双苯甲酰胺类雄激素受体共激活剂抑制剂的构效关系研究。

A Structure-Activity Relationship Study of Bis-Benzamides as Inhibitors of Androgen Receptor-Coactivator Interaction.

机构信息

Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX 75080, USA.

Departments of Urology and Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.

出版信息

Molecules. 2019 Jul 31;24(15):2783. doi: 10.3390/molecules24152783.

The interaction between androgen receptor (AR) and coactivator proteins plays a critical role in AR-mediated prostate cancer (PCa) cell growth, thus its inhibition is emerging as a promising strategy for PCa treatment. To develop potent inhibitors of the AR-coactivator interaction, we have designed and synthesized a series of bis-benzamides by modifying functional groups at the N/C-terminus and side chains. A structure-activity relationship study showed that the nitro group at the N-terminus of the bis-benzamide is essential for its biological activity while the C-terminus can have either a methyl ester or a primary carboxamide. Surveying the side chains with various alkyl groups led to the identification of a potent compound that exhibited antiproliferative activity (IC value of 16 nM) on PCa cells. In addition, biochemical studies showed that exerts its anticancer activity by inhibiting the AR-PELP1 interaction and AR transactivation.

雄激素受体 (AR) 与共激活蛋白之间的相互作用在 AR 介导的前列腺癌 (PCa) 细胞生长中起着关键作用，因此抑制这种相互作用成为治疗 PCa 的一种有前途的策略。为了开发有效的 AR-共激活蛋白相互作用抑制剂，我们通过修饰 N/C 末端和侧链上的官能团设计并合成了一系列双苯甲酰胺。构效关系研究表明，双苯甲酰胺 N 末端的硝基是其生物活性所必需的，而 C 末端可以是甲酯或伯酰胺。用各种烷基侧链进行考察，确定了一种有效的化合物，该化合物对 PCa 细胞表现出抗增殖活性（IC 值为 16 nM）。此外，生化研究表明，通过抑制 AR-PELP1 相互作用和 AR 反式激活，发挥其抗癌活性。