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Synthesis of 16β-derivatives of 3-(2-bromoethyl)-estra-1,3,5(10)-trien-17β-ol as inhibitors of 17β-HSD1 and/or steroid sulfatase for the treatment of estrogen-dependent diseases.

Authors
  • Lespérance, Maxime1
  • Roy, Jenny1
  • Djiemeny Ngueta, Adrien1
  • Maltais, René1
  • Poirier, Donald2
  • 1 Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center (CHUL, T4), Québec, QC G1V4G2, Canada. , (Canada)
  • 2 Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center (CHUL, T4), Québec, QC G1V4G2, Canada; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC G1V0A6, Canada. Electronic address: [email protected] , (Canada)
Type
Published Article
Journal
Steroids
Publication Date
May 01, 2021
Volume
172
Pages
108856–108856
Identifiers
DOI: 10.1016/j.steroids.2021.108856
PMID: 33945801
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) and steroid sulfatase (STS) are involved in the synthesis of the most potent estrogen in the human body, estradiol (E2). These enzymes are known to play a pivotal role in the progression of estrogen-dependent diseases, such as breast cancer and endometriosis. Therefore, the inhibition of 17β-HSD1 and/or STS represents a promising avenue to modulate the growth of estrogen-dependent tumors or lesions. We recently established the key role of a bromoethyl side chain added at the C3-position of a 16β-carbamoyl-benzyl-E2 nucleus to covalently inhibit 17β-HSD1. To extend the structure-activity relationship study to the C16β-position of this new selective irreversible inhibitor (PBRM), we synthesized a series of analog compounds by changing the nature of the C16β-side chain but keeping the 2-bromoethyl group at position C3. We determined their 17β-HSD1 inhibitions in T-47D cells (transformation of E1 into E2), but we did not obtain a stronger 17β-HSD1 inhibitor than PBRM. Compounds 16 and 17 were found to be more likely to bind to the catalytic site and showed a promising but moderate inhibitory activity with estimated IC50 values of 0.5 and 0.7 µM, respectively (about 10 times higher than PBRM). Interestingly, adding one or two sulfamate groups in the D-ring's surroundings did not significantly decrease compounds' potential to inhibit 17β-HSD1, but clearly improved their potential to inhibit STS. These results open the door to the development of a new family of steroid derivatives with dual (17β-HSD1 and STS) inhibiting actions. Copyright © 2021 Elsevier Inc. All rights reserved.

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