Oxidation of 2-Hydroxynevirapine, a Phenolic Metabolite of the Anti-HIV Drug Nevirapine Evidence for an Unusual Pyridine Ring Contraction 英文参考文献.docVIP

Molecules 2012, 17, 2616-2627; doi:10.3390/moleculeOPEN ACCESS molecules ISSN 1420-3049 /journal/molecules 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,*, Muna Sidarus 1, David A. Novais 1, Shrika G. Harjivan 1, Pedro P. Santos 1, Jo?o 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; E-Mail: alexandra.antunes@ist.utl.pt; Tel.: +351-21-8419388; Fax: +351-21-8464455. Received: 15 January 2012; in revised form: 18 February 2012 / Accepted: 27 February 2012 / Published: 5 March 2012 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 enzy