Discovery of certain benzyl/phenethyl thiazolidinone-indole hybrids as potential anti-proliferative agents: Synthesis,molecular modeling and tubulin polymerization inhibition study |
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| Institution: | 1. Fluoro-Agrochemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India;2. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India;3. Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India;1. Department of Drug Chemistry and Technologies, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, I-00185 Roma, Italy;2. Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States;3. Institute of Molecular Biology and Pathology (IBPM), CNR Consiglio Nazionale Delle Ricerche, C/o Sapienza University of Rome, Via Degli Apuli 4, I-00185 Roma, Italy;4. Laboratorio di Ricerca Pre-Clinica e Traslazionale, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Centro di Riferimento Oncologico Della Basilicata, Via Padre Pio 1, I-85028, Rionero in Vulture, Italy;5. Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, I-56126 Pisa, Italy;6. Experimental Therapeutics IFOM-the FIRC Institute of Molecular Oncology Foundation, Via Adamello 16, 20139 Milan, Italy;7. APHAD, Via Della Resistenza 65, 20090 Buccinasco MI, Italy;1. Department of Medical Biotechnology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran;2. Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran;3. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran;1. Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Istanbul University, Istanbul, Turkey;2. Department of Chemical Engineering, Bogazici University, Bebek, 34342, Istanbul, Turkey;3. Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, United States;4. Faculty of Pharmacy, Istanbul Yeni Yuzyil University, Istanbul, Turkey;1. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India;2. Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India;3. School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi 110062, India |
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| Abstract: | A series of certain benzyl/phenethyl thiazolidinone-indole hybrids were synthesized for the study of anti-proliferative activity against A549, NCI-H460 (lung cancer), MDA-MB-231 (breast cancer), HCT-29 and HCT-15 (colon cancer) cell lines by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). We found that compound G37 displayed highest cytotoxicity with IC50 value of 0.92 ± 0.12 µM towards HCT-15 cancer cell line among all the synthesized compounds. Moreover, compound G37 was also tested on normal human lung epithelial cells (L132) and was found to be safe in contrast to HCT-15 cells. The lead compound G37 showed significant G2/M phase arrest in HCT-15 cells. Additionally, compound G37 significantly inhibited tubulin polymerization with IC50 value of 2.92 ± 0.23 µM. Mechanistic studies such as acridine orange/ethidium bromide (AO/EB) dual staining, DAPI nuclear staining, annexinV/propidium iodide dual staining, clonogenic growth inhibition assays inferred that compound G37 induced apoptotic cell death in HCT-15 cells. Moreover, loss of mitochondrial membrane potential with elevated intracellular ROS levels was observed by compound G37. These compounds bind at the active pocket of the α/β-tubulin with higher number of stable hydrogen bonds, hydrophobic and arene-cation interactions confirmed by molecular modeling studies. |
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| Keywords: | Benzyl/phenethyl thiazolidinone-indole hybrids Cytotoxicity Tubulin polymerization Apoptosis Molecular modeling |
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