Design, synthesis and biological evaluation of novel tubulin inhibitors targeting colchicine sites

• Published in: Bioorganic & medicinal chemistry letters Vol. 83; p. 129166
• Main Authors: Yuan, Minghua, Su, Jingtian, Zhang, Yixin, Qin, Jinling, Yang, Hua, Duan, Yongtao, Yao, Yongfang, Sun, Moran
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.03.2023; Elsevier
• Subjects: Antineoplastic Agents - chemistry; Antitumor; Binding Sites; Cell Line, Tumor; Cell Proliferation; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Colchicine; Colchicine - chemistry; Drug Screening Assays, Antitumor; Heterocyclic; Life Sciences & Biomedicine; Oxime; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Structure-Activity Relationship; Tubulin; Tubulin - metabolism; Tubulin Modulators - chemistry; Oxime; Tubulin; Colchicine; Heterocyclic; Antitumor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2023.129166

[Display omitted] Tubulin, a potential target for antitumor drug discovery, contains three main binding sites for clinical inhibitors: colchicine, vinblastine, and paclitaxel. CA-4 has been reported to be a classic tubulin inhibitor targeting the colchicine site. Herein, based on the structural modification of CA-4, 48 novel compounds were designed and synthesized by selecting structural fragments with various biological activities to replace the cis double bond of CA-4. Among these compounds, compound 8p was the most effective tubulin inhibitor (IC50 = 65 nM aganist HepG2 cells). Immunofluorescence experiment confirmed the anti-tumor effect of 8p by destroying the network structure of microtubules. Further studies showed that 8p induced tumor cell apoptosis, arrested cell cycle, inhibited tumor cell migration and invasion.