Modified norcantharidins: synthesis, protein phosphatases 1 and 2A inhibition, and anticancer activity

Fourteen modified norcantharidin analogues have been synthesised and screened for their ability to inhibit the serine/ threonine protein phosphatases 1 and 2A. The most potent compounds found were 10 (PP1 IC50= 13+/-5 muM; PP2A IC50 = 7+/-3 muM) and 16 (PP1 IC50= 18+/-8 muM; PP2A IC50= 3.2+/-0.4 muM). Overall, only analogues possessing at least one acidic residue at the former anhydride warhead displayed any PPI or PP2A inhibitory action. The ability of these analogues to inhibit PP1 and PP2A correlates well with their observed anti-cancer activity against a panel of five cancer cell lines: A2780 (human ovarian carcinoma), G401 (human kidney carcinoma), HT29 (human colorectal carcinoma), H460 (human lung carcinoma) and L1210 (murine leukemia). (C) 2004 Elsevier Ltd. All rights reserved.