ASCJ-15

In a continuing study of curcumin analogues as potential drug candidates to treat prostate cancer at both androgen-dependent and androgen-refractory stages, we designed and synthesized over 40 new analogues classified into four series: monophenyl analogues (series A), heterocycle-containing analogues (series B), analogues bearing various substituents on the phenyl rings (series C), and analogues with various linkers (series D). These new compounds were tested for cytotoxicity against two human prostate cancer cell lines, androgen-dependent LNCaP and androgen-independent PC-3. Antiandrogenic activity was also evaluated in LNCaP cells and PC-3 cells transfected with wild-type androgen receptor. Ten compounds possessed potent cytotoxicity against both LNCaP and PC-3 cells, seven only against LNCaP, and one solely against PC-3. This study established an advanced structure-activity relationship (SAR), and these correlations will guide the further design of new curcumin analogues with better anti-prostate cancer activity.

4-Ethoxycarbonylethyl curcumin (ECECur) (3) is a current drug candidate for the treatment of prostate cancer. Due to problems inherent in the tautomerism of ECECur, 4-fluoro-4-ethoxycarbonylethyl curcumin (4) and 4-ethoxycarbonylethylenyl curcumin (5) were designed and synthesized. These two target compounds and their synthetic intermediates (4-9) were evaluated for their inhibitory activity against androgen receptor transcription in LNCaP and PC-3 prostate cancer cell lines. While the enol-keto analogs showed varying anti-androgen potencies, the di-keto analogs showed no activity. Tetrahydropyranylation of the phenoxy groups had a positive impact on the anti-AR activity of 4-ethoxycarbonylethylenyl curcumin, but a negative impact on the activity of ECECur. With potent anti-AR activity, di-tetrapyranylated 4-ethoxycarbonylethylenyl curcumin (9), which exists in only one form, is a good drug lead for further structural modification. Based on the SAR information obtained from the above study, five new compounds were designed and subsequently synthesized. Among them, compound 10 was found to be the most potent anti-AR agent and is considered to be a promising drug candidate for the treatment of prostate cancer.