Development of potent and selective inhibitors of aldo-keto reductase 1C3 (type 5 17β-hydroxysteroid dehydrogenase) based on N-phenyl-aminobenzoates and their structure-activity relationships.
Development of potent and selective inhibitors of aldo-keto reductase 1C3 (type 5 17β-hydroxysteroid dehydrogenase) based on N-phenyl-aminobenzoates and their structure-activity relationships.
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DOI：
10.1021/jm201547v
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发表时间：
2012-03-08
影响因子：
7.3
通讯作者：
Penning, Trevor M.
中科院分区：
文献类型：
--
作者：
Adeniji, Adegoke O.;Twenter, Barry M.;Byrns, Michael C.;Jin, Yi;Chen, Mo;Winkler, Jeffrey D.;Penning, Trevor M.
醛酮还原酶1C 3（AKR 1C 3; 5型17β-羟基类固醇脱氢酶）在去势抵抗性前列腺癌（CRPC）中过表达，并参与睾酮和5α-二氢睾酮的肿瘤内生物合成。需要选择性AKR 1C 3抑制剂，因为化合物不应抑制参与5α-二氢睾酮失活的高度相关的AKR 1C 1和AKR 1C 2亚型。NSAID，特别是N-苯基邻氨基苯甲酸酯是有效但非选择性的AKR 1C 3抑制剂。以氟芬那酸、2-{[3-（三氟甲基）苯基]氨基}苯甲酸为先导化合物，合成了5类结构类似物，并评价了它们对AKR 1C 3的抑制效力和选择性。构效关系（SAR）研究表明，相对于胺的间位羧酸基团赋予明显的AKR 1C 3选择性而不损失效力，而苯氨基B环上的吸电子基团对于AKR 1C 3抑制是最佳的。在LNCaP-AKR 1C 3细胞中，先导化合物不抑制考克斯-1或考克斯-2，但阻断AKR 1C 3介导的睾酮产生。这些化合物为CRPC的新疗法提供了有希望的线索。
Aldo-keto reductase 1C3 (AKR1C3; type 5 17β-hydroxysteroid dehydrogenase) is overexpressed in castrate resistant prostate cancer (CRPC) and is implicated in the intratumoral biosynthesis of testosterone and 5α-dihydrotestosterone. Selective AKR1C3 inhibitors are required since compounds should not inhibit the highly related AKR1C1 and AKR1C2 isoforms which are involved in the inactivation of 5α-dihydrotestosterone. NSAIDs, N-phenylanthranilates in particular are potent but non-selective AKR1C3 inhibitors. Using flufenamic acid, 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid as lead compound, five classes of structural analogs were synthesized and evaluated for AKR1C3 inhibitory potency and selectivity. Structure activity relationship (SAR) studies revealed that a meta-carboxylic acid group relative to the amine conferred pronounced AKR1C3 selectivity without loss of potency, while electron withdrawing groups on the phenylamino B-ring were optimal for AKR1C3 inhibition. Lead compounds did not inhibit COX-1 or COX-2 but blocked the AKR1C3 mediated production of testosterone in LNCaP-AKR1C3 cells. These compounds offer promising leads towards new therapeutics for CRPC.
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影响因子：
10.9
作者：
Knudsen, Karen E.;Penning, Trevor M.
通讯作者：
Penning, Trevor M.
DOI：
10.1158/1078-0432.ccr-08-2660
发表时间：
2009-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Knudsen KE;Scher HI
通讯作者：
Scher HI
影响因子：
15
作者：
Hamann, BC;Hartwig, JF
通讯作者：
Hartwig, JF
DOI：
10.1016/j.jsbmb.2010.11.004
发表时间：
2011-05
影响因子：
4.1
作者：
Byrns, Michael C.;Jin, Yi;Penning, Trevor M.
通讯作者：
Penning, Trevor M.
影响因子：
7.3
作者：
Jung ME;Ouk S;Yoo D;Sawyers CL;Chen C;Tran C;Wongvipat J
通讯作者：
Wongvipat J