ELABORATION OF CURCUMIN INTO DIKETONE MODIFIED ANALOGUES DEVOID OF NUCLEOPHILIC ADDITION CAPABILITY; IMPLICATIONS FOR THEIR ANTITUMOR AND CHEMOSENSITIZING ACTIVITIES

Abstract

Curcumin (CUR), a polyphenolic compound extracted from Curcuma longa L.,can beconsidered as a good lead compound for the design of new drugs for the treatment of cancer and other therapeutic purposes. CUR is endowed with a diketone function, which appears to be important for its antitumor activity: also depending on the dose, the compound may show complex either pro-oxidant or anti-oxidant effects, which both may, at least in part, be linked to this structural moiety. In the lower concentration, "chemopreventive", range, CUR behaves mainly as an antioxidant; at higher concentrations, the a, b-unsaturated 1,3-diketone, as a Michael acceptor, can form adducts with the –SH groups and generate reactive oxygen species. This may lead to induction of apoptosis through different possible mechanisms. Structure-activity relationship studies may clarify the importance of the redox activities in the antitumor effects of the drug. We have elaborated the diketone moiety of CUR into the isoxazole (ISO) and pyrazole (PYR) derivatives. These derivatives should be much less prone to nucleophilic addition than CUR and benzyl mercaptan addition and mass spectrometry analyses showed that indeed they do not form isolable conjugated products. When compared with CUR, ISO and PYR exhibited increased cell growth inhibitory and pro-apoptotic effects in liver cancer HA22T/VGH cells as well as in other, also multidrug resistant, tumor types; in contrast to CUR, theantitumor effects of ISO or PYR were not influenced bythe concomitant administration of N-acetylcysteine, as a source of –SH groups, or of buthionine sulfoximine, as an inhibitor of glutathione synthesis. Further, short-term treatment with CUR, but not with ISO, sharply decreased the content of reduced glutathione in the HA22T/VGH cells. Finally, ISO and PYR lacked the ability of the parent compound to sensitize theHA22T/VGH cells to cisplatin (CIS), an effect which appeared to occur through an interaction of CUR and CIS at the level of the -SH groups and of reduced glutathione. Thus, the ability of interacting with cell thiols might not be requested for the more potent antitumor activities of these new diketone modified CUR derivatives, which might rely on other mechanisms, though possibly devoid of chemosensitization capabilities.