Design, Synthesis and Biological Evaluation of Novel 4-(4-Methoxynaphthalen-1-yl)-5-arylpyrimidin-2-amines as Tubulin Polymerization Inhibitors

• Published in: Chemical & pharmaceutical bulletin Vol. 68; no. 12; pp. 1184 - 1192
• Main Authors: Liu, Wenjing, Wang, Guangcheng, Peng, Zhiyun, Li, Yongjun
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 01.12.2020; Pharmaceutical Society of Japan; Pharmaceutical Soc Japan; Japan Science and Technology Agency
• Subjects: Amines; anticancer; Anticancer properties; Apoptosis; Biotechnology; Cell cycle; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Cisplatin; Colchicine; Life Sciences & Biomedicine; Molecular modelling; naphthalene; Pharmacology & Pharmacy; Physical Sciences; Polymerization; pyrimidine; Science & Technology; Tubulin; tubulin polymerization inhibitor; Tumor cell lines; POTENTIAL ANTICANCER AGENTS; PYRIMIDINE-DERIVATIVES; naphthalene; MECHANISMS; IDENTIFICATION; pyrimidine; tubulin polymerization inhibitor; BINDING; anticancer
• ISSN: 0009-2363; 1347-5223; 1347-5223
• DOI: 10.1248/cpb.c20-00575

A novel series of 4-(4-methoxynaphthalen-1-yl)-5-arylpyrimidin-2-amines were designed, synthesized, and evaluated for their anticancer activities. Most of the synthesized compounds exhibited moderate to high antiproliferative activity in comparison to the standard drug cisplatin. Among them, 5i bearing ethoxy at the 4-position of the phenyl was found to be the most active on MCF-7 and HepG2 cancer cell lines, with IC50 values of 3.77 ± 0.36 and 3.83 ± 0.26 µM, respectively. Further mechanism study shown that 5i potently inhibited tubulin polymerization, induced cell cycle arrest at G2/M phase and cell apoptosis in MCF-7 cell line. Furthermore, molecular modeling study suggested that 5i probably binds to the colchicine site of tubulin.