Chemical Biology & Drug Design

Cover image for Vol. 89 Issue 2

Early View (Online Version of Record published before inclusion in an issue)

Edited By: David Selwood

Impact Factor: 2.802

ISI Journal Citation Reports © Ranking: 2015: 26/59 (Chemistry Medicinal); 138/289 (Biochemistry & Molecular Biology)

Online ISSN: 1747-0285


  1. 1 - 100
  2. 101 - 107

    1. Novel nucleoside analogues targeting HCV replication through an NS5A-dependent inhibition mechanism

      Nikolaos Lougiakis, Efseveia Frakolaki, Panagiota Karmou, Nicole Pouli, Panagiotis Marakos, Vanesa Madan, Ralf Bartenschlager and Niki Vassilaki

      Version of Record online: 24 MAR 2017 | DOI: 10.1111/cbdd.12966

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      A number of new tricyclic nucleosides were synthesized and their inhibitory potential against HCV was evaluated. The benzylamino derivative 15d reduced HCV replication and possessed selectivity index 4.97 in 1b genotype. Resistance mutation studies were performed, suggesting that this compound could possess a NS5A-dependent mechanism of action, which is unexpected for nucleoside derivatives.

    2. Structure-based derivation of peptide inhibitors to target TGF-β1 receptor for the suppression of hypertrophic scarring fibroblast activation

      Huan Hu, Songlin Yang, Jianghong Zheng and Guangyu Mao

      Version of Record online: 24 MAR 2017 | DOI: 10.1111/cbdd.12954

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      A structure-based approach is described to derive peptide inhibitor from the complex interface of TGF-β1 with TβRII. The peptide is extended and cyclized by introducing a disulfide bond across its terminal residues. Computational analysis and fluorescence-based assay suggest that the cyclization can largely reduce the peptide flexibility and considerably minimize entropy penalty upon the peptide binding to TβRII.

    3. Radiolabeling, quality control, and biological characterization of 177Lu-labeled kanamycin

      Muhammad Usman Akbar, Tanveer Hussain Bokhari, Muhammad Khalid, Muhammad Razeen Ahmad, Samina Roohi, Saira Hina, Sajid Mehmood, Muhammad Sohaib and Tania Jabbar

      Version of Record online: 15 MAR 2017 | DOI: 10.1111/cbdd.12960

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      99mTc-kanamycin, used for bacterial infection imaging, is short-lived and cannot be transported over long distances. To resolve this, kanamycin was labeled with lutetium-177, a long-lived isotope that emits β- and γ-radiation. Radiolabeling of 177Lu-kanamycin was optimized. 177Lu-kanamycin was prepared with a very high yield (~100%) and showed excellent stability in vitro. Biodistribution and scintigraphy studies in mice and rabbit showed rapid clearance from body, suggesting that 177Lu-kanamycin could be used for medical imaging.

    4. Synthesis and characterization of a novel series of 1,4-dihydropyridine analogues for larvicidal activity against Anopheles arabiensis

      Bhaskara D. Dharma Rao, Subhrajyoti Bhandary, Deepak Chopra, Katharigatta N. Venugopala, Raquel M. Gleiser, Kabange Kasumbwe and Bharti Odhav

      Version of Record online: 11 MAR 2017 | DOI: 10.1111/cbdd.12957

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      The title compounds were synthesized by a one-pot multi-component Hantzsch ester synthesis in aqueous medium under catalyst-free conditions. Larvicidal results revealed that the presence of different substituents, namely nitro, chloro, and methoxy groups, influenced the larvicidal activity when compared to the standard compound. A promising larvicidal compound from the series has been characterized using single crystal X-ray diffraction.

    5. Controlled release of an endostatin peptide using chitosan nanoparticles

      Sanaz Ebrahimi Samani, Zahra Seraj, Hossein Naderimanesh, Khosro Khajeh, Ahmad Reza Esmaeili Rastaghi, Taher Droudi, Peirhosein Kolivand, Hadi Kazemi and S. Mohsen Asghari

      Version of Record online: 11 MAR 2017 | DOI: 10.1111/cbdd.12959

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      Application of anticancer peptides is limited by fast elimination from the systemic circulation. In this study, chitosan nanoparticles are used for the controlled release of an engineered antiangiogenic peptide derived from the N-terminal fragment of human endostatin. The nanoparticles were characterized before and after peptide loading by FTIR, zeta sizer and SEM. Our measurements revealed that chitosan nanoparticles are able to adsorb the peptide as ~70% and complete release took place after 80 h. According to in vitro studies, the loaded peptide was much more toxic for endothelial cells than cancer cell lines. These results underscore the promise of chitosan nanoparticles as therapeutics nanosystems.

    6. Caffeic acid phenethyl ester (CAPE) revisited: Covalent modulation of XPO1/CRM1 activities and implication for its mechanism of action

      Sijin Wu, Keren Zhang, Hongqiang Qin, Mingshan Niu, Weijie Zhao, Mingliang Ye, Hanfa Zou and Yongliang Yang

      Version of Record online: 8 MAR 2017 | DOI: 10.1111/cbdd.12905

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      Caffeic acid phenethyl ester (CAPE) is the bioactive constituent of propolis from honeybee hives. We revisited the cellular mechanism underlying the diverse biological effects of CAPE and demonstrated that XPO1/CRM1, a major nuclear export receptor, is a cellular target of CAPE. Importantly, we identified that CAPE specifically targets the Cys528 of XPO1 by a series of computational and experimental studies.

    7. Investigation of the bindings of a class of inhibitors with GSK3β kinase using thermodynamic integration MD simulation and kinase assay

      Chia-Jen Hsu, Wen-Chi Hsu, Der-Jay Lee, An-Lun Liu, Chia-Ming Chang, Huei-Jhen Shih, Wun-Han Huang, Guey-Jen Lee-Chen, Hsiu Mei Hsieh-Li, Guan-Chiun Lee and Ying-Chieh Sun

      Version of Record online: 6 MAR 2017 | DOI: 10.1111/cbdd.12946

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      GSk3β kinase is an important protein target for several diseases. Finding new small-molecule inhibitors may yield new lead compounds, and spur drug discovery. Based on an existing ligand–GSK3β kinase complex structure, thermodynamic integration MD simulation was utilized to investigate binding for a class of analogous compounds. The binding affinities of three new selected compounds were measured using a kinase assay. This article reports the binding affinities and predicted binding modes of these compounds.

    8. Molecular basis for covalent inhibition of glyceraldehyde-3-phosphate dehydrogenase by a 2-phenoxy-1,4-naphthoquinone small molecule

      Stefano Bruno, Elisa Uliassi, Mirko Zaffagnini, Federica Prati, Christian Bergamini, Riccardo Amorati, Gianluca Paredi, Marilena Margiotta, Paola Conti, Maria Paola Costi, Marcel Kaiser, Andrea Cavalli, Romana Fato and Maria Laura Bolognesi

      Version of Record online: 6 MAR 2017 | DOI: 10.1111/cbdd.12941

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      Herein, using multiple chemical and biological approaches and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) orthologs, we report on the ability of 2-phenoxy-1,4-naphthoquinone (1) to act as a covalent GAPDH inhibitor, by a cysteine trapping mechanism. Chemical probes 24 allowed us to further investigate the proposed mechanism of interaction. Moreover, we preliminarily evaluated the selectivity of 1 over other two thiol-dependent enzymes, supporting its suitability as a warhead fragment for GAPDH inhibitor design.

    9. In silico analysis of the deleterious nsSNPs (missense) in the homeobox domain of human HOXB13 gene responsible for hereditary prostate cancer

      Gopalakrishnan Chandrasekaran, Eu Chang Hwang, Taek Won Kang, Dong Deuk Kwon, Kwangsung Park, Je-Jung Lee and Vinoth-Kumar Lakshmanan

      Version of Record online: 6 MAR 2017 | DOI: 10.1111/cbdd.12938

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      In silico analysis and screening of the nsSNPs present in the DNA-binding domain (homeobox) of human HOXB13 gene is of crucial importance, since nsSNPs are known to be the prime cause for hereditary prostate cancer. Further, in silico protein mutation studies and subsequent validation by Ramachandran plot revealed P222R, G216C, W263R, and K218R to render serious damaging effects on the HOXB13 protein structure, stability, and function. However, the exact mechanism and pathology of these nsSNPs should be studied in depth in vitro/ in vivo.

  2. Research Articles

    1. Synthesis and mechanistic studies of curcumin analog-based oximes as potential anticancer agents

      Hua-Li Qin, Jing Leng, Bahaa G. M. Youssif, Muhammad Wahab Amjad, Maria Abdul Ghafoor Raja, Muhammad Ajaz Hussain, Zahid Hussain, Syeda Naveed Kazmi and Syed Nasir Abbas Bukhari

      Version of Record online: 6 MAR 2017 | DOI: 10.1111/cbdd.12964

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      Newly synthesized oxime analogs showed strong antiproliferative activity against the cancer cell lines. The mechanistic effects of compounds on EGFR-TK kinases and tubulin polymerization and BRAFV600E were also investigated.


    1. NMR structure-based optimization of Staphylococcus aureus sortase A pyridazinone inhibitors

      Albert H. Chan, Sung Wook Yi, Ethan M. Weiner, Brendan R. Amer, Christopher K. Sue, Jeff Wereszczynski, Carly A. Dillen, Silvia Senese, Jorge Z. Torres, J. Andrew McCammon, Lloyd S. Miller, Michael E. Jung and Robert T. Clubb

      Version of Record online: 6 MAR 2017 | DOI: 10.1111/cbdd.12962

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      NMR spectroscopy was used to determine the structure of Staphylococcus aureus sortase A transpeptidase enzyme in complex with a pyridazinone-based small molecule, a potential anti-infective agent. Computational and synthetic chemistry methods led to second-generation analogs that are 70-fold more potent than the lead molecule, less cytotoxic and effective at impairing sortase A-mediated protein display on the surface of S. aureus. These pyridazinone analogues are attractive candidates for further development into anti-infective agents.

    2. A platinum blue complex exerts its cytotoxic activity via DNA damage and induces apoptosis in cancer cells

      Zelal Adiguzel, Seniz Ozalp-Yaman, Gokalp Celik, Safia Salem, Tugba Bagci-Onder, Filiz Senbabaoglu, Yüksel Cetin and Ceyda Acilan

      Version of Record online: 6 MAR 2017 | DOI: 10.1111/cbdd.12940

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      A novel Pt-blue complex induces DNA damage leading to apoptosis through oxidative stress and elevation of proapoptotic proteins in cancer cells.

    3. Anxiolytic-like effect of 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol is mediated through the benzodiazepine and nicotinic pathways

      Adriane F. Brito, James O. Fajemiroye, Hiasmin F. S. Neri, Dayane M. Silva, Daiany P. B. Silva, Germán Sanz, Boniek G. Vaz, Flávio S. de Carvalho, Paulo C. Ghedini, Luciano M. Lião, Ricardo Menegatti and Elson A. Costa

      Version of Record online: 6 MAR 2017 | DOI: 10.1111/cbdd.12961

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      LQFM032 showed anxiolytic-like activity without motor impairment. anxiolytic-like activity of LQFM032 was antagonized by flumazenil and mecamylamine; LQFM032 did not alter mnemonic activity.

    4. Importance of functional groups in predicting the activity of small molecule inhibitors for Bcl-2 and Bcl-xL

      Vishnupriya Kanakaveti, Ramasamy Sakthivel, S. K. Rayala and M. Michael Gromiha

      Version of Record online: 1 MAR 2017 | DOI: 10.1111/cbdd.12952

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      Developed scaffold-specific models for predicting Bcl-2 and Bcl-xL small molecule inhibitors. Explored the important functional groups affecting BH3 mimicking. Hydrogen bonding, flexibility, volume and surface area of atoms are vital for BH3 mimicking. Designed a Web server for predicting the activity of novel compounds. Screened novel compounds for all the seven scaffolds.

    5. A novel mitochondria-targeting fluorescent probe for hydrogen sulfide in living cells

      Wei Shi, Miaobo Pan, Hao Qiang, Qianqian Qiu, Wenlong Huang, Haiyan Lin, Hai Qian and Liang Ge

      Version of Record online: 28 FEB 2017 | DOI: 10.1111/cbdd.12948

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      A novel mitochondria-targeting fluorescent probe compound S-N3 as the monitor of hydrogen sulfide (H2S) in living cells has been designed and synthesized in this study.

  4. Research Articles

    1. Design, synthesis, biological evaluation, and 3D-QSAR analysis of podophyllotoxin–dioxazole combination as tubulin targeting anticancer agents

      Zi-Zhen Wang, Wen-Xue Sun, Xue Wang, Ya-Han Zhang, Han-Yue Qiu, Jin-Liang Qi, Yan-Jun Pang, Gui-Hua Lu, Xiao-Ming Wang, Fu-Gen Yu and Yong-Hua Yang

      Version of Record online: 28 FEB 2017 | DOI: 10.1111/cbdd.12942

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      It proves that compound 7c conjugated in the colchicine site of tubulin (1SA0) perfectly and cyclin A2 and CDK2 are involved in the cell cycle process induced by 7c.


    1. Danazol has potential to cause PKC translocation, cell cycle dysregulation, and apoptosis in breast cancer cells

      Suman Jyoti Deka, Ashalata Roy, Vibin Ramakrishnan, Debasis Manna and Vishal Trivedi

      Version of Record online: 27 FEB 2017 | DOI: 10.1111/cbdd.12921

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      Danazol fits well into the PKC C1 domain. MDAMB-231 cells stimulated with danazol exhibit translocation of PKCα to the plasma membrane. Danazol stimulation causes appearance of phosphorylated proteins in cancer cell. It affects PMA-induced intracellular signaling in MDAMB-231 cells. Danazol treatment halted the cancer cells in the G1 phase. It has reduced the viability of MDAMB-231 cells with an IC50 of 65 ± 4.27 µg/ml. It induces apoptotic in cancer cells following mitochondrial pathways.

    2. Virtual screening, SAR, and discovery of 5-(indole-3-yl)-2-[(2-nitrophenyl)amino] [1,3,4]-oxadiazole as a novel Bcl-2 inhibitor

      Noha I. Ziedan, Rania Hamdy, Alessandra Cavaliere, Malamati Kourti, Filippo Prencipe, Andrea Brancale, Arwyn T. Jones and Andrew D. Westwell

      Version of Record online: 24 FEB 2017 | DOI: 10.1111/cbdd.12936

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      A new series of oxadiazoles were designed to act as Bcl-2 inhibitors. Virtual screening led to the discovery of new hits as Bcl-2 inhibitors. SAR study was further performed leading to discovery of a novel lead. Most active compound has submicromolar growth inhibition IC50 for both MDa-MB-231 and HeLa cancer cell lines, and Bcl-2 inhibition in the low micromolar range as demonstrated by ELISA binding assay.

    3. Identification of promising DNA GyrB inhibitors for Tuberculosis using pharmacophore-based virtual screening, molecular docking and molecular dynamics studies

      Md Ataul Islam and Tahir S. Pillay

      Version of Record online: 24 FEB 2017 | DOI: 10.1111/cbdd.12949

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      Pharmacophore-based virtual screening was performed on DNA GyrB inhibitors. The best selected pharmacophore model explained that two each of hydrogen bond acceptor and hydrophobicity were critical for inhibition of DNA GyrB. On virtual screening of molecular databases using the pharmacophore model, three molecules were found to be promising as antibacterial agents, which was also confirmed by molecular docking and molecular dynamics studies.


    1. In silico approaches and chemical space of anti-P-type ATPase compounds for discovering new antituberculous drugs

      Paola Santos, Fabian López-Vallejo and Carlos-Y. Soto

      Version of Record online: 24 FEB 2017 | DOI: 10.1111/cbdd.12950

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      In this review, we provide an overview on the different models implemented toward the rational design of new anti-TB drugs, encompassing the biological and structural features of Mycobacterium tuberculosis P-type ATPases as possible therapeutic targets. In addition, the chemical space distribution based on the structure and molecular properties of compounds with anti-TB and anti-P-type ATPase activity was assessed and compared to a natural products library. We consider that this library could assist researchers to identify novel chemical scaffolds with potential antituberculous activity.


    1. Synthesis, QSAR studies, and metabolic stability of novel 2-alkylthio-4-chloro-N-(5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)benzenesulfonamide derivatives as potential anticancer and apoptosis-inducing agents

      Beata Żołnowska, Jarosław Sławiński, Aneta Pogorzelska, Krzysztof Szafrański, Anna Kawiak, Grzegorz Stasiłojć, Mariusz Belka, Joanna Zielińska and Tomasz Bączek

      Version of Record online: 24 FEB 2017 | DOI: 10.1111/cbdd.12955

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      • New N-(5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)benzenesulfonamides was synthesized
      • The cytotoxic activity toward MCF-7, HeLa, HCT-116 was investigated
      • The 5-oxo-1,2,4-trizines exhibited apoptosis-inducing activity in the HeLa cells
      • The quantitative structure-activity relationship of cytotoxic activity was found
      • Metabolic stability was studied using pooled human liver microsomes and NADPH

    1. Design, synthesis and cytotoxic evaluation of nitric oxide-releasing derivatives of isosteviol

      Yan Liu, Tingting Wang, Yong Ling, Na Bao, Wei Shi, Li Chen and Jianbo Sun

      Version of Record online: 22 FEB 2017 | DOI: 10.1111/cbdd.12956

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      Four series of different types of NO donor-isosteviol derivatives were synthesized and screened for cytotoxic activities against four human cancer cell lines with sunitinib as the positive control.


    1. Synthesis of primaquine glyco-conjugates as potential tissue schizontocidal antimalarial agents

      Chandra S. Azad, Mridula Saxena, Arif J. Siddiqui, Jyoti Bhardwaj, Sunil K. Puri, Guru P. Dutta, Nitya Anand and Anil K. Saxena

      Version of Record online: 22 FEB 2017 | DOI: 10.1111/cbdd.12944

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      The three compounds viz glucoside (15a), galactoside (15b), and mannoside (15c) with high activity were tested and most active compound 15b showed twofold activity than the standard drug Primaquine diphosphate.

    2. Structural improvement of new thiazolidinones compounds with antinociceptive activity in experimental chemotherapy-induced painful neuropathy

      Diogo Rodrigo Magalhaes Moreira, Dourivaldo Silva Santos, Renan Fernandes do Espírito Santo, Flávia Evangelista dos Santos, Gevanio Bezerra de Oliveira Filho, Ana Cristina Lima Leite, Milena Botelho Pereira Soares and Cristiane Flora Villarreal

      Version of Record online: 22 FEB 2017 | DOI: 10.1111/cbdd.12951

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      Chemotherapy-induced neuropathy is a refractory pain condition resulting from chemotherapy for cancers. In the present study, we describe the structural design, synthesis, chemical and pharmacological characterization of thiazolidinones with antinociceptive effects in a mice model of oxaliplatin-induced neuropathic pain. Thiazolidinones displayed dose-dependent and potent antinociceptive effects, possibly mediated by agonistic properties in PPAR. The structural design of thiazolidinones is an efficient strategy to optimize its pharmacological properties, aiming the control of the refractory neuropathic pain.

    3. Synthesis and biological evaluation of 1,2,4-triazole-3-thione and 1,3,4-oxadiazole-2-thione as antimycobacterial agents

      Amol D. Sonawane, Navnath D. Rode, Laxman Nawale, Rohini R. Joshi, Ramesh A. Joshi, Anjali P. Likhite and Dhiman Sarkar

      Version of Record online: 16 FEB 2017 | DOI: 10.1111/cbdd.12939

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      A series of 1,2,4-triazole-3-thione and 1,3,4-oxadiazole-2-thione derivatives have been synthesized and screened for their antitubercular activity against Mycobacterium tuberculosis H37Ra. Triazole thiones showed high antitubercular activity against the dormant stage of M. tuberculosis H37Ra. These compounds were shown to have more specificity toward mycobacteria than other Gram-negative and Gram-positive pathogenic bacteria. The cytotoxicity was almost insignificant up to 100 µg/ml against THP-1, A549, and PANC-1 human cancer cell lines.

    4. 1-[(2,3-Dihydro-1-benzofuran-2-yl) methyl]piperazines as novel anti-inflammatory compounds: Synthesis and evaluation on H3R/H4R

      Michelle Fidelis Corrêa, Marina Themoteo Varela, Aleksandro Martins Balbino, Ana Claudia Torrecilhas, Richardt Gama Landgraf, Lanfranco Ranieri Paolo Troncone and João Paulo dos Santos Fernandes

      Version of Record online: 16 FEB 2017 | DOI: 10.1111/cbdd.12947

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      Histamine H3R and H4R receptors have been explored as targets for drug discovery. We present herein four non-cytotoxic compounds with moderate affinity for these targets. The compound LINS01005 has shown promising anti-inflammatory activity in murine asthma model.


    1. (Z)-2-(3-Chlorobenzylidene)-3,4-dihydro-N-(2-methoxyethyl)-3-oxo-2H-benzo[b][1,4]oxazine-6-carboxamide as GSK-3β inhibitor: Identification by virtual screening and its validation in enzyme- and cell-based assay

      Prashant Joshi, Mehak Gupta, Ram A. Vishwakarma, Ajay Kumar and Sandip B. Bharate

      Version of Record online: 16 FEB 2017 | DOI: 10.1111/cbdd.12913

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      Herein, we report identification of benzo[b][1,4]oxazine-6-carboxamide class of GSK-3beta inhibitor through virtual screening. The validation of the identified lead was demonstrated in enzyme- and cell-based assays.


    1. Physicochemical and biological evaluation of a cinnamamide derivative R,S-(2E)-1-(3-hydroxypiperidin-1-yl)-3-phenylprop-2-en-1-one (KM-608) for nervous system disorders

      Agnieszka Gunia-Krzyżak, Ewa Żesławska, Florence M. Bareyre, Wojciech Nitek, Anna M. Waszkielewicz and Henryk Marona

      Version of Record online: 16 FEB 2017 | DOI: 10.1111/cbdd.12943

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      R,S-(2E)-1-(3-hydroxypiperidin-1-yl)-3-phenylprop-2-en-1-one (KM-608), a cinnamamide derivative, with confirmed structure and purity was tested in mice and rats. The compound is a potent anticonvulsant and antiepileptogenic agent. In vivo pharmacological profile of KM-608 corresponds with the activity of valproic acid.

    2. Synthesis, molecular docking and biological evaluation of 1-phenylsulphonyl-2-(1-methylindol-3-yl)-benzimidazole derivatives as novel potential tubulin assembling inhibitors

      Yan-Ting Wang, Xun-Chao Cai, Tian-Qi Shi, Ya-Liang Zhang, Zhong-Chang Wang, Chang-Hong Liu and Hai-Liang Zhu

      Version of Record online: 15 FEB 2017 | DOI: 10.1111/cbdd.12932

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      Crystal structure diagram of compound 15. 3D diagram of the interaction between compound 33 and the colchicine-binding site. Compounds of novel 1-phenylsulphonyl-2-(1-methylindol-3-yl)-benzimidazole derivatives containing different substituent groups were designed, synthesized and evaluated for their inhibitory activity against tubulin polymerization and cancer cell growth. Docking simulation and the QSAR study were conducted.

    3. Fusion of Ssm6a with a protein scaffold retains selectivity on NaV1.7 and improves its therapeutic potential against chronic pain

      Chuan Wang, Bin Shan, Qiong Wang, Qunyuan Xu, Hailin Zhang and Huimeng Lei

      Version of Record online: 15 FEB 2017 | DOI: 10.1111/cbdd.12915

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      We fuse the venom peptide Ssm6a with an artificially engineered human protein scaffold to design a fusion protein that not only retains bioactivity of Ssm6a as a potent selective Nav1.7 inhibitor but can be cytosolically produced in Escherichia coli with favorably altered kinetics upon its target. We show that the fusion protein exhibits significant in vivo analgesic effects through DRG-targeted delivery.

    4. Antileukemic action of novel diamine Pt(II) halogenido complexes: Comparison of the representative novel Pt(II) with corresponding Pt(IV) complex

      Sonja Misirlić Denčić, Jelena Poljarević, Andjelka M. Isakovic, Ivanka Marković, Tibor J. Sabo and Sanja Grgurić-Šipka

      Version of Record online: 14 FEB 2017 | DOI: 10.1111/cbdd.12945

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      This study presents the synthesis, characterization, and antitumor action of five new Pt(II) halogenido complexes with edda type of ligands. Their cytotoxic action, investigated in four human tumor cell lines, showed that novel Pt(II) complexes exhibited comparable or better antitumor action in comparison with cisplatin, precursor ligands, and corresponding Pt(IV) complex.

    5. In silico design and bioevaluation of selective benzotriazepine BRD4 inhibitors with potent antiosteoclastogenic activity

      Vishwa Deepak, Binglin Wang, Dwayne Koot, Abe Kasonga, Xiao Xing Stander, Magdalena Coetzee and Andre Stander

      Version of Record online: 11 FEB 2017 | DOI: 10.1111/cbdd.12930

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      Benzotriazepine bromodomain 4 inhibitors capable of inhibiting osteoclast differentiation without cytotoxic effects on murine RAW264.7 osteoclast progenitors, as well as human CD14+ monocytes, were in silico designed and synthesized. This study demonstrates that in silico docking and molecular dynamics simulations are useful to identify BRD inhibitors with a particular selectivity profile. Furthermore, the compounds identified in this study have remarkable antiosteoclastogenic potential and warrant further studies for drug development against bone loss diseases characterized by excessive osteoclast activity.

    6. Identification and characterization of novel host defense peptides from the skin secretion of the fungoid frog, Hydrophylax bahuvistara (Anura: Ranidae)

      Thundi Parambil Vasanth Kumar Vineeth Kumar, Radhamony Asha, Gopal Shyla and Sanil George

      Version of Record online: 11 FEB 2017 | DOI: 10.1111/cbdd.12937

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      Two novel peptides (brevinin1 HYba1 and brevinin1 HYba2) were identified from the skin secretion of the frog Hydrophylax bahuvistara. Amidation proved to be a favorable modification, which enhanced the biological activity of the brevinin1 peptides without affecting its low hemolytic property. These peptides also showed very high cytotoxicity toward Hep 3B cancer cell lines.

    7. Antilipolytic effects of 1,8-naphthyridine derivatives β-adrenoceptor antagonists in rat white adipocytes

      Jalal A. Aljamal and Muwaffag Badawneh

      Version of Record online: 11 FEB 2017 | DOI: 10.1111/cbdd.12933

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      A series of novel 1,8-naphthyridine derivatives variously modified were synthesized and their β-AR blocking activities were determined. Preliminary evidence suggests that the inhibitory effects of the newly synthesized 1,8-naphthyridine analogues 3 and 10 on either alprenolol or isoprenaline-induced lipolysis in rat fat cells may result from inhibition of the low-affinity β3-adrenoceptor.

    8. Biofocussed chemoprospecting: An efficient approach for drug discovery

      Balmukund Sureshkumar Thakkar, Marte Albrigtsen, John Sigurd Svendsen, Jeanette H. Andersen and Richard Alan Engh

      Version of Record online: 7 FEB 2017 | DOI: 10.1111/cbdd.12934

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      “Biofocussed chemoprospecting” represents a hybrid of bioprospecting and a scaffold-based approach and includes property filtering to optimize qualities such as diversity, drug likeness, ease of synthesis, low cost and “bio likeness.” To demonstrate this approach, we generated two dipeptide-based libraries, first as large virtual libraries, followed by focussed synthesis. The resultant libraries demonstrated a hit rate comparable to target-based approaches, with additional potential to identify new targets and mechanisms.

    9. Synthesis and investigation of anticancer potential of radiolabeled naphthalene monoimide bearing imidazolium salt

      Fatma Yurt Lambrecht, Kasim Ocakoglu, Suleyman Gokhan Colak, Onur Alp Ersoz and Ozge Er

      Version of Record online: 7 FEB 2017 | DOI: 10.1111/cbdd.12935

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      In this study, the antitumor potential of 131I-NMI in HEK-293, CaCo-2, MCF-7, and PC-3 cell lines were evaluated with the intracellular uptake studies. 131I-labeled NMI showed significant uptake efficiency in MCF-7 and PC-3 cell lines. Further investigation is also necessary in tumor-bearing animals to clarify the potential of radiolabeled NMI for breast and prostate tumor imaging.

    10. New 3-alkylpyridine marine alkaloid analogues as promising antitumor agents against the CD44+/high/CD24−/low subset of triple-negative breast cancer cell line

      Aline Brito de Lima, Camila de Souza Barbosa, Alessandra Mirtes Marques Neves Gonçalves, Fabio Vieira dos Santos, Gustavo Henrique Ribeiro Viana, Fernando de Pilla Varotti and Luciana Maria Silva

      Version of Record online: 7 FEB 2017 | DOI: 10.1111/cbdd.12923

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      Triple-negative breast cancer (TNBC) is one of the most aggressive cancers in women. In this study, six synthetic 3-alkylpyridine marine alkaloid analogues were tested for cytotoxic activity against TNBC cell line and tumorspheres derived from BT-549.


    1. Synthesis and biological evaluation of N-acylated tyramine sulfamates containing C–F bonds as steroid sulfatase inhibitors

      Mateusz Daśko, Janusz Rachon, Maciej Masłyk, Konrad Kubiński and Sebastian Demkowicz

      Version of Record online: 7 FEB 2017 | DOI: 10.1111/cbdd.12931

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      In this study, we report convenient methods for the synthesis and biological evaluation of N-acylated tyramine sulfamates containing C–F bonds exhibiting STS activity. Additionally, their binding modes have been modeled using docking techniques. New tyramine analogs occurred to be potent STS inhibitors and revealed promising activity in vitro.


    1. Molecular dynamics simulation on the inhibition mechanism of peptide-based inhibitor of islet amyloid polypeptide (IAPP) to islet amyloid polypeptide (IAPP22–28) oligomers

      Shuangyan Zhou, Qianqian Wang, Mengdan Ren, Ai Zhang, Huanxiang Liu and Xiaojun Yao

      Version of Record online: 7 FEB 2017 | DOI: 10.1111/cbdd.12924

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      Molecular dynamics (MD) simulations were performed for NFGAIL oligomers, with the outer edge of the β-sheet in the state of N-methylation at position Gly24 and Ile26 or not, to explore the inhibition mechanism of peptide inhibitor under template induction process.

    2. Synthesis of new pyrazolo[3,4-d]pyrimidine derivatives and evaluation of their anti-inflammatory and anticancer activities

      Heba A. Abd El Razik, Mohamad Mroueh, Wissam H. Faour, Wassim N. Shebaby, Costantine F. Daher, Hayam M. A. Ashour and Hanan M. Ragab

      Version of Record online: 6 FEB 2017 | DOI: 10.1111/cbdd.12929

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      Compounds showing dual anticancer/anti-inflammatory activity are of increasing interest for the treatment of cancer due to the implication of inflammatory mechanisms in most malignancies. This spurred the synthesis of compounds containing a purine character (a scaffold for anticancer drugs) together with a pyrazole moiety (a scaffold for anti-inflammatory agents). Among these compounds, 10b was the most active against all used cell lines.

    3. Structural insight into the antiprion compound inhibition mechanism of native prion folding over misfolding

      Jiwon Choi, Rajiv Gandhi Govindaraj, Jae Wook Hyeon, Kyungro Lee, SongLing Ma, Su Yeon Kim, Jeongmin Lee and Kyoung Tai No

      Version of Record online: 6 FEB 2017 | DOI: 10.1111/cbdd.12916

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      This study demonstrates that our previously discovered small-molecule antiprion compounds and the reported GN8 compound bind to the hotspot region of the prion to maintain its structural stability. Molecular dynamics (MD) simulations and essential dynamics results suggest that the structural dynamics of prion misfolding upon acidic pH were stabilized by the antiprion compounds. These findings will further our knowledge regarding the mechanism underlying the inhibition of prion misfolding by antiprion compounds via the stabilization of misfolding regions.

    4. Simplified, serine-rich theta-defensin analogues as antitumour peptides

      Paulina Strzelecka, Dominika Czaplinska, Rafal Sadej, Anna Wardowska, Michal Pikula and Adam Lesner

      Version of Record online: 6 FEB 2017 | DOI: 10.1111/cbdd.12927

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      θ-defensins are cyclic, host defence peptides with strong antimicrobial activity. In the current study, we aimed to define anticancer potential of θ-defensin analogues. Their serine-containing derivatives were more cytotoxic against breast cancer cells (SKBR3, MDA-MB-231) than against mammary epithelial cells (HB2). Analogues also enhanced the effect of cisplatin and doxorubicin hydrochloride on triple-negative breast cancer cell line (MDA-MB-231).


    1. Emerging biopharmaceuticals from bioactive peptides derived from marine organisms

      Komal Anjum, Syed Qamar Abbas, Najeeb Akhter, Bibi Ibtesam Shagufta, Sayed Asmat Ali Shah and Syed Shams ul Hassan

      Version of Record online: 6 FEB 2017 | DOI: 10.1111/cbdd.12925

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      Marine peptides are a drug treasure house. Marine peptides are one of the major needs for pharmaceutical and nutraceuticals. The mode of action of every biomolecule is one of the basic tools to be known for transformation of bioactive compound into medicines.


    1. Synthesis, cytotoxic activity, and 2D- and 3D-QSAR studies of 19-carboxyl-modified novel isosteviol derivatives as potential anticancer agents

      Cong-Jun Liu, Tao Zhang, Shu-Ling Yu, Xing-Jie Dai, Ya Wu and Jing-Chao Tao

      Version of Record online: 2 FEB 2017 | DOI: 10.1111/cbdd.12910

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      Two series of novel isosteviol-linked acylthiosemicarbazide and oxadiazole were synthesized and screened for their in vitro cytotoxic activities against HCT-116, HGC-27, and JEKO-1 cell lines. On the basis of bioassay results, these derivatives were further investigated by 2D- and 3D-QSAR techniques to afford good predictive models.

    2. Design, synthesis and pharmacophoric model building of new 3-alkoxymethyl/3-phenyl indole-2-carboxamides with potential antiproliferative activity

      Mostafa H. Abdelrahman, Ahmed S. Aboraia, Bahaa G. M. Youssif and Bakheet E. M. Elsadek

      Version of Record online: 31 JAN 2017 | DOI: 10.1111/cbdd.12928

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      1. Novel 3-alkoxymethyl/3-phenyl indole-2-carboxamide derivatives were synthesized and biologically evaluated for anticancer potential.

      2. Pharmacophore study was conducted which indicated that the enhancement of the activity could be achieved through addition of acceptor or donating groups to the already-present indole nucleus.

    3. Comparative molecular field analysis (CoMFA), topomer CoMFA, and hologram QSAR studies on a series of novel HIV-1 protease inhibitors

      Afsane Heidari and Mohammad H. Fatemi

      Version of Record online: 30 JAN 2017 | DOI: 10.1111/cbdd.12917

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      CoMFA, topomer CoMFA and HQSAR studies have been performed on 40 newly synthesized HIV-1 protease inhibitors. A new method for molecular alignment by aid of crystallographic structure was applied. Based on the obtained information, some new inhibitors were suggested.

    4. Mapping of inhibitors and activity data to the human kinome and exploring promiscuity from a ligand and target perspective

      Ye Hu, Ryo Kunimoto and Jürgen Bajorath

      Version of Record online: 30 JAN 2017 | DOI: 10.1111/cbdd.12919

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      Shown is a phylogenetic tree representation of the human kinome onto which activity cliffs (dots) formed by kinase inhibitors are mapped.

    5. Structure-based approaches for the design of benzimidazole-2-carbamate derivatives as tubulin polymerization inhibitors

      Rodrigo Aguayo-Ortiz, Lucia Cano-González, Rafael Castillo, Alicia Hernández-Campos and Laura Dominguez

      Version of Record online: 30 JAN 2017 | DOI: 10.1111/cbdd.12926

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      β-Tubulin isotypes are attractive therapeutic targets for the design of specific anticancer treatments. Herein, we carried out docking and molecular dynamics simulations to determine the binding mode of a series of benzimidazole-2-carbamete derivatives in the βI-, βIII-, and βVI-tubulin isotypes. Finally, we propose novel approaches in the design of BzCs as microtubule polymerization inhibitors with a potential higher affinity to βI and βIII isotypes compared to that to the βVI isotype.

    6. Design, synthesis and in vitro antiplasmodial activity of some bisquinolines against chloroquine-resistant strain

      Srinivasarao Kondaparla, Pooja Agarwal, Kumkum Srivastava, Sunil K. Puri and Seturam B. Katti

      Version of Record online: 27 JAN 2017 | DOI: 10.1111/cbdd.12914

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      Novel side chain-modified bisquinolines were designed and synthesized. We assessed bisquinolines for in vitro antiplasmodial activity. We identified two compounds with enhanced activity than CQ against CQ-resistant strain (K1).

    7. Mannich bases of 1,2,4-triazole-3-thione containing adamantane moiety: Synthesis, preliminary anticancer evaluation, and molecular modeling studies

      Milorad Z. Milošev, Katarina Jakovljević, Milan D. Joksović, Tatjana Stanojković, Ivana Z. Matić, Milka Perović, Vesna Tešić, Selma Kanazir, Milan Mladenović, Marko V. Rodić, Vukadin M. Leovac, Snežana Trifunović and Violeta Marković

      Version of Record online: 25 JAN 2017 | DOI: 10.1111/cbdd.12920

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      Eighteen novel N-Mannich bases of 5-adamantyl-1,2,4-triazole-3-thione were synthesized, and their cytotoxicity was determined against four cancer and MRC-5 non-cancer cells. Most compounds exerted pronounced cancer selectivity, and the Western blot analysis of key proteins involved in apoptosis was performed. The interaction of Bax protein with compound 5b was investigated by means of molecular modeling.

    8. Reactivity of 9-aminoacridine drug quinacrine with glutathione limits its antiprion activity

      Martin Šafařík, Tibor Moško, Zbigniew Zawada, Eva Šafaříková, Martin Dračínský, Karel Holada and Jaroslav Šebestík

      Version of Record online: 25 JAN 2017 | DOI: 10.1111/cbdd.12918

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      Conjugation of quinacrine with glutathione reduces its antiprion activity, which is even enhanced by catalytic decomposition of the conjugate to practically insoluble acridone.

    9. Structure–function relationship of Chikungunya nsP2 protease: A comparative study with papain

      Chandrasekaran Ramakrishnan, Nidamarthi H. V. Kutumbarao, Sivasubramanian Suhitha and Devadasan Velmurugan

      Version of Record online: 5 JAN 2017 | DOI: 10.1111/cbdd.12901

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      Structure–function relationship of Chikungunya virus-nsP2 and papain proteases is studied. Based on the active site similarity, the papain inhibitors were analyzed using in silico studies for their efficacy in binding Chikungunya virus-nsP2. Based on molecular docking and MD simulation results, we report that four papain inhibitors can be good lead compounds for Chikungunya virus-nsP2 protease inhibition.


    1. Breast tumor stroma: A driving force in the development of resistance to therapies

      Maryam Majidinia and Bahman Yousefi

      Version of Record online: 2 JAN 2017 | DOI: 10.1111/cbdd.12893

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      Tumor stroma is a key player in cancer progression and response to therapy. Breast tumor–stromal interaction is a driving force in multidrug-resistant development. A better understanding of the clinically active breast tumor–stromal interactions might help to developing effective therapeutic strategies for patients with drug-resistant status.


    1. CCND1-BCL2 Gene Network: A direct target of Amifostine in human acute megakaryocytic leukemia cells

      Feng Zhang, Bo Yang, Kailiang Zhang, Mei-Ling Hou, Xue-chun Lu and Yu-Xin Li

      Version of Record online: 2 JAN 2017 | DOI: 10.1111/cbdd.12889

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      In order to examine the effects and mechanisms underlying the effects of amifostine on human acute megakaryocytic leukemia, we evaluated the efficacy of amifostine against Dami cells and observed a cell cycle arrest in G2/M phase. Amifostine treatment also induced cell apoptosis of Dami cell which corresponds to formal studies. Through whole-genome microarray and bioinformatics analyses, we found that amifostine affected the gene expression of CCND1, BCL2, CASP3 which revealed the mechanism amifostine acted on Dami cells. Thus, CCND1-BCL2 Gene Network is predicted to be a direct target of amifostine treating human acute magakaryocytic leukemia.

    2. Synthesis and biological evaluation of novel imidazopyrimidin-3-amines as anticancer agents

      Mohammad Mahdavi, Shima Dianat, Behnaz Khavari, Setareh Moghimi, Mohammad Abdollahi, Maliheh Safavi, Arash Mouradzadegun, Sussan Kabudanian Ardestani, Reyhaneh Sabourian, Saeed Emami, Tahmineh Akbarzadeh, Abbas Shafiee and Alireza Foroumadi

      Version of Record online: 29 DEC 2016 | DOI: 10.1111/cbdd.12904

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      A series of imidazo[1,2-a]pyrimidines 6a–o were synthesized as novel anticancer agents. Some of them were more potent than etoposide. Particularly, compound 6c was fivefold more potent than etoposide against T-47D cells (IC50 = 6.72 μm).

  18. Research Articles

    1. You have full text access to this OnlineOpen article
      Gemcitabine-(5′-phosphoramidate)-[anti-IGF-1R]: molecular design, synthetic organic chemistry reactions, and antineoplastic cytotoxic potency in populations of pulmonary adenocarcinoma (A549)

      Cody P. Coyne and Lakshmi Narayanan

      Version of Record online: 20 DEC 2016 | DOI: 10.1111/cbdd.12845

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      A multistage organic chemistry reaction strategy was utilized to synthesize gemcitabine-(5′-phosphoramidate)-[anti-IGF-1R] that possesses properties of selective ‘targeted’ delivery and antineoplastic cytotoxic potency. The flexible non-dedicated synthesis method is rapid and efficient with minimal or no side reactions. Attributes of gemcitabine-(5′-phosphoramidate)-[anti-IGF-1R] include a high gemcitabine molar incorporation index, ability to effectively evoke cytotoxic antineoplastic activity, potential to provide a wide margin of safety, and an ability to evoke greater levels of selective ‘targeted’ antineoplastic cytotoxicity in vivo through activation of antibody-dependent cell cytotoxicity, complement pathways, and opsonization.

    2. ENRI: A tool for selecting structure-based virtual screening target conformations

      Rahmad Akbar, Siti Azma Jusoh, Rommie E. Amaro and Volkhard Helms

      Version of Record online: 20 DEC 2016 | DOI: 10.1111/cbdd.12900

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      Selecting optimal SBVS targets remains a challenging undertaking. We present here a method to extract optimal targets for SBVS experiments. Among seven nuclear receptors, the method was able to identify high-enrichment targets in six of seven nuclear receptors. The best performing target identified by our method yielded a twofold enrichment over the corresponding experimentally determined conformation.

    3. Protective effects of β-sheet breaker α/β-hybrid peptide against amyloid β-induced neuronal apoptosis in vitro

      Sourav Kumar, Ashim Paul, Sourav Kalita, Anup Kumar Ghosh, Bhubaneswar Mandal and Amal Chandra Mondal

      Version of Record online: 20 DEC 2016 | DOI: 10.1111/cbdd.12912

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      This study demonstrated that BSBHp could effectively ameliorate Aβ40-induced oxidative stress and apoptosis in human neuroblastoma SF-SY5Y cell in vitro by inhibiting Aβ40 aggregation. This is the first report to demonstrate that BSBHp has the neuroprotective effects against Aβ-induced neurotoxicity in SH-SY5Y cells. The protection effects of BSBHp against neuronal atrophy may help to provide the pharmacological basis for the treatment of Alzheimer's disease.

    4. Synthesis and anticholinesterase activity of new substituted benzo[d]oxazole-based derivatives

      Behjat Pouramiri, Setareh Moghimi, Mohammad Mahdavi, Hamid Nadri, Alireza Moradi, Esmat Tavakolinejad-Kermani, Loghman Firoozpour, Ali Asadipour and Alireza Foroumadi

      Version of Record online: 11 DEC 2016 | DOI: 10.1111/cbdd.12902

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      A series of novel benzo[d]oxazole-based derivatives were synthesized as novel anticholinesterase agents. The inhibitory activities against AChE and BChE were more potent than donepezil. 2-(4-((Piperidin-1-yl)methyl)phenyl)benzo[d]oxazole exhibited dual inhibitory activity against BChE (two times stronger than reference drug) and moderate activity against AChE.

  19. Review Articles

    1. Structural and biochemical insights into the allosteric activation mechanism of AMP-activated protein kinase

      Jin Li, Shuying Li, Fengzhong Wang and Fengjiao Xin

      Version of Record online: 9 DEC 2016 | DOI: 10.1111/cbdd.12897

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      AMP-activated protein kinase (AMPK) is widely studied as a potential drug target for treatment of type 2 diabetes (T2D), cancers, and cardiovascular diseases. Its phosphorylation in α-Thr172 by upstream kinases is crucial for basal activity and AMP, and its analogues binding to γ subunit causes further allosteric activation. The review summarizes the domain constitutions of mammalian AMPK and then systematically describes its allosteric activation mechanism from a structural and biochemical view.

  20. Research Articles

    1. Identification and structure–activity relationship of purine derivatives as novel MTH1 inhibitors

      Ashutosh Kumar, Tatsuro Kawamura, Makoto Kawatani, Hiroyuki Osada and Kam Y. J. Zhang

      Version of Record online: 7 DEC 2016 | DOI: 10.1111/cbdd.12909

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      A series of compounds belonging to the purine scaffold have been screened for MTH1 inhibitory activity, and several new inhibitors with potency in the submicromolar range have been discovered. The structure activity relationship of these compounds has been analyzed, and their associated binding modes to MTH1 have been predicted using molecular docking. These studies have provided insights for the development of highly potent MTH1 inhibitors.

    2. Theoretical studies on the selective mechanisms of GSK3β and CDK2 by molecular dynamics simulations and free energy calculations

      Sufang Zhao, Jingyu Zhu, Lei Xu and Jian Jin

      Version of Record online: 7 DEC 2016 | DOI: 10.1111/cbdd.12907

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      A computational strategy, which combines molecular docking, molecular dynamics simulations, free energy calculations and umbrella sampling simulations, was employed to explore the binding mechanisms of two selective inhibitors to GSK3β and CDK2. The inhibitor specificity between GSK3β and CDK2 is determined by the additive contributions of multiple amino acids.

    3. Downregulation of MicroRNA-320d predicts poor overall survival and promotes the growth and invasive abilities in glioma

      Chong-Zhen Qin, Qiao-Li Lv, Yan-Tao Yang, Jing-Min Zhang, Xiao-Jian Zhang and Hong-Hao Zhou

      Version of Record online: 5 DEC 2016 | DOI: 10.1111/cbdd.12906

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      This study is the first to demonstrate that miR-320d expression was significantly decreased in glioma tissues and cell lines. Mechanism analysis showed that overexpression of miR-320d could significantly suppress cell growth, migration and invasion, and induced cell apoptosis, cell cycle at G0/G1 arrest, as well as invasion-related molecules in U87 and U251 cell lines, indicating that miR-320d may serve as a prognostic and therapy biomarker in glioma.

    4. Graph theoretical analysis, insilico modeling, design, and synthesis of compounds containing benzimidazole skeleton as antidepressant agents

      Panneerselvam Theivendren, Arumugam Subramanian, Indhumathy Murugan, Shrinivas D. Joshi and Uttam A. More

      Version of Record online: 2 DEC 2016 | DOI: 10.1111/cbdd.12894

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      The 4-(1H-benzo[d]imidazol-2-yl)-N-(substituted phenyl)-4-oxobutanamide (3a–j) have been synthesized to meet the structural requirements essential for antidepressant activity.

    5. Design, synthesis, and biological evaluation of pyrimidine derivatives as potential inhibitors of human calcium/calmodulin-dependent protein kinase IV

      Ehtesham Jameel, Huma Naz, Parvez Khan, Mohd. Tarique, Jitendra Kumar, Syed Mumtazuddin, Shahzaib Ahamad, Asimul Islam, Faizan Ahmad, Nasimul Hoda and Md. Imtaiyaz Hassan

      Version of Record online: 2 DEC 2016 | DOI: 10.1111/cbdd.12898

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      Seven molecules were successfully synthesized having pyrimidine scaffolds. Compound 1 is showing best binding affinity to calcium/calmodulin-dependent protein kinase IV. Compound 1 has best IC50 value, and anticancer properties.

    6. Synthesis and preliminary evaluation of a 99mTc-labeled folate-PAMAM dendrimer for FR imaging

      Manli Song, Zhide Guo, Mengna Gao, Changrong Shi, Duo Xu, Linyi You, Xiaowei Wu, Xinhui Su, Rongqiang Zhuang, Weimin Pan, Ting Liu and Xianzhong Zhang

      Version of Record online: 2 DEC 2016 | DOI: 10.1111/cbdd.12899

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      A FA-conjugated PAMAM dendrimer was synthesized and radiolabeled with 99mTc successfully. Our results show that this folate-PAMAM dendrimer has the potential as a non-invasive radioactive diagnostic imaging agent for the detection of FR-positive cancers. Furthermore, this versatile strategy can be extended to sensitive multimodal imaging and/or enhanced therapy of different cancers.

    7. New insights into the structure of the trace amine-associated receptor 2: Homology modelling studies exploring the binding mode of 3-iodothyronamine

      Elena Cichero and Michele Tonelli

      Version of Record online: 29 NOV 2016 | DOI: 10.1111/cbdd.12903

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      mTAAR2 and hTAAR2 homology models have been built for the first time. At present, only 3-iodothyronamine (T1AM) acts as TAAR2 ligand, being also able to bind other TAARs, making the discovery of selective compounds an urgent need to derive efficient tools for studying this family of receptors. The two models have been compared with those we previously built about the mTAAR1 and hTAAR1 receptors. New insights guiding for species specificity and selectivity between the TAAR1 and TAAR2 receptors have been derived.

    8. 1H-1,2,3-triazole-tethered uracil-ferrocene and uracil-ferrocenylchalcone conjugates: Synthesis and antitubercular evaluation

      Amandeep Singh, Christophe Biot, Albertus Viljoen, Christian Dupont, Laurent Kremer, Kewal Kumar and Vipan Kumar

      Version of Record online: 29 NOV 2016 | DOI: 10.1111/cbdd.12908

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      Synthesis and antitubercular evaluation of 1H-1,2,3-triazole-tethered uracil-ferrocene and uracil-ferrocenylchalcone conjugates.

    9. Designed inhibitor for nuclear localization signal of polo-like kinase 1 induces mitotic arrest

      Fangjin Chen, Xiaolong Zhuo, Tan Qin, Xiao Guo, Chuanmao Zhang and Luhua Lai

      Version of Record online: 24 NOV 2016 | DOI: 10.1111/cbdd.12896

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      Inhibitor target the nuclear localization signal (NLS) of polo-like kinase 1 (Plk1) was rationally designed through virtual screening. The NLS inhibitor D110 strongly inhibits the activity of Plk1 with the IC50 of 85 nm. D110 inhibits the translocation of Plk1 into nucleus in HeLa cells during interphase.

    10. Microsecond molecular dynamics simulations provide insight into the ATP-competitive inhibitor-induced allosteric protection of Akt kinase phosphorylation

      Linkai Mou, Tongwei Cui, Weiguang Liu, Hong Zhang, Zhanxiu Cai, Shaoyong Lu and Guojun Gao

      Version of Record online: 24 NOV 2016 | DOI: 10.1111/cbdd.12895

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      Molecular dynamics simulations were performed to illustrate the molecular mechanism for allosteric regulation of Akt1 kinase phosphorylation by binding of ATP-competitive inhibitor GDC-0068 to the ATP-binding site. We propose a potential mechanism and identify a communication pathway from GDC-0068 to pT308 in Akt1. This result yields important new insights into the molecular mechanism of allosteric regulation of Akt kinase activity.

    11. 5-Amino-3-methyl-4-isoxazolecarboxylic acid hydrazide derivatives with in vitro immunomodulatory activities

      Angelika Drynda, Bożena Obmińska-Mrukowicz, Ewa Zaczyńska, Michał Zimecki, Iwona Kochanowska, Stanisław Ryng and Marcin Mączyński

      Version of Record online: 24 NOV 2016 | DOI: 10.1111/cbdd.12892

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      Two of the most active isoxazole derivatives were chosen from the obtained series of 5-amino-3-methyl-4-isoxazolecarboxylic acid semicarbazides and thiosemicarbazides. Immunomodulatory activity in primary cell cultures of ‘old’ and ‘young’ mice and possible mechanism of action is reported. 06K derivative showed different, immunosuppressive characteristics than the parent compound, while 01K compound exhibited promising regulatory activity in cells isolated from ‘old’ mice.

  21. Research Letters

    1. Synthesis of new arylisoxazole–oxindole conjugates as potent antiproliferative agents

      Gajjela Bharath Kumar, Syed Nasir Abbas Bukhari and Hua-Li Qin

      Version of Record online: 19 NOV 2016 | DOI: 10.1111/cbdd.12884

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      Development of an efficient and versatile convergent synthetic procedure for the preparation of a new series of arylisoxazole–oxindole conjugates. Compounds with methoxy substituent on D ring exhibited better cytotoxic effect against all the cell lines than the compounds bearing nitro substituent in the same ring.

  22. Research Articles

    1. Validation of flavonoids as potential dipeptidyl peptidase III inhibitors: Experimental and computational approach

      Dejan Agić, Hrvoje Brkić, Sanja Tomić, Zrinka Karačić, Marija Špoljarević, Miroslav Lisjak, Drago Bešlo and Marija Abramić

      Version of Record online: 19 NOV 2016 | DOI: 10.1111/cbdd.12887

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      Fifteen flavonoids were studied for their inhibitory activity against human dipeptidyl peptidase III (hDPP III) combining an in vitro assay with an in silico molecular modeling study. All analyzed flavonoids showed inhibitory effects against hDPP III; 3D QSAR studies indicate that the presence of hydrophilic regions at a flavonoid molecule increases its inhibitory activity while molecular dynamics results clearly provide valuable information explaining the importance of flavonoid hydroxyl groups in the mechanism for the binding pattern at the active site of hDPP III.

    2. Synthesis and evaluation of novel amonafide–polyamine conjugates as anticancer agents

      Yuxia Wang, Jianying Zhang, Meng Li, Ming Li, Songqiang Xie and Chaojie Wang

      Version of Record online: 19 NOV 2016 | DOI: 10.1111/cbdd.12888

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      The in vitro trials revealed that the presence of aspirin elevated the potency of 6k against tumor cells. The in vivo trials on three H22 tumor transplant models demonstrated that the combination of 6k and aspirin markedly improved the efficacy in terms of inhibitive effect, pulmonary metastasis, and extension of the life span. More importantly, the combination of 6k and aspirin displayed the reduced side effects compared to that of amonafide.

    3. Positive cooperative regulation of double binding sites for human acetylcholinesterase

      Hao Liu, Wei Ye and Hai-Feng Chen

      Version of Record online: 19 NOV 2016 | DOI: 10.1111/cbdd.12891

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      Dynamics correlation network of hAChE/TZ5 includes hub nodes.

  23. Research Letter

    1. Synthesis and biological evaluation of 1, 2, 4-oxadiazole derivatives as novel GPR119 agonists

      Suhong Fu, Wei Xiang, Jinying Chen, Liang Ma and Lijuan Chen

      Version of Record online: 19 NOV 2016 | DOI: 10.1111/cbdd.12890

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      Twenty-five 1, 2, 4-oxadiazol derivatives were evaluated their abilities in GPR119-transfected HEK293T cells by the assay of cAMP concentration. SAR study indicated that six-membered ring containing two nitrogen atoms was favorable for potency. All compounds showed acceptable agonistic effects on GPR119. Among these compounds, compound 4p showed highly potent agonistic activity (EC50 = 20.6 nm).

