Al-Soud Yaseen A, Bey Emmanuel, Oster Alexander, Marchais-Oberwinkler Sandrine, Werth Ruth, Kruchten Patricia, Frotscher Martin, Hartmann Rolf W
8.2 Pharmaceutical and Medicinal Chemistry, Saarland University, PO Box 15 11 50, D-66041 Saarbrücken, Germany.
Mol Cell Endocrinol. 2009 Mar 25;301(1-2):212-5. doi: 10.1016/j.mce.2008.09.012. Epub 2008 Sep 19.
17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is responsible for the catalytic reduction of the weak estrogen estrone (E1) into the highly potent 17beta-estradiol (E2). As 17beta-HSD1 is often overexpressed in mammary tumors and endometriosis, the selective inhibition of this enzyme is discussed as a promising approach for the treatment of estrogen-dependent diseases. Recently, we reported on bis(hydroxyphenyl)azoles as a new class of potent inhibitors of 17beta-HSD1. In this paper, we focused on bis(hydroxyphenyl)triazoles. The influence of nitrogens on the potency as well as the space available around the heterocycle was investigated. Substituents were introduced on the triazole core in order to establish additional interactions with the enzyme active site. The compounds were evaluated for activity towards 17beta-HSD1 and selectivity with regard to 17beta-HSD2, the enzyme which is responsible for the deactivation of E2 into E1. 3-[4-(4-Hydroxyphenyl)-1H-1,2,3-triazol-1-yl]phenol (3) was the most active compound discovered in this study with an IC(50) value of 840nM and a reasonable selectivity towards 17beta-HSD2.
17β-羟类固醇脱氢酶1型（17β-HSD1）负责将弱雌激素雌酮（E1）催化还原为高效能的17β-雌二醇（E2）。由于17β-HSD1在乳腺肿瘤和子宫内膜异位症中常常过度表达，对该酶的选择性抑制作为一种治疗雌激素依赖性疾病的有前景的方法受到了讨论。最近，我们报道了双（羟苯基）唑类作为一类新型的17β-HSD1强效抑制剂。在本文中，我们聚焦于双（羟苯基）三唑类。研究了氮原子对活性的影响以及杂环周围的可用空间。在三唑核心上引入取代基，以便与酶活性位点建立额外的相互作用。评估了这些化合物对17β-HSD1的活性以及对17β-HSD2（负责将E2失活为E1的酶）的选择性。3-[4-(4-羟苯基)-1H-1,2,3-三唑-1-基]苯酚（3）是本研究中发现的活性最高的化合物，其IC50值为840 nM，对17β-HSD2具有合理的选择性。
