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Chemical Biology & Drug Design

Amol D Sonawane, Navnath D Rode, Laxman Nawale, Rohini R Joshi, Ramesh A Joshi, Anjali P Likhite, Dhiman Sarkar
Resistance among dormant mycobacteria leading to multi-drug resistant (MDR) and extremely-drug resistant(XDR) tuberculosis is one of the major threats. Hence, a series of 1,2,4-triazole-3-thione and 1,3,4-oxadiazole-2-thione derivatives (4a-5c) have been synthesised and screened for their anti-tubercular activity against Mycobacterium tuberculosis H37Ra (H37Ra). Thetriazolethiones4b and 4v showed high anti-tubercular activity (both MIC and IC50 ) against the dormant H37Ra by in vitro and ex vivo. They were shown to have more specificity towards mycobacteria than other gram-negative and gram-positive pathogenic bacteria...
January 12, 2017: Chemical Biology & Drug Design
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, Maria Laura Bolognesi
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has recently gained attention as an anti-protozoan and anti-cancer drug target. We have previously identified 2-phenoxy-1,4-naphthoquinone as an inhibitor of both Trypanosoma brucei and human GAPDH. Herein, through multiple chemical, biochemical, and biological studies, and through the design of analogs, we confirmed the formation of a covalent adduct, we clarified the inhibition mechanism and we demonstrated antitrypanosomal, antiplasmodial and cytotoxic activities in cell cultures...
January 12, 2017: Chemical Biology & Drug Design
Zelal Adiguzel, Seniz Ozalp-Yaman, Gokalp Celik, Safia Salem, Tugba Bagci-Onder, Filiz Senbabaoglu, Yüksel Cetin, Ceyda Acilan
Here, we describe the characteristics of a Pt-blue complex [Pt4 (2-atp)8 (H2 O)(OH)] (2-atp: 2-aminothiophenol) as a prodrug for its DNA-binding properties and its use in cancer therapy. The nature of the interaction between the Pt-blue complex and DNA was evaluated based on spectroscopic measurements, the electronic absorption spectra, thermal behavior, viscosity, fluorometric titration and agarose gel electrophoresis. Our results suggested that the compound was able to partially intercalate DNA and appeared to induce both single and double stranded breaks (DBS) on DNA in vitro, but no DSBs in cells...
January 12, 2017: Chemical Biology & Drug Design
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, Yong-Hua Yang
The advancement of cancer fighting drugs has never been a simple linear process. Those drugs design professionals begin to find inspiration from the nature after failing to find the ideal products by creative drugs design and high-throughput screening. To obtain new molecules for inhibiting tubulin, podophyllotoxin was adopted as the leading compound and 1,3,4-oxadiazole was brought in to the C-4 site of podophyllotoxin in this research. A series of seventeen podophyllotoxin derived esters have been achieved and then evaluated their antitumor activities against four different cancer cell lines: A549, MCF-7, HepG2 and HeLa...
January 12, 2017: Chemical Biology & Drug Design
Gopalakrishnan Chandrasekaran, Eu Chang Hwang, Taek Won Kang, Dongdeuk Kwon, Kwangsung Park, Je-Jung Lee, Vinoth-Kumar Lakshmanan
The human HOXB13 gene encodes a transcription factor containing a DNA-binding homeobox domain and a HoxA13 N-terminal domain. SNP is considered to be the primary genetic cause for hereditary prostate cancer (PCa). The study of functional nsSNP's would give an insight into the exact cause underlying the onset of hereditary PCa and possible methodologies for the cure or early management of the disease. Several in silico tools were used to screen and map the deleterious nsSNP's to the protein structure for predicting the structure-function effects...
January 10, 2017: Chemical Biology & Drug Design
T V Vineeth Kumar, R Asha, G Shyla, Sanil George
Two novel peptides (brevinin1 HYba1 and brevinin1 HYba2) were identified from the skin secretion of the frog Hydrophylax bahuvistara, endemic to Western Ghats, India, and their amino acid sequences were confirmed using cDNA cloning and LC/MS/MS. Antibacterial, hemolytic and cytotoxic activities of brevinin1 peptides and their synthetic analogs (amidated C-terminus) were investigated and compared. All the peptides except the acidic forms showed antibacterial activity against all tested Gram -positive and negative bacteria...
January 10, 2017: Chemical Biology & Drug Design
Noha I Ziedan, Rania Hamdy, Alessandra Cavaliere, Malamati Kourti, Filippo Prencipe, Andrea Brancale, Arwyn T Jones, Andrew D Westwell
A new series of oxadiazoles were designed to act as inhibitors of the anti-apoptotic Bcl-2 protein. Virtual screening led to the discovery of new hits that interact with Bcl-2 at the BH3 binding pocket. Further study of the structure-activity relationship of the most active compound of the first series, compound 1, led to the discovery of a novel oxadiazole analogue, compound 16j, that was a more potent small molecule inhibitor of Bcl-2. 16j had good in vitro inhibitory activity with sub-micromolar IC50 values in a metastatic human breast cancer cell line (MDA-MB-231) and a human cervical cancer cell line (HeLa)...
