Personne : Barbeau, Xavier
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Département de biochimie, microbiologie et bio-informatique, Faculté des sciences et de génie, Université Laval
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- PublicationRestreintImpact 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(Pergamon, 2015-10-28) Barbeau, Xavier; Poirier, Donald; Maltais, René.; Lin, Sheng-Xiang; Lagüe, Patrick; Thériault, Jean-François; Trottier, Alexandre; Perreault, MartinThe 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.
- PublicationAccès libreInterfacial supramolecular biomimetic epoxidation catalysed by cyclic dipeptides(Taylor & Francis group, 2016-10-13) Barbeau, Xavier; Delcey, Nicolas; Bérubé, Christopher; Cardinal, Sébastien; Bouchard, Corinne; Lagüe, Patrick; Boudreault, Pierre-Luc.; Voyer, NormandWe synthesised a library of cis- and trans-cyclic dipeptides and evaluated their efficacy as catalysts in the asymmetric Weitz-Scheffer epoxidation of trans-chalcone. A thorough investigation relying on structure-activity studies and computational studies provided insights into the mechanism of the process. Our results revealed some structural features required for efficient conversion and for introduction of chirality into the product. The cyclic dipeptide acts as a catalyst by templating a supramolecular arrangement at the aqueous-organic interface required for efficient transformations to occur. Among all cyclic dipeptides investigated, cyclo(Leu-Leu) was the most efficient supramolecular catalyst.
- PublicationAccès libreRevisiting the Juliá–Colonna enantioselective epoxidation : supramolecular catalysis in water(Royal Society of Chemistry, 2017-04-12) Barbeau, Xavier; Bérubé, Christopher; Lagüe, Patrick; Voyer, NormandWe describe an efficient epoxidation process leading to chiral epoxyketones using the reusable homo-oligopeptide poly-L-leucine (PLL) in pure water, without any organic co-solvent. A range of substituted epoxyketones can be accessed with good conversions and high enantioselectivities. Based on the experimental results and computational studies, we propose a mechanism that demonstrates the importance of both the α-helical structure and the presence of a hydrophobic groove of the homo-oligopeptide catalyst for reactivity and selectivity