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

Guifang Han; Lihua Qing; Meng Wu; Yuxiang Wang; Yuxiu Liu; Xueling Liu; Ziwen Wang; Jian Ding; Ling-Hua Meng; Qingmin Wang

doi:10.1016/j.bmc.2019.05.030

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

Bioorg Med Chem. 2019 Jul 15;27(14):3070-3081. doi: 10.1016/j.bmc.2019.05.030. Epub 2019 May 21.

Authors

Guifang Han¹, Lihua Qing², Meng Wu³, Yuxiang Wang², Yuxiu Liu³, Xueling Liu², Ziwen Wang³, Jian Ding², Ling-Hua Meng⁴, Qingmin Wang⁵

Affiliations

¹ State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, PR China; Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China.
² Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, PR China.
³ State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, PR China.
⁴ Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, PR China. Electronic address: [email protected].
⁵ State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, PR China. Electronic address: [email protected].

PMID: 31171403
DOI: 10.1016/j.bmc.2019.05.030

Abstract

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.

Keywords: Anti-cancer activity; Anti-cancer mechanism; Phenanthroindolizidine; Structural modification; Structure-activity-relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / therapeutic use*
Humans
Structure-Activity Relationship

Substances

Antineoplastic Agents