January 9, 2017: Chemical Biology & Drug Design
Fatma Yurt Lambrecht, Kasim Ocakoglu, Suleyman Gokhan Colak, Onur Alp Ersoz, Ozge Er
Imidazolium salts and derivatives have anti-tumor efficacy and toxic effects in different microorganisms. In present study, an imidazolium bromide salt (NMI) was synthesized, and its antitumor potential was investigated by in vitro studies. Radiolabeling of synthesized NMI was carried out by iodogen method using (131) I radionuclide. The yield of radiolabeling was determined as 98.5±0.1%. After that, cytotoxicity and intracellular uptake studies were evaluated in various cell lines. The cytotoxicity of NMI was determined as 35 μM, 20 μM, 10 μM and 1 μM for HEK-293, PC-3, CaCo-2 and MCF-7 cells, respectively...
January 9, 2017: Chemical Biology & Drug Design
Jalal A Aljamal, Muwaffag Badawneh
The rat fat cell β-adrenoceptors was investigated by studying the effects of new 1,8-naphthyridine derivatives synthesized starting from 7-amino-2-chloro-3-phenyl-1,8-naphthyridine on lipolysis induced by isoprenaline, and alprenolol. Lipolysis induced by isoprenaline agonist was competitively antagonized by the 1,8-naphthyridine analogue with a 7-hydroxy-2-(4'-methoxybenzylamine)-6-nitro-3-phenyl substituent designated as 3. In contrast, 10, 50 and 100 μM of 7-methoxy and 7-ethoxy derivatives did not modify the concentration-response curve of isoprenaline...
January 5, 2017: Chemical Biology & Drug Design
Maryam Majidinia, Bahman Yousefi
Breast cancer is the most common cancer and the second leading cause of cancer-related death in women worldwide. In spite of huge advancements in early detection and ever-increasing knowledge of breast cancer biology, approximately 30% of patients with early-stage breast cancer experience disease recurrence. Most patients are chemosensitive and cancer free immediately after the treatment. About 50% to 70% of breast cancer patients, however, will relapse within 1 year. Such a relapse is usually concomitant with adenocarcinoma cells acquiring a chemoresistant phenotype...
January 2, 2017: Chemical Biology & Drug Design
Mateusz Daśko, Janusz Rachon, Maciej Masłyk, Konrad Kubiński, Sebastian Demkowicz
Steroid sulfatase (STS) is responsible for the hydrolysis of biologically inactive sulfated steroids into their active un-sulfated forms and promote the growth of various hormone-dependent cancers (e.g., breast cancer). Therefore, the STS enzyme is a promising therapeutic target for the treatment of steroid-sensitive cancers. Herein, we report the synthesis and biological evaluation of sulfamate analogs as potential STS inhibitors based on N-acylated tyramines that contain C-F bonds. The inhibitory effects of the analogs were tested using STS isolated from human placenta...
December 29, 2016: Chemical Biology & Drug Design
Vishwa Deepak, Binglin Wang, Dwayne Koot, Abe Kasonga, Xiao Xing Stander, Magdalena Coetzee, Andre Stander
The bromodomain (BRD) and extra-terminal domain (BET) protein family binds to acetylated histones on lysine residues and act as epigenetic readers. Recently, the role of this protein family in bone loss has been gaining attention. Earlier studies have reported that benzotriazepine (Bzt) derivatives could be effective inhibitors of BET proteins. In this study by using in silico tools we designed three Bzt analogs (W49, W51, and W52). By docking, molecular simulations and chemiluminescent alpha screen binding assay we show that the studied analogs were selective at inhibiting BRD4 when compared to BRD2...
December 29, 2016: Chemical Biology & Drug Design
Heba A Abd El Razik, Mohamed Mroueh, Wissam H Faour, Wassim N Shebaby, Costantine F Daher, Hayam M A Ashour, Hanan M Ragab
The present study reports the synthesis of two series of new purine bioisosteres comprising a pyrazolo[3,4-d]pyrimidine scaffold linked to piperazine moiety through different amide linkages. The newly synthesized compounds were evaluated for anticancer activity against four cell lines (MDA-MB-231, MCF-7, SF-268, B16F-10), and cyclooxygenase (COX-2) protein expression inhibition in lipopolysaccharide (LPS)-activated rat monocytes. The results revealed that most of the synthesized compounds showed moderate to high cytotoxic activity against at least one cell line, with compound 10b being the most active against all used cell lines (IC50 values 5...
