title: Synthesis and oxidation of 2-hydroxynevirapine, a metabolite of the HIV reverse transcriptase inhibitor nevirapine.
abstract: Nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, NVP) is a non-nucleoside HIV-1 reverse transcriptase inhibitor used to prevent mother-to-child transmission of the virus. However, severe hepatotoxicity and serious adverse cutaneous effects have raised concerns about the safety of NVP administration. NVP metabolism yields several phenol-type derivatives conceivably capable of undergoing further metabolic oxidation to electrophilic quinoid species that could react with bionucleophiles. The covalent adducts thus formed might be at the genesis of toxic responses. As an initial step to test this hypothesis, we synthesized the phenolic metabolite, 2-hydroxy-NVP, and investigated its oxidation in vitro. Using potassium nitrosodisulfonate and sodium periodate as model oxidants, we obtained evidence for fast generation of an electrophilic quinone-imine, which readily underwent hydrolytic conversion to fully characterized spiro derivatives, 1'-cyclopropyl-4-methyl-1H,1'H-spiro[pyridine-2,2'-pyrido[2,3-d]pyrimidine]-3,4',6(3'H)-trione in aqueous media and 1'-cyclopropyl-4-methyl-1'H,2H-spiro[pyridine-3,2'-pyrido[2,3-d]pyrimidine]-2,4',6(1H,3'H)-trione in non-aqueous media. The spiro compound generated in aqueous solution underwent subsequent hydrolytic degradation of the NVP ring system, whereas the one formed in non-aqueous media was stable to hydrolysis. The product profile observed with the chemical oxidants in aqueous solution was replicated using lactoperoxidase-mediated oxidation of 2-hydroxy-NVP. These observations suggest that metabolic activation of NVP, via Phase I oxidation to 2-hydroxy-NVP and subsequent generation of a quinone-imine, could occur in vivo and play a role in NVP-induced toxicity.
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade Técnica de Lisboa, 1049-001, Lisboa, Portugal. alexandra.antunes@ist.utl.pt
authors.forename: Alexandra M M
authors.initials: AM
authors.lastname: Antunes
authors.forename: David A
authors.initials: DA
authors.lastname: Novais
authors.forename: J L Ferreira
authors.initials: JL
authors.lastname: da Silva
authors.forename: Pedro P
authors.initials: PP
authors.lastname: Santos
authors.forename: M Conceição
authors.initials: MC
authors.lastname: Oliveira
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Beland
authors.forename: M Matilde
authors.initials: MM
authors.lastname: Marques
mesh_terms: D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control; D019829:Nevirapine / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000627:therapeutic use; D016877:Oxidants / Q000737:chemistry; D010084:Oxidation-Reduction; D010504:Periodic Acid / Q000737:chemistry; D010636:Phenols / Q000737:chemistry / Q000378:metabolism*; D011247:Pregnancy; D011725:Pyridines / Q000737:chemistry; D011809:Quinones / Q000737:chemistry / Q000378:metabolism*; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D012996:Solutions; D014867:Water
chemical_list: D019380:Anti-HIV Agents; D016877:Oxidants; D010636:Phenols; D011725:Pyridines; D011809:Quinones; D018894:Reverse Transcriptase Inhibitors; D012996:Solutions; D014867:Water; D010504:Periodic Acid; D019829:Nevirapine; C009288:metaperiodate; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase