Design, synthesis, and biological activity evaluation of novel tubulin polymerization inhibitors based on pyrimidine ring skeletons

• Published in: Bioorganic & medicinal chemistry letters Vol. 84; p. 129195
• Main Authors: Kang, Yingying, Pei, Yuanyuan, Qin, Jinling, Zhang, Yixin, Duan, Yongtao, Yang, Hua, Yao, Yongfang, Sun, Moran
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.03.2023; Elsevier
• Subjects: Antineoplastic Agents - pharmacology; Antitumor; Cell Line, Tumor; Cell Proliferation; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Colchicine site; Drug Design; Drug Screening Assays, Antitumor; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Polymerization; Pyrimidine; Pyrimidines - pharmacology; Science & Technology; Structure-Activity Relationship; Tubulin; Tubulin - metabolism; Tubulin inhibitors; Tubulin Modulators - pharmacology; Tubulin; Colchicine site; Tubulin inhibitors; Antitumor; Pyrimidine; DERIVATIVES; DISCOVERY
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2023.129195

[Display omitted] •A series of novel inhibitors of microtubule protein polymerization targeting the colchicine site were designed and synthesized.•K10 exhibited nanomolar anti-proliferative efficacies with IC50 values of 0.07–0.80 μM against four cancer cell lines.•K10 caused cycle arrest and apoptosis and inhibit tubulin polymerization by binding to the colchicine site.•K10 inhibited the migration and invasion of HepG2 cells in a dose-dependent manner. A library of new pyrimidine analogs was designed and synthesized of these, compound K10 bearing a 1,4‑benzodioxane moiety and 3,4,5‑trimethoxyphenyl group, exhibiting the most potent activity, with IC50 values of 0.07–0.80 μM against four cancer cell lines. Cellular-based mechanism studies elucidated that K10 inhibited microtubule polymerization, blocked the cell cycle at the G2/M phase, and eventually induced apoptosis of HepG2 cells. Additionally, K10 inhibited the migration and invasion of HepG2 cells in a dose-dependent manner. Overall, our work indicates that the tubulin polymerization inhibitor incorporating pyrimidine and the 3,4,5‑trimethoxyphenyl ring may deserve consideration for cancer therapy.