Design, synthesis, and biological activity evaluation of (-)-6-O-desmethylantofine analogues as potent anti-cancer agents

• Published in: Bioorganic & medicinal chemistry 2019-07, Vol.27 (14), p.3070-3081
• Main Authors: Han, Guifang, Qing, Lihua, Wu, Meng, Wang, Yuxiang, Liu, Yuxiu, Liu, Xueling, Wang, Ziwen, Ding, Jian, Meng, Ling-hua, Wang, Qingmin
• Format: Article
• Language: English
• Subjects: Anti-cancer activity; Anti-cancer mechanism; Phenanthroindolizidine; Structural modification; Structure-activity-relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2019.05.030

[Display omitted] Phenanthroindolizidine alkaloids that possess profound anti-proliferative activity and unique mode of action have recently attracted much attention as potential anti-cancer drug candidates. To intensively study the structure-activity-relationship, we designed, synthesized, and evaluated a series of derivatives of 6-desmethylantofine at C-6 position. Most of the derivatives exhibited potent anti-proliferative activity in BEL-7402 and HL60cells. Compound R-12, the cyanomethyl ether of 6-desmethylantofine, exhibited significant anti-cancer activity and inhibited the proliferation of a panel of 30 cancer cell lines including 2 multi-drug-resistant cell lines with an average IC50 value of 18.7 nM, which suggests that R-12 is a promising new anti-cancer agent. Our studies suggest that R-12 displayed potent inhibitory effect on cell growth and colony formation, which is associated with delaying S phase progression by inhibiting DNA synthesis in human hepatoma cancer BEL-7402, SMMC-7721 and ZIP-177 cells.