Synthesis,molecular properties prediction and biological evaluation of indole-vinyl sulfone derivatives as novel tubulin polymerization inhibitors targeting the colchicine binding site |
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| Affiliation: | 1. State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China;2. State Key Laboratory of Chemical Biology and Drug Discovery, and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong;3. Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham NG7 2RD, UK;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;1. Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari ‘AldoMoro’, Via Orabona, 4, 70126, Bari, Italy;2. Istituto Tumori IRCCS Giovanni Paolo II, Viale O. Flacco 65, 70124, Bari, Italy;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. Institute of Drug Discovery and Development, Kafrelsheikh University, Kafrelsheikh, Egypt;2. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt;3. Zewail City of Science and Technology, 6th of October, Giza, Egypt;4. Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt;1. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University, New Damietta, Egypt |
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| Abstract: | Twenty-two novel indole-vinyl sulfone derivatives were designed, synthesized and evaluated as tubulin polymerization inhibitors. The physicochemical and drug-likeness properties of all target compounds were predicted by Osiris calculations. All compounds were evaluated for their antiproliferative activities, among them, compound 7f exhibited the most potent activity against a panel of cancer cell lines, which was 2–7 folds more potent than our previously reported compound 4. Especially, 7f displayed about 8-fold improvement of selective index as compared with compound 4, indicating that 7f might have lower toxicity. Besides, 7f inhibited the microtubule polymerization by binding to the colchicine site of tubulin. Further investigations showed that compound 7f effectively disrupted microtubule network, caused cell cycle arrest at G2/M phase and induced cell apoptosis in K562 cells. Moreover, 7f reduced the cell migration and disrupted capillary-like tube formation in HUVEC cells. Importantly, the in vivo anti-tumor activity of 7f was validated in H22 liver cancer xenograft mouse model without apparent toxicity, suggesting that 7f is a promising anti-tubulin agent for cancer therapy. |
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| Keywords: | Tubulin inhibitor Vinyl sulfone Indole Colchicine site Drug-likeness |
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