Design and Synthesis of Androgen Receptor Full Antagonists Bearing a p-Carborane Cage: Promising Ligands for Anti-Androgen Withdrawal Syndrome
Design and Synthesis of Androgen Receptor Full Antagonists Bearing a p-Carborane Cage: Promising Ligands for Anti-Androgen Withdrawal Syndrome
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DOI：
10.1021/jm100316f
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发表时间：
2010-07-08
影响因子：
7.3
通讯作者：
Endo, Yasuyuki
中科院分区：
文献类型：
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作者：
Goto, Tokuhito;Ohta, Kiminori;Endo, Yasuyuki
纯雄激素受体（AR）完全拮抗剂是治疗抗雄激素难治性前列腺癌的候选药物。我们之前开发了一种含碳硼烷的 AR 拮抗剂 3-(12-羟甲基-1,12-二碳-closo-十二硼烷-1-基)苯甲腈 (BA341)，它比羟基氟他胺 (4) 更有效，但可作为表达 T877A AR 突变体的 LNCaP 前列腺癌细胞的激动剂。在这里，我们基于临床使用的AR完全拮抗剂(R)-比卡鲁胺(5)在结构上设计并合成了新型AR完全拮抗剂，以检验我们的假设，即碳硼烷笼适合作为AR配体的疏水药效基团。化合物7b和8b在AR结合和反式激活测定中显示出良好的生物学特征，并且剂量依赖性地抑制睾酮诱导的LNCaP细胞以及SC-3细胞的增殖。化合物7b和8b的IC50值分别为3.8×10(-7)和4.2×10(-7)M[5,8.7×10(-7)M]。由于化合物7b和8b在功能测定中没有表现出任何激动活性，因此它们似乎是纯AR完全拮抗剂，因此是治疗抗雄激素戒断综合征的候选药物。
Pure androgen receptor (AR) full antagonists are candidates to treat anti-androgen refractory prostate cancers. We previously developed a carborane-containing AR antagonist, 3-(12-hydroxymethyl-1,12-dicarba-closo-dodecaborane-1-yl)benzonitrile (BA341), which was more potent than hydroxyflutamide (4) but acted as an agonist toward LNCaP prostate cancer cells expressing T877A AR mutant. Here, we designed and synthesized novel AR full antagonists structurally based upon the clinically used AR full antagonist (R)-bicalutamide (5) to test our hypothesis that the carborane cage is suitable as a hydrophobic pharmacophore for AR ligands. Compounds 7b and 8b showed good biological profiles in AR binding and transactivation assays and dose-dependently inhibited the testosterone-induced proliferation of LNCaP cells, as well as SC-3 cells. The IC50 values of compounds 7b and 8b were 3.8 x 10(-7) and 4.2 x 10(-7) M, respectively [5, 8.7 x 10(-7) M]. Since compounds 7b and 8b did not show any agonistic activity in functional assays, they seem to be pure AR full antagonists and are therefore candidates for treatment of anti-androgen withdrawal syndrome.