| Abstract
| - A number of curcumin analogues were prepared and evaluated as potentialandrogen receptorantagonists against two human prostate cancer cell lines, PC-3 andDU-145, in the presenceof androgen receptor (AR) and androgen receptor coactivator, ARA70.Compounds 4 [5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one], 20 [5-hydroxy-1,7-bis[3-methoxy-4-(methoxycarbonylmethoxy)phenyl]-1,4,6-heptatrien-3-one], 22 [7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-methoxyphenyl)acryloyl]-5-oxohepta-4,6-dienoicacid ethyl ester], 23 [7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-methoxyphenyl)acryloyl]5-oxohepta-4,6-dienoicacid], and 39 [bis(3,4-dimethoxyphenyl)-1,3-propanedione]showed potent antiandrogenic activities andwere superior to hydroxyflutamide, which is the currently availableantiandrogen for thetreatment of prostate cancer. Structure−activity relationship(SAR) studies indicated that thebis(3,4-dimethoxyphenyl) moieties, the conjugated β-diketonemoiety, and the intramolecularsymmetry of the molecules seem to be important factors related toantiandrogenic activity.The data further suggest that the coplanarity of the β-diketonemoiety and the presence of astrong hydrogen bond donor group were also crucial for the antiandrogenicactivity, which isconsistent with previous SAR results for hydroxyflutamide analogues.When the pharmacophoric elements of dihydrotestosterone (DHT) andcompound 4 are superposed, the resultingconstruct implies that the curcumin analogues may function as a 17α-substitutedDHT.Compounds 4, 20, 22, 23, and 39 have been identified as a new classof antiandrogen agents,and these compounds or their new synthetic analogues could be developedinto clinical trialcandidates to control androgen receptor-mediated prostate cancer growth.
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