Blocking oestradiol synthesis pathways with potent and selective coumarin derivatives
Niinivehmas, S., Postila, P., Rauhamäki, S., Manivannan, E., Kortet, S., Ahinko, M., . . . Pentikäinen, O. (2018). Blocking oestradiol synthesis pathways with potent and selective coumarin derivatives. Journal of Enzyme Inhibition and Medicinal Chemistry, 33 (1), 743-754. doi:10.1080/14756366.2018.1452919
Published inJournal of Enzyme Inhibition and Medicinal Chemistry
© 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License.
A comprehensive set of 3-phenylcoumarin analogues with polar substituents was synthesised for blocking oestradiol synthesis by 17-b-hydroxysteroid dehydrogenase 1 (HSD1) in the latter part of the sulphatase pathway. Five analogues produced 62% HSD1 inhibition at 5 mM and, furthermore, three of them produced 68% inhibition at 1 mM. 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-b-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. ...