Norcantharimides, synthesis and anticancer activity: Synthesis of new norcantharidin analogues and their anticancer evaluation

A range of amines was reacted with norcantharidin ( 2) to provide the corresponding norcantharimides ( 9– 43). Treatment of norcantharidin with allylamine afforded the corresponding allyl-norcantharimide ( 20) which was amenable to epoxidation (mCPBA, 22) and subsequent ring opening (MeOH/H +; 23) or alternatively, osmylation (OsO 4/NMO; 24). These simple synthetic modifications of 2 facilitated the development of a novel series of norcantharimides displaying modest to good broad spectrum cytotoxicity against HT29 and SW480 (colorectal carcinoma); MCF-7 (breast adenocarcinoma); A2780 (ovarian carcinoma); H460 (lung carcinoma); A431 (epidermoid carcinoma); DU145 (prostate carcinoma); BE2-C (neuroblastoma); and SJ-G2 (glioblastoma). Analogues possessing a C 10, C 12 or C 14 alkyl chain or a C 12 linked bis-norcantharimide displayed the highest levels of cytotoxicity.