Abstract
Local biosynthesis of estrogens, especially estradiol (E2), is thought to be important for the maintenance and growth of estrogen-sensitive diseases. To control E2 formation, we have investigated a series of epoxide and furanic E2 derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), the enzyme responsible for the conversion of estrone (E1) into E2. We report here a strategy to synthesize a series of E2-furanic derivatives from E1. An intermediate epoxide was first obtained and then reduced to give a furanic steroid, which allowed us to introduce a molecular diversity like alcohol, bromide, ester, acid and amide. The inhibition of the transformation of [14C]-E1 (100 nM) into [14C]-E2 by these compounds was first evaluated with homogenated HEK-293 cells overexpressing 17β-HSD1. The epoxide and butylamide derivatives showed the best inhibitions with 72% and 66%, respectively, at 10 μM. All furanic compounds showed a lower 17β-HSD1 inhibitory potency in intact T-47D breast cancer cells than in homogenated cells, but a great improvement of the inhibitory activity was observed for the epoxide, which gave 62% and 90% of inhibition of the [14C]-E1 (60 nM) into [14C]-E2 transformation at 1 and 10 μM, respectively.
Keywords: 17β-hydroxysteroid dehydrogenase, enzyme, inhibitor, steroid, synthesis, cancer, estrogens, estrone, epoxide, steroidogenesis, mammary tumors, furanic, VWR, TLC
Medicinal Chemistry
Title: Chemical Synthesis, Characterisation and Biological Evaluation of Furanic- Estradiol Derivatives as Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1
Volume: 7 Issue: 2
Author(s): Siham Farhane, Yannick Laplante and Donald Poirier
Affiliation:
Keywords: 17β-hydroxysteroid dehydrogenase, enzyme, inhibitor, steroid, synthesis, cancer, estrogens, estrone, epoxide, steroidogenesis, mammary tumors, furanic, VWR, TLC
Abstract: Local biosynthesis of estrogens, especially estradiol (E2), is thought to be important for the maintenance and growth of estrogen-sensitive diseases. To control E2 formation, we have investigated a series of epoxide and furanic E2 derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), the enzyme responsible for the conversion of estrone (E1) into E2. We report here a strategy to synthesize a series of E2-furanic derivatives from E1. An intermediate epoxide was first obtained and then reduced to give a furanic steroid, which allowed us to introduce a molecular diversity like alcohol, bromide, ester, acid and amide. The inhibition of the transformation of [14C]-E1 (100 nM) into [14C]-E2 by these compounds was first evaluated with homogenated HEK-293 cells overexpressing 17β-HSD1. The epoxide and butylamide derivatives showed the best inhibitions with 72% and 66%, respectively, at 10 μM. All furanic compounds showed a lower 17β-HSD1 inhibitory potency in intact T-47D breast cancer cells than in homogenated cells, but a great improvement of the inhibitory activity was observed for the epoxide, which gave 62% and 90% of inhibition of the [14C]-E1 (60 nM) into [14C]-E2 transformation at 1 and 10 μM, respectively.
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Farhane Siham, Laplante Yannick and Poirier Donald, Chemical Synthesis, Characterisation and Biological Evaluation of Furanic- Estradiol Derivatives as Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1, Medicinal Chemistry 2011; 7 (2) . https://dx.doi.org/10.2174/157340611794859352
DOI https://dx.doi.org/10.2174/157340611794859352 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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