Synthesis and biological evaluation of podophyllotoxin congeners as tubulin polymerization inhibitors |
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| Institution: | 1. Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India;2. IICT-RMIT Research Centre, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India;3. Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India;4. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India;1. Laboratory of Pharmaceutical Design & Synthesis, College of Sciences, Northwest A&F University, Yangling 712100, Shaanxi Province, People’s Republic of China;2. College of Agriculture, Shanxi Agriculture University, Taigu 030801, Shanxi Province, People’s Republic of China;1. School of Public Health, Wuhan University, 185 Donghu Road, Wuhan, Hubei 430071, PR China;2. Hubei Provincial Key Laboratory of Applied Toxicology, Hubei Provincial Assessment Center for Foodstuff and Drug Safety, Wuhan, Hubei 430075, PR China;3. Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, Hubei 430068, PR China;1. Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Tarnaka, Hyderabad 500 007, India;2. Center for Chemical Biology, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Tarnaka, Hyderabad 500 007, India;1. Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India;2. IICT-RMIT Research Centre, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India;3. Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India;4. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India;1. School of Pharmacy, Zunyi Medical University, Zunyi 563003, PR China;2. CSIRO Manufacturing Flagship, PO Box 218, Lindfield, NSW 2070, Australia |
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| Abstract: | A series of new podophyllotoxin derivatives containing structural modifications at C-7, C-8, and C-9 were synthesized and evaluated for their cytotoxic activity against three human cancer cell lines. All the synthesized compounds showed significant growth inhibition with GI50 values in micromolar levels while some of the compounds were several times more potent against MCF-7 and HeLa cell lines than MIAPACA cell line. Three compounds (12a, 12d and 12e) emerged as potent compounds with broad spectrum of cytotoxic activity against all the tested cell lines with GI50 values in the range of 0.01–2.1 μM. These compounds induce microtubule depolymerization and arrests cells at the G2/M phase of the cell cycle. Moreover, compounds 12d and 12e disrupted microtubule network and accumulated tubulin in the soluble fraction in a similar manner to their parent podophyllotoxin scaffold. In addition, structure activity relationship studies within the series were also discussed. Molecular docking studies of these compounds into the colchicine-binding site of tubulin, revealed possible mode of inhibition by these compounds. |
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| Keywords: | Podophyllotoxin Benzimidazole Cytotoxicity Tubulin polymerization Molecular docking |
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