Enzymology and ToxicitySelective, competitive and mechanism-based inhibitors of human cytochrome P450 2J2
Section snippets
Commercial chemicals
All chemicals used in this study were of the highest purity available. Organic and HPLC solvents were purchased from SDS (Peypin, France); ebastine was provided by Almirall (Paris, France). NADP+, glucose 6-phosphate and glucose 6-phosphate dehydrogenase were purchased from Boehringer-Mannheim (Mannheim, Germany). Paclitaxel, amodiaquine, reduced glutathione (GSH), 7-benzyloxyresorufin, resorufin, diclofenac, testosterone, ticlopidine, sulfaphenazole and ketoconazole were obtained from Sigma
Synthesis of three series of derivatives of terfenadone, dehydro-terfenadone and ebastine
The choice of terfenadone, 1, and ebastine as starting points for the design of high-affinity inhibitors of CYP2J2 was based on: (i) the high regioselectivity of the CYP2J2-catalyzed hydroxylations of 1 and ebastine, in favor of the least reactive part of these substrates (Fig. 1), which implies their strict positioning in the CYP2J2 active site to keep their t-butyl group in close proximity of the heme iron for transfer of an oxygen atom from O2, and (ii) the high affinity of 1 and ebastine
Conclusion
Starting from the structures of terfenadone and ebastine, 24 derivatives have been synthesized and evaluated as inhibitors of CYP2J2. Many of them exhibit a good affinity for this isoform with IC50s at the micromolar level. A comparison of these IC50s has shown the importance of three structural features for a good recognition by CYP2J2: (i) the presence of a short hydrophobic alkyl chain at one end of the molecule, (ii) the presence of a keto group para to this alkyl chain on the terminal aryl
Acknowledgments
We thank Dr. Didier Buisson (UMR8601) for a gift of compounds 2, 10, 16 and 25. This research was supported by the C.N.R.S. (Centre National de la Recherche Scientifique) and Ministère de la Recherche (France), and by the Intramural Research Program of the National Institutes of Environmental Health Sciences, National Institutes of Health (USA).
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