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

DC FieldValueLanguage
dc.contributor.authorMaltais, René-
dc.contributor.authorTrottier, Alexandre-
dc.contributor.authorBarbeau, Xavier-
dc.contributor.authorLagüe, Patrick-
dc.contributor.authorPerreault, Martin-
dc.contributor.authorThériault, Jean-François-
dc.contributor.authorLin, Sheng-Xiang-
dc.contributor.authorPoirier, Donald-
dc.date.accessioned2016-05-17T17:31:39Z-
dc.date.available10000-01-01-
dc.identifier.issn0960-0760fr_CA
dc.identifier.urihttp://hdl.handle.net/20.500.11794/1348-
dc.description.abstractThe 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.fr_CA
dc.languageengfr_CA
dc.publisherPergamonfr_CA
dc.subjectSteroidfr_CA
dc.subjectEnzyme inhibitorfr_CA
dc.subjectEstrogenfr_CA
dc.subjectChemical synthesisfr_CA
dc.subjectEstradiol isomerfr_CA
dc.titleImpact 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 activityfr_CA
dc.typeCOAR1_1::Texte::Périodique::Revue::Contribution à un journal::Article::Article de recherche-
dcterms.bibliographicCitationJournal of Steroid Biochemistry & Molecular Biology, (2015)fr_CA
dc.audienceProfesseurs (Enseignement supérieur)fr_CA
dc.audienceÉtudiantsfr_CA
dc.audienceDoctorantsfr_CA
dc.audienceBiochimistesfr_CA
dc.identifier.doi10.1016/j.jsbmb.2015.10.020fr_CA
dc.identifier.pubmed26519987fr_CA
dc.subject.rvmStéroïdesfr_CA
dc.subject.rvmAntienzymesfr_CA
dc.subject.rvmŒstrogènesfr_CA
dc.subject.rvm17-bêta-hydroxystéroïde déshydrogénase type 1fr_CA
dc.subject.rvmComposés organiques -- Synthèsefr_CA
dc.subject.rvmŒstradiolfr_CA
dcterms.date.accepted2015-10-25-
rioxxterms.versionVersion of Recordfr_CA
rioxxterms.version_of_recordhttps://doi.org/10.1016/j.jsbmb.2015.10.020fr_CA
rioxxterms.project.funder_nameirscfr_CA
bul.rights.periodeEmbargoInfinifr_CA
Collection:Articles publiés dans des revues avec comité de lecture

Files in this item:
SizeFormat 
1-s2.0-S0960076015301229-main.pdf
2.38 MBAdobe PDF    Request a copy
All documents in CorpusUL are protected by Copyright Act of Canada.