CHUQ-CHUL Research Center (Laboratory of Medicinal Chemistry, Endocrinology and Genomic Unit and Laval University, Faculty of Medicine, Quebec G1V 4G2, Canada.
Eur J Med Chem. 2011 Sep;46(9):4227-37. doi: 10.1016/j.ejmech.2011.06.027. Epub 2011 Jun 28.
Steroid sulfatase (STS) controls the levels of 3-hydroxysteroids available from circulating steroid sulfates in several normal and malignant tissues. This and the known involvement of active estrogens and androgens in diseases such as breast and prostate cancers thus make STS an interesting therapeutic target. Here we describe the chemical synthesis and characterization of an extended series of 17α-derivatives of estradiol (E2) using different strategies. A variant of the samarium-Barbier reaction with stoichiometric samarium metal and catalytic Kagan reagent formation was used for introducing low reactive benzyl substrates in position 17 of estrone (E1) whereas heterocyclic substrates were metalated and reacted with either the carbonyl or the 17-oxirane of E1. In vitro evaluation of the inhibitory potency of the new compounds against STS identified new inhibitors and allowed a more complete structure-activity relationship study of this family of 17α-derivatives of E2.
甾体硫酸酯酶 (STS) 控制着几种正常和恶性组织中循环甾体硫酸酯中 3-羟基甾体的水平。这一事实以及已知的活性雌激素和雄激素在乳腺癌和前列腺癌等疾病中的作用，使得 STS 成为一个有趣的治疗靶点。在这里，我们描述了使用不同策略对雌二醇 (E2) 的 17α-衍生物进行的化学合成和表征。使用等摩尔钐金属和催化 Kagan 试剂形成的钐-Barbier 反应变体用于在雌酮 (E1) 的 17 位引入低反应性苄基底物，而杂环底物则被金属化并与 E1 的羰基或 17-环氧乙烷反应。对新化合物抑制 STS 活性的体外评估鉴定出了新的抑制剂，并允许对这一系列 E2 的 17α-衍生物进行更完整的构效关系研究。
