Molecules 2012, 17(3), 2616-2627; doi:10.3390/molecules17032616
Article

Oxidation of 2-Hydroxynevirapine, a Phenolic Metabolite of the Anti-HIV Drug Nevirapine: Evidence for an Unusual Pyridine Ring Contraction

Alexandra M. M. Antunes 1,* email, Muna Sidarus 1 , David A. Novais 1 , Shrika G. Harjivan 1 , Pedro P. Santos 1 , João L. Ferreira da Silva 1 , Frederick A. Beland 2  and M. Matilde Marques 1
1 Centro de Química Estrutural, Instituto Superior Técnico, Universidade Técnica de Lisboa, Lisboa 1049-001, Portugal 2 National Center for Toxicological Research, Jefferson, AR 72079, USA
* Author to whom correspondence should be addressed.
Received: 15 January 2012; in revised form: 18 February 2012 / Accepted: 27 February 2012 / Published: 5 March 2012
(This article belongs to the Special Issue ECSOC-15)
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Abstract: Nevirapine (NVP) is an anti-HIV drug associated with severe hepatotoxicity and skin rashes, which raises concerns about its chronic administration. There is increasing evidence that metabolic activation to reactive electrophiles capable of reacting with bionucleophiles is likely to be involved in the initiation of these toxic responses. Phase I NVP metabolism involves oxidation of the 4-methyl substituent 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 Phase I phenolic NVP 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 of a 1H-pyrrole-2,5-dione derivative as a major product, stemming from an unusual pyridine ring contraction.
Keywords: anti-HIV drug; nevirapine; oxidation; pyridine ring contraction

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MDPI and ACS Style

Antunes, A.M.M.; Sidarus, M.; Novais, D.A.; Harjivan, S.G.; Santos, P.P.; Ferreira da Silva, J.L.; Beland, F.A.; Marques, M.M. Oxidation of 2-Hydroxynevirapine, a Phenolic Metabolite of the Anti-HIV Drug Nevirapine: Evidence for an Unusual Pyridine Ring Contraction. Molecules 2012, 17, 2616-2627.

AMA Style

Antunes AMM, Sidarus M, Novais DA, Harjivan SG, Santos PP, Ferreira da Silva JL, Beland FA, Marques MM. Oxidation of 2-Hydroxynevirapine, a Phenolic Metabolite of the Anti-HIV Drug Nevirapine: Evidence for an Unusual Pyridine Ring Contraction. Molecules. 2012; 17(3):2616-2627.

Chicago/Turabian Style

Antunes, Alexandra M. M.; Sidarus, Muna; Novais, David A.; Harjivan, Shrika G.; Santos, Pedro P.; Ferreira da Silva, João L.; Beland, Frederick A.; Marques, M. Matilde. 2012. "Oxidation of 2-Hydroxynevirapine, a Phenolic Metabolite of the Anti-HIV Drug Nevirapine: Evidence for an Unusual Pyridine Ring Contraction." Molecules 17, no. 3: 2616-2627.

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