  24. Research Articles

    1. Computed insight into a peptide inhibitor preventing the induced fit mechanism of MurA enzyme from Pseudomonas aeruginosa

      Anderson H. Lima, Alberto M. dos Santos, Cláudio Nahum Alves and Jerônimo Lameira

      Version of Record online: 16 NOV 2016 | DOI: 10.1111/cbdd.12882

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      In this article, theoretical simulations were used to analyze, for the first time, the interaction of the PEP 1354 peptide with MurA enzyme from Pseudomonas aeruginosa. Our modeling results suggest that the peptide binds to the same active site of the natural substrate UDP-N-acetylglucosamine. Additionally, the MurA–peptide complex reveals that the peptide seems to act preventing the closure of the loop Pro114-123 and consequently, the open–closed transition of MurA structure.

    2. The small-molecule 3G11 inhibits HIV-1 reverse transcription

      Silvana Opp, Thomas Fricke, Caitlin Shepard, Dmytro Kovalskyy, Akash Bhattacharya, Frank Herkules, Dmitri N. Ivanov, Baek Kim, Jose Valle-Casuso and Felipe Diaz-Griffero

      Version of Record online: 15 NOV 2016 | DOI: 10.1111/cbdd.12886

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      3G11 binds to capsid and blocks HIV-1 reverse transcription during infection.

    3. Structure–activity relationship of caffeic acid phenethyl ester analogs as new 5-lipoxygenase inhibitors

      Jérémie A. Doiron, Luc M. Leblanc, Martin J. G. Hébert, Natalie A. Levesque, Aurélie F. Paré, Jacques Jean-François, Marc Cormier, Marc E. Surette and Mohamed Touaibia

      Version of Record online: 15 NOV 2016 | DOI: 10.1111/cbdd.12874

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      A series of caffeic acid phenethyl ester (CAPE) analogs was synthesized and screened in vitro for their ability to inhibit 5-lipoxygenase (5-LO) along with 2,2-diphenyl-1-picrylhydrazyl free radical scavenging assay. Many screened compounds outperformed CAPE in concentration-dependent assays on HEK293 cell models and human polymorphonuclear leukocytes, caffeoyl ethers 7a–b being roughly sevenfold and 16-fold more potent than Zileuton, the only 5-LO inhibitor currently approved for human therapy.

    4. Anionic chlorido(triphenyl)tin(IV) bearing N-phthaloylglycinato or 1,2,4-benzenetricarboxylato 1,2-anhydride ligands: potential cytotoxic and apoptosis-inducing agents against several types of cancer

      Denise Hübner, Milena R. Kaluđerović, Santiago Gómez-Ruiz and Goran N. Kaluđerović

      Version of Record online: 15 NOV 2016 | DOI: 10.1111/cbdd.12885

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      Two ionic triphenyltin(IV) chloride carboxylate compounds (N-phthaloylglycine, 1; 1,2,4-benzenetricarboxylate 1,2-anhydride ligand, 2) were tested for the in vitro activity against 518A2 (melanoma), FaDu (head and neck carcinoma), HT-29 (colon cancer), MCF-7 (breast carcinoma), and SW1736 (thyroid cancer) cell lines. Both organotin(IV) compounds showed potent cytotoxic and apoptotic properties against tested cancer cell lines.

    5. Synthesis and preliminary evaluation of a 18F-labeled ethisterone derivative [18F]EAEF for progesterone receptor targeting

      Xiaowei Wu, Linyi You, Deliang Zhang, Mengna Gao, Zijing Li, Duo Xu, Pu Zhang, Lumei Huang, Rongqiang Zhuang, Hua Wu and Xianzhong Zhang

      Version of Record online: 15 NOV 2016 | DOI: 10.1111/cbdd.12878

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      A novel ethisterone derivative-based probe [18F]EAEF was developed for positron emission tomography imaging of progesterone receptor. High uptakes in PR-positive tissues (breast tumor, uterus, and ovary) and good target-to-background ratios were observed in tumor bearing mice, indicating that [18F]EAEF might be a promising candidate for PR-positive breast cancer diagnosis with positron emission tomography imaging.

    6. Preparation, characterization, and in vitro evaluation of bleomycin-containing nanoliposomes

      Mohsen Chiani, Mohammad Ali Shokrgozar, Kayhan Azadmanesh, Dariush Norouzian, Mohammad Reza Mehrabi, Aazam Najmafshar and Azim Akbarzadeh

      Version of Record online: 10 NOV 2016 | DOI: 10.1111/cbdd.12869

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      Bleomycin-containing nanoliposomes were successfully prepared and characterized. PEG-nLip-BLM showed excellent stability, high loading efficacy, and improved cytotoxicity against LLC1 cells and good retention capability compare to nLip-BLM and free drug. These findings will facilitate the production of a new formulation of BLM with long-acting action and more efficient anticancer activity for testing on human subjects.

    7. Design, synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives as potential antitumor candidate

      Panhu Zhu, Wenfeng Ye, Jiaming Li, Yanchun Zhang, Weijun Huang, Mohan Cheng, Yujun Wang, Yang Zhang, Huicai Liu and Jian Zuo

      Version of Record online: 10 NOV 2016 | DOI: 10.1111/cbdd.12873

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      A novel class of tetrahydroisoquinoline derivatives was designed and synthesized. The antiproliferative activities of all the target compounds on HUVEC, MCF-7, and HT-29 were evaluated, and 17d and 17e exhibited outstanding activity on MCF-7. Our research confirmed that 17d and 17e were better inhibitor of tubulin polymerization. In addition, compounds 17d and 17e demonstrated potent in vivo efficacy. In summary, these findings suggest that 17d and 17e are promising novel agents for the potential treatment of cancer.

    8. Clarifying binding difference of ATP and ADP to extracellular signal-regulated kinase 2 by using molecular dynamics simulations

      Jianzhong Chen

      Version of Record online: 10 NOV 2016 | DOI: 10.1111/cbdd.12877

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      Insight into the binding difference of ADP and ATP to extracellular signal-regulated kinase 2 (ERK2) is significant for designs of potent inhibitors targeting ERK2.

  25. Research Letter

    1. Identification of ginkgolide targets in brain by photoaffinity labeling

      Akira Kawamura, Ilyas Washington, Doina M. Mihai, Francesca Bartolini, Gregg G. Gundersen, Milica Tesic Mark and Koji Nakanishi

      Version of Record online: 10 NOV 2016 | DOI: 10.1111/cbdd.12883

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      Photoactive analogs of ginkgolide selectively photolabeled α-tubulin in bovine hippocampus homogenate. Furthermore, ginkgolides exhibited unique effects on tubulin biology, including inhibition of microtubule detyrosination. The finding heralds a new chapter of the research on ginkgolides whose biological potential is yet to be discovered.

  26. Research Articles

    1. Discovery of selective protein arginine methyltransferase 5 inhibitors and biological evaluations

      Sen Ji, Shuang Ma, Wen-Jing Wang, Shen-Zhen Huang, Tian-qi Wang, Rong Xiang, Yi-Guo Hu, Qiang Chen, Lin-Li Li and Sheng-Yong Yang

      Version of Record online: 10 NOV 2016 | DOI: 10.1111/cbdd.12881

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      In this investigation, we discovered new potent PRMT5 inhibitors with the aid of computer-aided virtual screening and structure–activity relationship analysis. P5i-6 could be used as a chemical probe to investigate new functions of PRMT5 in biology and also served as a good lead compound for the development of new PRMT5-targeting therapeutic agents.

    2. 99mTc-anti-epidermal growth factor receptor nanobody for tumor imaging

      Majid Piramoon, Seyed Jalal Hosseinimehr, Kobra Omidfar, Zohreh Noaparast and Seyed Mohammad Abedi

      Version of Record online: 5 NOV 2016 | DOI: 10.1111/cbdd.12871

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      This study described the preparation and radiolabeling of anti-EGFR nanobody, OA-cb6. The nanobody was labeled using 99mTc-tricarbonyl. Results showed that radioconjugate had fast blood clearance and a favorable tumor uptake in A431-xenografted nude mice.

    3. Synthesis and evaluation of anti-inflammatory properties of silver nanoparticle suspensions in experimental colitis in mice

      Krzysztof Siczek, Hubert Zatorski, Anna Chmielowiec-Korzeniowska, Jolanta Pulit-Prociak, Magdalena Śmiech, Radzisław Kordek, Leszek Tymczyna, Marcin Banach and Jakub Fichna

      Version of Record online: 2 NOV 2016 | DOI: 10.1111/cbdd.12876

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      Two silver nanoparticle aqueous solutions NanoAg1 and NanoAg2 varying in size and shape were developed by one-step chemical reduction with the involvement of tannic acid. NanoAg1 and NanoAg2 significantly ameliorated colitis in mouse models of colonic inflammation mimicking human ulcerative colitis and Crohn's disease. The anti-inflammatory effect was dependent on the shape and diameter of silver nanoparticles. Our study shows that NanoAg1 and NanoAg2 have the potential to become valuable agents for the treatment of IBD.

