Antitumor agents 290. Design synthesis and biological evaluation of new LNCaP and PC-3 cytotoxic curcumin analogs conjugated with anti-androgens

摘要

In our continuing study of curcumin analogs as potential anti-prostate cancer drug candidates, 15 new curcumin analogs were designed, synthesized and evaluated for cytotoxicity against two human prostate cancer cell lines, androgen-dependent LNCaP and androgen-independent PC-3. Twelve analogs (>5->12, >15, >16, >19, and >20) are conjugates of curcumin (>1) or methyl curcumin (>2) with a flutamide- or bicalutamide-like moiety. Two compounds (>22 and >23) are C4-mono- and difluoro-substituted analogs of dimethyl curcumin (DMC, >21). Among the newly synthesized conjugates compound >15, a conjugate of >2 with a partial bicalutamide moiety, was more potent than bicalutamide alone and essentially equipotent with >1 and >2 against both prostate tumor cell lines with IC50 values of 41.8 μM (for LNCaP) and 39.1 μM (for PC-3). A cell morphology study revealed that the cytotoxicity of curcumin analogs or curcumin-antiandrogen conjugates detected from both prostate cancer cell lines might be due to the suppression of pseudopodia formation. A molecular intrinsic fluorescence experiment showed that >1 accumulated mainly in the nuclei, while conjugate >6 was distributed in the cytosol. At the tested conditions, antiandrogens suppressed pseudopodia formation in PC-3 cells, but not in LNCaP cells. The evidence suggests that distinguishable target proteins are involved, resulting in the different outcomes toward pseudopodia suppression.