Synthesis and cytotoxic activities of spin-labeled derivatives of Cinobufagin

Two series of novel spin-labeled derivatives of Cinobufagin(compounds 5 and 8 a― 8 f in series 1 with five-membered ring nitroxyl free radical and compounds 6 and 9 a― 9 f in series 2 with six-membered ring nitroxyl free radical) were synthesized. The cytotoxic activities in vitro against two tumor cell lines(HepG2 and HeLa) were evaluated, and the results indicate that all compounds display potent cytotoxicity against HepG2 and HeLa cells, and most compounds show better activities on HeLa cells than on HepG2 cells except for compounds 8 a and 9 d. Generally, the compounds in series 2 have more potent cytotoxic activity against HepG2 than the compounds in series 1. Especially, compounds 6 and 9 f in series 2 exhibit even more potent activities against the two tumor cell lines than Cinobufagin. Thus incorporation of different L -amino acids as the linker changed the cytotoxic profile of the spin-labeled Cinobufagin. In addition, the representative compound 9 f significantly changed the cell cycle distribution and led to HeLa cell cycle arrested at G 2 /M phase.