    4. In silico prediction and in vitro and in vivo validation of acaricide fluazuron as a potential inhibitor of FGFR3 and a candidate anticancer drug for bladder carcinoma

      Kunbin Ke, Hongjian Li, Hong Yao, Xi-Nan Shi, Chao Dong, Ying Zhu, Xu Liu, Ling Li, Kwong-Sak Leung, Man-Hon Wong, Xiao-Dong Liu, Hsiang-fu Kung and Marie Chia-mi Lin

      Version of Record online: 2 NOV 2016 | DOI: 10.1111/cbdd.12872

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      We utilized the free and open-source protein–ligand docking software idock to prospectively identify potential inhibitors of FGFR3. The fluazuron exhibited the highest anticancer effect in human bladder carcinoma cell lines, RT112 and RT4, and inhibited the FGFR3 signaling pathway in vitro. Oral treatment with fluazuron significantly inhibited tumor growth in BALB/C nude mice. These results suggested for the first time that fluazuron is a potential inhibitor of FGFR3 and a candidate anticancer drug for the treatment of bladder cancer.

    5. Synthesis of honokiol analogues and evaluation of their modulating action on VEGF protein secretion and telomerase-related gene expressions

      María Sánchez-Peris, Juan Murga, Eva Falomir, Miguel Carda and Juan Alberto Marco

      Version of Record online: 2 NOV 2016 | DOI: 10.1111/cbdd.12880

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      A group of 36 biphenyl derivatives structurally related to honokiol were synthesized by means of Suzuki coupling reactions. Their cytotoxicities were evaluated and compared to that of honokiol. Some of the compounds were then evaluated for their ability to downregulate the secretion of the VEGF protein and the expression of the VEGF, hTERT, and c-Myc genes; the two latter involved in the activation of telomerase in tumoral cells.

    6. Synthesis and cytotoxic activity of certain benzothiazole derivatives against human MCF-7 cancer cell line

      Lamia W. Mohamed, Azza T. Taher, Ghada S. Rady, Mamdouh M. Ali and Abeer E. Mahmoud

      Version of Record online: 2 NOV 2016 | DOI: 10.1111/cbdd.12879

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      A new series of benzothiazole has been synthesized as cytotoxic agents. The new derivatives were tested for their cytotoxic activity toward the human breast cancer MCF-7 cell line against cisplatin as the reference drug. Many derivatives revealed good cytotoxic effect, whereas four of them, 4, 5c, 5d, and 6b, were more potent than cisplatin, with IC50 values being 8.64, 7.39, 7.56, and 5.15 µm compared to 13.33 µm of cisplatin.

    7. In vitro evaluation of apoptotic effect of bis(acetylacetonato-k2 O,O′)(1,10-phenanthroline-k2 N,N′)Zn(II) complex

      Cristina Trejo-Solis, Mayra A. Alvarez-Lemus, Dolores Jiménez-Farfán, Isabel Anaya-Rubio, Rosendo López-González, Guadalupe Palencia, Dora M. Frías-Márquez, Gerardo González-García, Carmen Rubio-Osornio, Minerva Calvillo-Velasco and Guadalupe Márquez-Chablé

      Version of Record online: 2 NOV 2016 | DOI: 10.1111/cbdd.12875

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      Antiproliferative and apoptotic effect of bis(acetylacetonate-k2 O,O)(1,10-phenanthroline-k2 N,N)Zn(II) or Zn(acac)2(phen) complex was determined in several cancer cell lines. Acetylacetonate and phenanthroline ligands promote selectivity toward cancer cells.

    8. ‘Click’-xylosides as initiators of the biosynthesis of glycosaminoglycans: Comparison of mono-xylosides with xylobiosides

      Aurore Chatron-Colliet, Charlotte Brusa, Isabelle Bertin-Jung, Sandrine Gulberti, Nick Ramalanjaona, Sylvie Fournel-Gigleux, Stéphane Brézillon, Murielle Muzard, Richard Plantier-Royon, Caroline Rémond and Yanusz Wegrowski

      Version of Record online: 2 NOV 2016 | DOI: 10.1111/cbdd.12865

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      ‘Click’-xylosides displayed a better activity as primers of GAG biosynthesis than the corresponding xylobiosides with a better cellular uptake and affinity of β4GalT7.

    9. Construction of explicit models to correlate the structure and the inhibitory activity of aldose reductase: Flavonoids and sulfonyl-pyridazinones as inhibitors

      Fengchao Cui, Lunyang Liu, Haifeng Tang, Kecheng Yang and Yunqi Li

      Version of Record online: 31 OCT 2016 | DOI: 10.1111/cbdd.12868

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      Two explicit models are constructed to correlate the binding energies with the AR inhibitory activities of flavonoids and sulfonyl-pyridazinones. The introduction of multiple complex states can help the clarification of structure–activity relationship. The contribution from each energy term and the favorite of protein–inhibitor complex states are present. The accommodation of alternative binding sites for identical inhibitors at the presence/absence of coenzyme and substrate is observed.

  27. Review Articles

    1. Ebola virus: A gap in drug design and discovery - experimental and computational perspective

      Marissa Balmith, Mbuso Faya and Mahmoud E. S. Soliman

      Version of Record online: 31 OCT 2016 | DOI: 10.1111/cbdd.12870

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      There is a huge gap in literature with regard to the guidelines toward the discovery of anti-Ebola inhibitors. This review focuses on inhibitors of the Ebola virus, drug repurposing to combat Ebola, as well as in silico methods which study drug–target interactions. This report will be immensely valuable toward the design of Ebola virus inhibitors.

  28. Research Letters

    1. Berberine-loaded Janus nanocarriers for magnetic field-enhanced therapy against hepatocellular carcinoma

      Zheng Wang, Ying-shuai Wang, Zhi-min Chang, Li Li, Yi Zhang, Meng-meng Lu, Xiao Zheng, Mingqiang Li, Dan Shao, Jing Li, Li Chen and Wen-fei Dong

      Version of Record online: 26 OCT 2016 | DOI: 10.1111/cbdd.12866

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      We have developed Janus magnetic mesoporous silica nanoparticles (Fe3O4-mSiO2 NPs) with exhibited uniform morphology, good superparamagnetic properties, high drug-loading amounts, superior endocytic ability, pH-responsive drug release and low cytotoxicity for berberine (Ber) delivery. An external magnetic field could significantly improve antitumor activity of Ber-loaded Fe3O4-mSiO2 NPs through enhancing berberine internalization. Janus nanocarriers driven by the magnetic field may provide an effective and safe way to facilitate clinical use of berberine against hepatocellular carcinoma.

  29. Research Articles

    1. Isonicotinohydrazones as inhibitors of alkaline phosphatase and ecto-5′-nucleotidase

      Pervaiz Ali Channar, Syed Jawad Ali Shah, Sidra Hassan, Zaib un Nisa, Joanna Lecka, Jean Sévigny, Jürgen Bajorath, Aamer Saeed and Jamshed Iqbal

      Version of Record online: 26 OCT 2016 | DOI: 10.1111/cbdd.12861

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      Putative binding mode of compound 3j (colored green) in the human e5′NT crystal structure (brown) and 3g (magenta) in the rat e5′NT homology model (cyan).

    2. Synthesis and biological evaluation of novel dasatinib analogues as potent DDR1 and DDR2 kinase inhibitors

      Lu Liu, Muzammal Hussain, Jinfeng Luo, Anna Duan, Chaonan Chen, Zhengchao Tu and Jiancun Zhang

      Version of Record online: 17 OCT 2016 | DOI: 10.1111/cbdd.12863

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      Novel dasatinib analogues as DDR1 and DDR2 inhibitors were designed and synthesized. Some of the compounds showed the potent inhibitory activities against both DDR1 and DDR2, as well as anticancer activity in low nanomolar range against K562 cell line; especially, compound 3j demonstrated significantly better inhibitory potency than the parental dasatinib against both DDRs and also demonstrated the potent inhibitory activity against K562 cell lines.

    3. Design and characterization of short hybrid antimicrobial peptides from pEM-2, mastoparan-VT1, and mastoparan-B

      Hamed Memariani, Delavar Shahbazzadeh, Reza Ranjbar, Mahdi Behdani, Mojtaba Memariani and Kamran Pooshang Bagheri

      Version of Record online: 5 OCT 2016 | DOI: 10.1111/cbdd.12864

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      In this study, for the first time, a series of short hybrid antimicrobial peptides (SHAMPs) combined by different fragments of venom-derived α-helical antimicrobial peptides pEM-2, mastoparan-VT1 (MP-VT1), and mastoparan-B (MP-B) were designed. All peptides had membrane-disrupting activity in a time-dependent manner. Collectively, current study highlights the potential for rational design of improved SHAMPs such as PV3 that was an ideal candidate for further assessment with the ultimate purpose of development of effective antimicrobial agents.

    4. Synthesis, in vitro evaluation and molecular docking studies of novel coumarin-isatin derivatives as α-glucosidase inhibitors

      Guangcheng Wang, Jing Wang, Dianxiong He, Xin Li, Juan Li and Zhiyun Peng

      Version of Record online: 5 OCT 2016 | DOI: 10.1111/cbdd.12867

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      A new series of coumarin-isatin derivatives were synthesized and evaluated for their α-glucosidase inhibitory activity. Among the newly derivatives, compound 5p was found to be the most active compound with IC50 values of 2.56 ± 0.08 μm. Molecular docking analysis revealed the existence of hydrophobic and hydrogen interactions between compound 5p and the active site of α-glucosidase.


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