Impact of structural modifications at positions 13, 16 and 17 of 16 b -( m -carbamoylbenzyl)-estradiol on 17 b -hydroxysteroid dehydrogenase type 1 inhibition and estrogenic activity

Authors: Maltais, René; Trottier, Alexandre; Barbeau, Xavier; Lagüe, Patrick; Perreault, Martin; Thériault, Jean-François; Lin, Sheng-XiangPoirier, Donald
Abstract: The chemical synthesis of four stereoisomers (compounds 5a–d) of 16ß-(m-carbamoylbenzyl)-estradiol, a potent reversible inhibitor of 17ß-hydroxysteroid dehydrogenase type 1 (17ß-HSD1), and two intermediates (compounds 3a and b) was performed. Assignment of all nuclear magnetic resonance signals confirmed the stereochemistry at positions 13, 16 and 17. Nuclear overhauser effects showed clear correlations supporting a C-ring chair conformation for 5a and b and a C-ring boat conformation for 5c and d. These compounds were tested as 17ß-HSD1 inhibitors and to assess their proliferative activity on estrogen-sensitive breast cancer cells (T-47D) and androgen-sensitive prostate cancer cells (LAPC-4). Steroid derivative 5a showed the best inhibitory activity for the transformation of estrone to estradiol (95, 82 and 27%, at 10, 1 and 0.1 µM, respectively), but like the other isomers 5c and d, it was found to be estrogenic. The intermediate 3a, however, was weakly estrogenic at 1 µM, not at all at 0.1 µM, and showed an interesting inhibitory potency on 17ß-HSD1 (90, 59 and 22%, at 10, 1 and 0.1 µM, respectively). As expected, no compound showed an androgenic activity. The binding modes for compounds 3a and b, 5a–d and CC-156 were evaluated from molecular modeling. While the non-polar interactions were conserved for all the inhibitors in their binding to 17ß-HSD1, differences in polar interactions and in binding conformational energies correlated to the inhibitory potencies.
Open Access Date: Restricted access
Document version: VoR
Permalink: http://hdl.handle.net/20.500.11794/1348
This document was published in: Journal of Steroid Biochemistry & Molecular Biology, (2015)
http://dx.doi.org/10.1016/j.jsbmb.2015.10.020
Pergamon
Alternative version: 10.1016/j.jsbmb.2015.10.020
http://www.ncbi.nlm.nih.gov/pubmed/26519987
Collection:Articles publiés dans des revues avec comité de lecture

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