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Synthesis and evaluation of benzoxazolinonic imidazoles and derivatives as non-steroidal aromatase inhibitors

TitreSynthesis and evaluation of benzoxazolinonic imidazoles and derivatives as non-steroidal aromatase inhibitors
Type de publicationJournal Article
Year of Publication2004
AuteursNativelle-Serpentini, C, Moslemi, S, Yous, S, Park, C-H, Lesieur, D, Sourdaine, P, Seralini, G-E
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume19
Pagination119–127
ISSN1475-6366
Résumé

New compounds were tested in vitro on aromatase activity in human placental and equine testicular microsomes. Equine aromatase, very well characterized biochemically, is used as a comparative model to understand the mechanism of aromatase inhibition. Among 15 molecules screened, 5 of them (11-15) strongly inhibit human and equine aromatases with IC50 values ranging from 13-85nM and from 23-103nM respectively. These results were corroborated by Ki/Km values. Moreover, spectral studies showed a type II spectrum with both enzymes, which is characteristic of an interaction between the nitrogen atom of the molecule and the heme of the cytochrome P450. Compound 12, which has the lowest IC50 and Ki/Km ratio, inactivates aromatase in a dose and time-dependent manner. This might be very important for the treatment of estrogen-dependent diseases such as breast cancer. Finally, MTT assays on E293 cells revealed that the molecules were not cytotoxic.