(benzylideneamino)phenol (8) were the most active compounds against the fungi studied. Such compounds inhibited efficiently the metabolism of C. neoformans mature biofilm.

    9. Synthesis, Saccharide-Binding and Anti-cancer Cell Proliferation Properties of Arylboronic Acid Derivatives of Indoquinolines (pages 816–825)

      Junxiu Meng, Shaoqing Yu, Shengbiao Wan, Sumei Ren and Tao Jiang

      Version of Record online: 15 SEP 2011 | DOI: 10.1111/j.1747-0285.2011.01196.x

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      A series of arylboronic acid derivatives of indoloquinoline was synthesized. Mass spectrometry experiments revealed these derivatives could bind to biologically important carbohydrates (sialic acid, fucose, glucose and galactose) by forming boronate di-esters in alkaline aqueous solution. Most of the arylboronic acid derivatives of indoquinolines inhibited human breast cancer cell (MDA–231) proliferation at a concentration of 5 μm, whereas the compound 17 exhibited highest percentages (76.74%) of the cancer cell proliferation inhibition.

    10. Pharmacophore Optimization and Design of Competitive Inhibitors of Thymidine Monophosphate Kinase Through Molecular Modeling Studies (pages 826–834)

      Trupti S. Chitre, Muthu K. Kathiravan, Kailash G. Bothara, Shashikant V. Bhandari and Rajeshwar R. Jalnapurkar

      Version of Record online: 20 SEP 2011 | DOI: 10.1111/j.1747-0285.2011.01200.x

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      The pharmacophore requirements for selective inhibition of Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) were optimized using molecular modelling studies.

    11. Rational Design of Peptides with Anti-HCV/HIV Activities and Enhanced Specificity (pages 835–843)

      Gui-Rong Li, Li-Yan He, Xiu-Ying Liu, Ai-Ping Liu, Yi-Bing Huang, Chao Qiu, Xiao-Yan Zhang, Jian-Qing Xu, Wei Yang and Yu-Xin Chen

      Version of Record online: 26 SEP 2011 | DOI: 10.1111/j.1747-0285.2011.01201.x

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      In the present study, the C5A sequence SWLRDIWDWICEVLSDFK was utilized as the framework to study the effect of the modulation of peptide helicity and hydrophobicity on its anti-HCV and anti-HIV activities. By modulating peptide helicity and hydrophobicity, we improved the specificity of C5A against HCV and HIV by 23- and 69-fold, respectively. Peptide I6L/I10L/V13L may be a promising antiviral therapeutic candidate against HCV and HIV co-infection in clinical practices.

    12. 1-[(2-Arylthiazol-4-yl)methyl]azoles as a New Class of Anticonvulsants: Design, Synthesis, In vivo Screening, and In silico Drug-like Properties (pages 844–852)

      Nematollah Ahangar, Adile Ayati, Eskandar Alipour, Arsalan Pashapour, Alireza Foroumadi and Saeed Emami

      Version of Record online: 15 SEP 2011 | DOI: 10.1111/j.1747-0285.2011.01211.x

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      A series of novel thiazole incorporated (arylalkyl)azoles were synthesized and screened for their anticonvulsant properties. Furthermore, a computational study was carried out for prediction of pharmacokinetic properties and drug-likeness.

    13. Computational-Aided Design for Dopamine Prodrugs Based on Novel Chemical Approach (pages 853–863)

      Rafik Karaman

      Version of Record online: 26 SEP 2011 | DOI: 10.1111/j.1747-0285.2011.01208.x

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      Schematic representation of the inter-conversion of dopamine prodrugs to dopamine in physiologic environment

    14. Antifungal Agents. Part 3: Synthesis and Antifungal Activities of 3-Acylindole Analogs against Phytopathogenic Fungi In Vitro (pages 864–868)

      Hui Xu, Wen bin Yang and Qin Wang

      Version of Record online: 15 SEP 2011 | DOI: 10.1111/j.1747-0285.2011.01212.x

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      It preliminarily revealed that 4- or 6-methyl and 3-acetyl or propionyl groups were the important structural properties for 3-acylindoles possessing good antifungal activities.

