Oxidation of The Nevirapine Metabolite, 2-Hydroxy-Nevirapine, With Frémy\'s Salt: Unusual Pyridine Ring Contraction

Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used against the human immunodeficiency virus type-1 (HIV-1), mostly to prevent mother-to-child HIV transmission in developing countries [1]. One of the limitations of NVP use is severe hepatotoxicity [2], which raises concerns about its chronic administration, particularly in the perinatal and pediatric settings. The reasons for the adverse effects of NVP administration are currently not clear, although there is increasing evidence that metabolic activation to reactive electrophiles capable of reacting with bionucleophiles is likely to be involved in the initiation of toxic responses. Phase I NVP metabolism involves oxidation of the 4-methyl substituent to 12-hydroxy-NVP , and the formation of phenolic derivatives that are conceivably capable of undergoing further metabolic oxidation to electrophilic quinoid species prone to react with bionucleophiles. The covalent adducts thus formed might be at the genesis of toxic responses. As part of a program aimed at evaluating the possible contribution of quinoid derivatives of NVP Phase I phenolic metabolites to the toxic responses elicited by the parent drug, we have investigated the oxidation of 2-hydroxy-NVP with dipotassium nitroso-disulfonate (Frémy\'s salt), mimicking the one-electron oxidation involved in enzyme-mediated metabolic oxidations. We report herein the isolation and full structural characterization (by NMR, MS and X-ray diffraction) of a 1H-pyrrole-2,5-dione derivative as a major product, stemming from an unusual pyridine ring contraction. References: [1] Lockman et al., N. Engl. J. Med. 2007, 356, 135-147. [2] Pollard et al., Clin. Ther 1998, 20, 1071–1092. Acknowledgments: We thank the Portuguese NMR Network (IST-UTL Center) and the Portuguese MS Network (IST-UTL Center) for providing access to the facilities. This work was supported in part by research