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


Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, PR China. Electronic address: [Email]


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.


Anti-cancer activity,Anti-cancer mechanism,Phenanthroindolizidine,Structural modification,Structure-activity-relationship,

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