Antitumor agents. 217. Curcumin analogues as novel androgen receptor antagonists with potential as anti-prostate cancer agents
Antitumor agents. 217. Curcumin analogues as novel androgen receptor antagonists with potential as anti-prostate cancer agents
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DOI：
10.1021/jm020200g
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发表时间：
2002-11-07
影响因子：
7.3
通讯作者：
Lee, KH
中科院分区：
文献类型：
--
作者：
Ohtsu, H;Xiao, ZY;Lee, KH
在雄激素受体（AR）和雄激素受体共激活剂ARA70存在的情况下，制备了一些姜黄素类似物，并对其作为潜在的雄激素受体拮抗剂对两种人前列腺癌细胞PC-3和DU-145进行了研究。化合物4[5-羟基-1,7-二（3,4-二甲氧基苯基）-1,4,6-庚基-3- 1]，20[5-羟基-1,7-二[3-甲氧基-4-甲氧基苯基]-1,4,6-庚基-3-甲氧基苯基]，22[7-（4-羟基-3-甲氧基苯基）-4-[3（4-羟基-3-甲氧基苯基）丙烯]-5-氧庚基-4,6-二烯酸乙酯]，23[7-（4-羟基-3-甲氧基苯基）-4-[3-（4-羟基-3-甲氧基苯基）丙烯基]-5-氧庚基-4,6-二烯酸]，39[双（3,4-二甲氧基苯基）-1,3-丙二酮]具有较强的抗雄激素活性，优于目前用于治疗前列腺癌的抗雄激素羟氟他胺。构效关系（SAR）研究表明，双（3,4-二甲氧基苯基）基团、共轭β -二酮基团和分子内对称性是影响抗雄激素活性的重要因素。数据进一步表明，β -二酮部分的共平面性和强氢键供体基团的存在对抗雄激素活性也至关重要，这与先前羟基氟他胺类似物的SAR结果一致。当二氢睾酮（DHT）和化合物4的药理成分叠加时，所得到的结构表明姜黄素类似物可能具有17 α取代DHT的功能。化合物4,20,22,23和39已被确定为一类新的抗雄激素药物，这些化合物或它们的新合成类似物可用于临床试验，以控制雄激素受体介导的前列腺癌的生长。
A number of curcumin analogues were prepared and evaluated as potential androgen receptor antagonists against two human prostate cancer cell lines, PC-3 and DU-145, in the presence of 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-(meth-oxycarbonylmethoxy)phenyl]-1,4,6-heptatrien-3-one], 22 [7-(4-hydroxy-3-methoxyphenyl)-4-[3(4-hydroxy-3-methoxyphenyl)acryloyl]-5-oxohepta-4,6-dienoic acid ethyl ester], 23 [7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-methoxyphenyl)acryloyl]5-oxohepta-4,6-dienoic acid], and 39 [bis(3,4-dimethoxyphenyl)-1,3-propanedione] showed potent antiandrogenic activities and were superior to hydroxyflutamide, which is the currently available antiandrogen for the treatment of prostate cancer. Structure-activity relationship (SAR) studies indicated that the bis(3,4-dimethoxyphenyl) moieties, the conjugated beta-diketone moiety, and the intramolecular symmetry of the molecules seem to be important factors related to antiandrogenic activity. The data further suggest that the coplanarity of the beta-diketone moiety and the presence of a strong hydrogen bond donor group were also crucial for the antiandrogenic activity, which is consistent with previous SAR results for hydroxyflutamide analogues. When the pharmacophoric elements of dihydrotestosterone (DHT) and compound 4 are superposed, the resulting construct implies that the curcumin analogues may function as a 17alpha-substituted DHT. Compounds 4, 20, 22, 23, and 39 have been identified as a new class of antiandrogen agents, and these compounds or their new synthetic analogues could be developed into clinical trial candidates to control androgen receptor-mediated prostate cancer growth.