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Design, synthesis, and antitumor evaluation of quinazoline-4-tetrahydroquinoline chemotypes as novel tubulin polymerization inhibitors targeting the colchicine site

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机构： [1]State Key Laboratory of Biotherapy and Cancer Center, Chinese Evidence-based Medicine Center, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, 610041, China [2]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, China [3]Course of Biological Sciences, Department of Life Science, Imperial College London, United Kingdom

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关键词： Tubulin Colchicine binding site inhibitors (CBSIs) Quinazoline-4-tetrahydroquinoline Structure-activity relationship (SAR) Co-crystal structure Antitumor

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We designed, synthesized, and evaluated the antitumor activity of a series of novel quinazoline-4-(6-methoxytetrahydroquinoline) analogues. Among the tested compounds, 4a4 exhibited the most potent antiproliferative activities across four human cancer cell lines with half-maximal inhibitory concentration (IC50) values ranging from 0.4 to 2.7 nM, more potent than the lead compound. The 2.71 Å resolution co-crystal structure of 4a4 with tubulin (PDB code: 8YER) confirmed its critical binding at the colchicine site. Moreover, 4a4 inhibited the polymerization of tubulin, colony formation, and tumor cell migration, while inducing G2/M phase arrest and apoptosis. In vivo, 4a4 significantly delayed primary tumor growth in the SKOV3 xenograft model without obvious side effect. Our research enhances the structure-activity relationships (SARs) understanding of the quinazoline-4-tetrahydroquinoline scaffold and provides new insights for potential structural optimization and the development of novel colchicine binding site inhibitors (CBSIs).Copyright © 2024. Published by Elsevier Masson SAS.

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大类 | 2 区

医学

小类 | 1 区药物化学

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第一作者机构： [1]State Key Laboratory of Biotherapy and Cancer Center, Chinese Evidence-based Medicine Center, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, 610041, China

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通讯机构： [1]State Key Laboratory of Biotherapy and Cancer Center, Chinese Evidence-based Medicine Center, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, 610041, China [2]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, China

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