title: Lack of nucleophilic addition in the isoxazole and pyrazole diketone modified analogs of curcumin; implications for their antitumor and chemosensitizing activities.
abstract: Curcumin (CUR) can be considered as a good lead compound for the design of new anticancer drugs. Further, structure-activity relationship studies may clarify the importance of the redox activities in the antitumor effects of the drug. We have elaborated the alpha,beta-unsaturated 1,3-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 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 tumor cell types; in contrast to CUR, the antitumor effects of ISO or PYR were not influenced by concomitant administration of N-acetylcysteine, as a source of -SH groups, or buthionine sulfoximine, as an inhibitor of glutathione synthesis. Further, treatment with CUR, but not with ISO or PYR, significantly decreased the content of reduced glutathione in the HA22T/VGH cells. Finally, ISO and PYR lacked the ability of the parent compound to sensitize the HA22T/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. Thus, the ability of interacting with cell thiols might not be requested for the more potent antitumor activities of new diketone modified CUR derivatives, which might rely on other mechanisms, though possibly devoid of chemosensitization capabilities.
authors.affiliation: Dipartimento di Scienze Farmacologiche Pietro Benigno, Università di Palermo, Via del Vespro 129, Palermo, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Labbozzetta
authors.forename: Riccardo
authors.initials: R
authors.lastname: Baruchello
authors.forename: Paolo
authors.initials: P
authors.lastname: Marchetti
authors.forename: Maria C
authors.initials: MC
authors.lastname: Gueli
authors.forename: Paola
authors.initials: P
authors.lastname: Poma
authors.forename: Monica
authors.initials: M
authors.lastname: Notarbartolo
authors.forename: Daniele
authors.initials: D
authors.lastname: Simoni
authors.forename: Natale
authors.initials: N
authors.lastname: D'Alessandro
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003474:Curcumin / Q000737:chemistry / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D011720:Pyrazoles / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007555:Isoxazoles; D011720:Pyrazoles; D019328:Buthionine Sulfoximine; D003474:Curcumin; D000111:Acetylcysteine