Niinivehmas Sanna, Postila Pekka A, Rauhamäki Sanna, Manivannan Elangovan, Kortet Sami, Ahinko Mira, Huuskonen Pasi, Nyberg Niina, Koskimies Pasi, Lätti Sakari, Multamäki Elina, Juvonen Risto O, Raunio Hannu, Pasanen Markku, Huuskonen Juhani, Pentikäinen Olli T
a Department of Biological and Environmental Science and Nanoscience Center , University of Jyvaskyla , Jyvaskyla , Finland.
b School of Pharmacy , Devi Ahilya University , Indore , India.
J Enzyme Inhib Med Chem. 2018 Dec;33(1):743-754. doi: 10.1080/14756366.2018.1452919.
A comprehensive set of 3-phenylcoumarin analogues with polar substituents was synthesised for blocking oestradiol synthesis by 17-β-hydroxysteroid dehydrogenase 1 (HSD1) in the latter part of the sulphatase pathway. Five analogues produced ≥62% HSD1 inhibition at 5 µM and, furthermore, three of them produced ≥68% inhibition at 1 µM. A docking-based structure-activity relationship analysis was done to determine the molecular basis of the inhibition and the cross-reactivity of the analogues was tested against oestrogen receptor, aromatase, cytochrome P450 1A2, and monoamine oxidases. Most of the analogues are only modestly active with 17-β-hydroxysteroid dehydrogenase 2 - a requirement for lowering effective oestradiol levels in vivo. Moreover, the analysis led to the synthesis and discovery of 3-imidazolecoumarin as a potent aromatase inhibitor. In short, coumarin core can be tailored with specific ring and polar moiety substitutions to block either the sulphatase pathway or the aromatase pathway for treating breast cancer and endometriosis.
合成了一组完整的带有极性取代基的3-苯基香豆素类似物，用于在后半段硫酸酯酶途径中阻断17-β-羟基类固醇脱氢酶1（HSD1）合成雌二醇。五种类似物在5μM时对HSD1的抑制率≥62%，此外，其中三种在1μM时的抑制率≥68%。进行了基于对接的构效关系分析，以确定抑制作用的分子基础，并测试了这些类似物与雌激素受体、芳香化酶、细胞色素P450 1A2和单胺氧化酶的交叉反应性。大多数类似物对17-β-羟基类固醇脱氢酶2的活性仅为中等水平，而这是降低体内有效雌二醇水平所必需的。此外，该分析还促成了3-咪唑香豆素作为一种强效芳香化酶抑制剂的合成与发现。简而言之，香豆素核心可以通过特定的环和极性部分取代进行定制，以阻断硫酸酯酶途径或芳香化酶途径，用于治疗乳腺癌和子宫内膜异位症。
