Design, Synthesis and Bio-Evaluation of New Curcumin Analogs as Potential Drug Candidates for The Treatment of Prostate Cancer
Curcumin is the major yellow pigment isolated from the rhizome of Curcuma longa, known as turmeric. Over a long period of study, curcumin has been found to possess a wide range of bioactivities including anti-prostate cancer activity in vitro and in vivo. Based on these observations, our laboratory has been using curcumin as the lead compound to develop various analogs as potential anti-prostate cancer agents. Two curcumin analogs, dimethyl curcumin (DMC, 4) and 4-ethoxycarbonylethyl curcumin (ECECur, 5) developed previously were found to be active anti-androgen receptor agents, which showed greater potency than hydroxyflutamide, an anti-androgen currently used clinically. However, the tautomerism of ECECur, which causes it to exist in both enol-keto and di-keto forms, may hinder its potential as a clinically useful drug. To solve the problem inherent in the tautomerism of ECECur, I subsequently designed, synthesized and evaluated several new curcumin analogs for the anti-androgen receptor activity as well as cytotoxicity in prostate cancer cell lines. To establish an extensive structure-activity relationship (SAR) for curcumin analogs as anti-prostate cancer agents, I designed and synthesized four series of new curcumin analogs having various structural features. Based on the structures and the bioactivities of these new compounds, I studied the structure-activity relationship of curcumin analogs in an extensive level and discovered several structural features of curcumin analogs responsible for their anti-prostate cancer activity including 3',4'-dimethoxy phenyl rings or 3'-methoxy-4'-hydroxy phenyl rings, unsaturated and conjugated linker, proper substitution at C4 position of the linker and so on. This new information will guide us for the further optimization of curcumin analogs as anti-prostate cancer agents. Besides three conjugates were designed and synthesized in this work. Through this study, the problem of tautomerism of ECECur has been solved successfully and sixteen new potent curcumin analogs (11, 12, 13, 14, 15, 16, 31, 34, 35, 37, 41, 43, 44, 50 and 52) were developed as promising anti-prostate cancer drug candidates for further investigation in vivo.