Bey Emmanuel, Marchais-Oberwinkler Sandrine, Kruchten Patricia, Frotscher Martin, Werth Ruth, Oster Alexander, Algül Oztekin, Neugebauer Alexander, Hartmann Rolf W
8.2 Pharmaceutical and Medicinal Chemistry, Saarland University, PO Box 15 11 50, D-66041 Saarbrücken, Germany.
Bioorg Med Chem. 2008 Jun 15;16(12):6423-35. doi: 10.1016/j.bmc.2008.04.073. Epub 2008 May 3.
The 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyses the reduction of the weakly active estrone (E1) into the most potent estrogen, 17beta-estradiol (E2). E2 stimulates the growth of hormone-dependent diseases via activation of the estrogen receptors (ERs). 17beta-HSD1 is often over-expressed in breast cancer cells. Thus, it is an attractive target for the treatment of mammary tumours. The combination of a ligand- and a structure-based drug design approach led to the identification of bis(hydroxyphenyl) azoles as potential inhibitors of 17beta-HSD1. Different azoles and hydroxy substitution patterns were investigated. The compounds were evaluated for activity and selectivity with regard to 17beta-HSD2, ERalpha and ERbeta. The most potent compound is 3-[5-(4-hydroxyphenyl)-1,3-oxazol-2-yl]phenol (18, IC(50)=0.31 microM), showing very good selectivity, high cell permeability and medium CaCo-2 permeability.
17β-羟基类固醇脱氢酶1型（17β-HSD1）催化将活性较弱的雌酮（E1）还原为活性最强的雌激素17β-雌二醇（E2）。E2通过激活雌激素受体（ERs）刺激激素依赖性疾病的发展。17β-HSD1在乳腺癌细胞中常过度表达。因此，它是治疗乳腺肿瘤的一个有吸引力的靶点。结合基于配体和基于结构的药物设计方法，确定了双（羟苯基）唑类化合物作为17β-HSD1的潜在抑制剂。研究了不同的唑类和羟基取代模式。对这些化合物针对17β-HSD2、ERα和ERβ的活性和选择性进行了评估。最有效的化合物是3-[5-（4-羟苯基）-1,3-恶唑-2-基]苯酚（18，IC50 = 0.31微摩尔），显示出非常好的选择性、高细胞通透性和中等的CaCo-2通透性。
