Laboratory of Medicinal Chemistry, Oncology and Nephrology Unit, CHU de Québec-Research Center (CHUL, T4-42) and Faculty of Medicine, Laval University , Québec City, Québec G1V 4G2, Canada.
J Med Chem. 2014 Jan 9;57(1):204-22. doi: 10.1021/jm401639v. Epub 2013 Dec 24.
17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is thought to play a pivotal role in the progression of estrogen-sensitive breast cancer by transforming estrone (E1) into estradiol (E2). We designed three successive series of E2-derivatives at position C3 of the potent inhibitor 16β-(m-carbamoylbenzyl)-E2 to remove its unwanted estrogenic activity. We report the chemical synthesis and characterization of 20 new E2-derivatives, their evaluation as 17β-HSD1 inhibitors, and their proliferative (estrogenic) activity on estrogen-sensitive cells. The structure-activity relationship study provided a new potent and steroidal nonestrogenic inhibitor of 17β-HSD1 named 3-{[(16β,17β)-3-(2-bromoethyl)-17-hydroxyestra-1(10),2,4-trien-16-yl]methyl}benzamide (23b). In fact, this compound inhibited the transformation of E1 into E2 by 17β-HSD1 in T-47D cells (IC50 = 83 nM), did not inhibit 17β-HSD2, 17β-HSD7, 17β-HSD12, and CYP3A4, and did not stimulate the proliferation of estrogen-sensitive MCF-7 cells. We also discussed the results of kinetic and molecular modeling (docking) experiments, suggesting that compound 23b is a competitive and irreversible inhibitor of 17β-HSD1.
17β-羟甾脱氢酶 1 型（17β-HSD1）被认为在雌激素敏感型乳腺癌的进展中起着关键作用，它将雌酮（E1）转化为雌二醇（E2）。我们在强效抑制剂 16β-（间-氨甲酰苄基）-E2 的 C3 位设计了三个连续的 E2 衍生物系列，以去除其不需要的雌激素活性。我们报告了 20 种新的 E2 衍生物的化学合成和表征，它们作为 17β-HSD1 抑制剂的评估，以及它们对雌激素敏感细胞的增殖（雌激素）活性。结构-活性关系研究提供了一种新的强效甾体非雌激素 17β-HSD1 抑制剂，命名为 3-[(16β,17β)-3-(2-溴乙基）-17-羟基雌甾-1(10),2,4-三烯-16-基]甲基]苯甲酰胺（23b）。事实上，该化合物在 T-47D 细胞中抑制了 E1 向 E2 的转化（IC50 = 83 nM），不抑制 17β-HSD2、17β-HSD7、17β-HSD12 和 CYP3A4，也不刺激雌激素敏感的 MCF-7 细胞的增殖。我们还讨论了动力学和分子建模（对接）实验的结果，表明化合物 23b 是 17β-HSD1 的竞争性和不可逆抑制剂。
