Synthesis of novel 10,11-methylenedioxy-camptothecin glycoside derivatives and investigation of their anti-tumor effects in vivo

10,11-Methylenedioxy-camptothecin (FL118) is a novel camptothecin analogue that possesses exceptional antitumor efficacy in human tumor xenograft models. The aim of the current study was to develop novel 20-substituted FL118 derivatives coupled with glycosyl-succinic acid esters with improved antitumor efficacy. These FL118 glycoside derivatives were designed, synthesized and their cytotoxicity evaluated in three tumor cell lines (A-549, MDA-MB-231 and RM-1). All of the derivatives showed superior in vitro cytotoxic activity and were more potent than irinotecan in A549 and MDA-MB-231 cells. In mouse prostate Cancer cells RM-1, 10,11-methylenedioxy-camptothecin rhamnoside 11b displayed significant activities with IC₅₀ of 48.27 nM. Western blot analysis demonstrated that 11b inhibited Survivin expression and induced Cancer cells Apoptosis. Further cell cycle analyses clearly showed 11b induced G2/M phase cell cycle arrest. Molecule docking studies suggested that the binding mode of 11b was different from that of the crystal complex of ligand topotecan in Top1/DNA. Importantly, 11b showed high in vivo antitumor efficacy in the RM-1 mouse model with transplantation of prostate Cancer (TGI = 44.9%) at dose of 9 mg kg^-1 without apparent toxicity.