December 29, 2016: Chemical Biology & Drug Design
Yan-Ting Wang, Xun-Chao Cai, Tian-Qi Shi, Ya-Liang Zhang, Zhong-Chang Wang, Chang-Hong Liu, Hai-Liang Zhu
A series of new 1-phenylsulfonyl-2-(1-methylindol-3-yl)-benzimidazole derivatives were designed, synthesized and evaluated as potential inhibitors of tubulin polymerization and anthropic cancer cell lines. Among them, compound 33 displayed the most potent tubulin polymerization inhibitory activity in vitro (IC50 = 1.41 μM) and strong antiproliferative activities against A549, Hela, HepG2 and MCF-7 cell lines in vitro with GI50 value of 1.6, 2.7, 2.9 and 4.3 μM, respectively comparable with the positive control colchicine (GI50 value of 4...
December 29, 2016: Chemical Biology & Drug Design
Mostafa H Abdelrahman, Ahmed S Aboraia, Bahaa G M Youssif, Bakheet E M Elsadek
Novel 3-alkoxymethyl/3-phenyl indole-2-carboxamide derivatives were synthesized and evaluated for their anticancer activity. Most of the tested compounds showed moderate to excellent activity against the tested cell lines (MCF7 and HCT116). 3-Phenyl substitution on indole with and p-piperidinyl phenethyl 24a and p-dimethylamino phenethyl 24c exhibited anticancer activity against MCF7 with IC50 of 0.13 and 0.14 μM respectively. Further mechanistic study of the most active compounds through their action on Cell cycle showed disturbance in cell cycle progression and cell cycle arrest...
December 26, 2016: Chemical Biology & Drug Design
Paulina Strzelecka, Dominika Czaplinska, Rafal Sadej, Anna Wardowska, Michal Pikula, Adam Lesner
θ-defensins belong to the family of host defense peptides. They are the only known example of cyclic polypeptides in animal proteomes. The current study presents the synthesis of simplified θ-defensin analogues with pairs of cysteine replaced either by alanine, leucine, or serine residues. Cytotoxicity tests were performed on human mammary epithelial (HB2) and breast cancer (SKBR3, MDA-MB-231) cell lines to determine whether peptides are selectively targeting cancer cells. The effect of these peptides was also evaluated in 3D Matrigel cultures which are based on extracellular matrix components, and therefore closely represent in vivo conditions...
December 22, 2016: Chemical Biology & Drug Design
Shuangyan Zhou, Qianqian Wang, Mengdan Ren, Ai Zhang, Huanxiang Liu, Xiaojun Yao
Aggregation of islet amyloid polypeptide (IAPP) is implicated in the development of type 2 diabetes (T2D) The modified NFGAIL with double N-methylated at Gly24 and Ile26 has the property of soluble, nonamyloidogenic, noncytotoxic and the ability of inhibiting amyloid formation and cytotoxicity of IAPP. To discover the inhibition mechanism of this peptide inhibitor and provide useful information to design more potential peptide inhibitors, molecular dynamics simulations in explicit solvent were performed. The simulation results reveal that Gly24 and Ile26 are of importance in IAPP aggregation, and N-methylation at these two key residues will disrupt the stability of formed oligomer and prevent the conformation transition of free monomer near the oligomer template...
December 22, 2016: Chemical Biology & Drug Design
Komal Anjum, Syed Qamar Abbas, Najeeb Akhter, Bibi Ibtesam Shagufta, Sayed Asmat Ali Shah, Syed Shams Ul Hassan
Biologically active natural products are spontaneous medicinal entrant, which encourage synthetic access for enhancing and supporting drug discovery and development. Marine bioactive peptides are considered as a rich source of natural products that may provide long term health, in addition to many prophylactic and curative medicinal drug treatments. In spite of the large literature concerning marine peptides have been collected, which shows high potential of nutraceutical and therapeutic efficacy encompassing wide spectra of bioactivities against a number of infection causing agents...
December 22, 2016: Chemical Biology & Drug Design
Rodrigo Aguayo-Ortiz, Lucia Cano-González, Rafael Castillo, Alicia Hernández-Campos, Laura Domínguez
Microtubules are highly dynamic assemblies of α/β-tubulin heterodimers whose polymerization inhibition is among one of the most successful approaches for anticancer drug development. Overexpression of the class I (βI) and class III (βIII) β-tubulin isotypes in breast and lung cancers and the highly expressed class VI (βVI) β-tubulin isotype in normal blood cells have increased the interest for designing specific tubulin-binding anticancer therapies. To this end, we employed our previously proposed model of the β-tubulin-nocodazole complex, supported by the recently determined X-ray structure, to identify the fundamental structural differences between β-tubulin isotypes...
December 22, 2016: Chemical Biology & Drug Design
Rahmad Akbar, Siti Azma Jusoh, Rommie E Amaro, Volkhard Helms
Finding pharmaceutically relevant target conformations from an arbitrary set of protein conformations remains a challenge in structure-based virtual screening (SBVS). The growth in the number of available conformations, either experimentally determined or computationally derived, obscures the situation further. While the inflated conformation space potentially contains viable druggable targets, the increase of conformational complexity, as a consequence, poses a selection problem. To address this challenge, we took advantage of machine learning methods, namely an over-sampling and a binary classification procedure, and present a novel method to select druggable receptor conformations...
December 20, 2016: Chemical Biology & Drug Design
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