    15. Synthesis and in vitro Evaluation of Novel Indole-Based Sigma Receptors Ligands (pages 869–875)

      Mine Yarim, Meric Koksal, Dirk Schepmann and Bernard Wünsch

      Version of Record online: 26 SEP 2011 | DOI: 10.1111/j.1747-0285.2011.01215.x

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      Synthesis and sigma receptor affinity of series of novel indole based ligands are presented. Cytotoxicity of the compounds was demonstrated on cancer cell lines from liver (HUH7), breast (MCF7) and colon (HCT-116) cancer cell lines.

    16. Synthesis and Antibacterial Activity of Aromatic and Heteroaromatic Amino Alcohols (pages 876–880)

      Camila G. de Almeida, Samira G. Reis, Angelina M. de Almeida, Claudio G. Diniz, Vânia L. da Silva and Mireille Le Hyaric

      Version of Record online: 21 SEP 2011 | DOI: 10.1111/j.1747-0285.2011.01231.x

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      Two series of aromatic and heteroaromatic amino alcohols were synthesized from alcohols and aldehydes and evaluated for their antibacterial activities. The octylated compounds displayed a better activity against the four bacteria tested.

    17. Synthesis and Biological Evaluation of Some Novel 1,4-Dihydropyridines as Potential AntiTubercular Agents (pages 881–886)

      Amit Trivedi, Dipti Dodiya, Bipin Dholariya, Vipul Kataria, Vimal Bhuva and Viresh Shah

      Version of Record online: 21 SEP 2011 | DOI: 10.1111/j.1747-0285.2011.01233.x

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      A series of novel 1,4-dihydropyridines bearing carbmethoxy and carbethoxy group at C-3 and C-5 of the DHP ring were synthesized and evaluated for their antimycobacterial activity. The lowest minimum inhibitory concentration value, 0.02 μg/mL, was found for compounds 3f, 4c and 4e, making it more potent than isoniazid.

  3. Research Letters

    1. Top of page
    2. Issue Information
    3. Research Articles
    4. Research Letters
    1. Metabolic Stability of Peptidomimetics: N-Methyl and Aza Heptapeptide Analogs of a PKB/Akt Inhibitor (pages 887–892)

      Yftah Tal-Gan, Noam S. Freeman, Shoshana Klein, Alexander Levitzki and Chaim Gilon

      Version of Record online: 26 SEP 2011 | DOI: 10.1111/j.1747-0285.2011.01207.x

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      The effects of N-methylation and aza amino acid insertion on metabolic stability were assessed by a Trypsin/Chymotrypsin assay. Modification of the inner residues resulted in increased metabolic stability whereas modification of the C or N terminal residues resulted in reduced metabolic stability.

    2. Pathway Analysis of Acinetobacter baylyi: A Combined Bioinformatic and Genomics Approach (pages 893–905)

      Shailza Singh, Priyanka Joshi and Balu A. Chopade

      Version of Record online: 6 SEP 2011 | DOI: 10.1111/j.1747-0285.2011.01191.x

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      Acinetobacter spp., source of numerous nosocomial infections deserves a close attention as various multidrug resistance strains are being discovered worldwide. An in silico comparative analysis of the metabolic pathways of the host Homo sapiens and the pathogen Acinetobacter baylyi was performed by using BLASTp search. This search is against the non-redundant database restricted to the Homo sapiens subset. Sixteen unique pathways identified enlisted a total of 183 drug targets out of which 31 belong to the metabolic pathways unique to pathogen having no human homologue. Out of these potential drug targets enlisted, RmlA enzyme (d-glucose-1 phosphate thymidylyltransferase) is the first enzyme in the polyketide sugar unit synthesis metabolic pathway which leads to the formation of l-rhamnose. In gram negative bacteria l-rhamnose is one of the important residues of the O-antigen of lipopolysaccharide, a key determinant factor for the virulence of these species. Moreover, these proteins are highly conserved amongst microorganisms and therefore conclusions drawn from the structure of a protein from one species will have strong implications for the corresponding enzyme structure of another origin. Homology Modeling of RmlA was performed by MODELLER and the PMDB ID obtained is PM0076419. Docking and molecular modeling simulations of chalcone (2) suggested that the dissociated 7-hydroxyl hydrogen bonds to Ala175 and Tyr 41 provides a good structural replacement.