Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 54, Issue -, Pages 804-812Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2012.06.042
Keywords
Lapachol; Naphtoquinones; Biomimetic oxidation; Jacobsen catalyst; Drug metabolism; Phase I metabolism
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Funding
- FAPESP
- CNPq
- INCT_if (CNPq) [573663/2008-4]
- CAPES (Brazil)
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The bioactive naphtoquinone lapachol was studied in vitro by a biomimetic model with Jacobsen catalyst (manganese(III) salen) and iodosylbenzene as oxidizing agent. Eleven oxidation derivatives were thus identified and two competitive oxidation pathways postulated. Similar to Mn(III) porphyrins, Jacobsen catalyst mainly induced the formation of para-naphtoquinone derivatives of lapachol, but also of two ortho-derivatives. The oxidation products were used to develop a GC MS (SIM mode) method for the identification of potential phase I metabolites in vivo. Plasma analysis of Wistar rats orally administered with lapachol revealed two metabolites, alpha-lapachone and dehydro-alpha-lapachone. Hence, the biomimetic model with a manganese salen complex has evidenced its use as a valuable tool to predict and elucidate the in vivo phase I metabolism of lapachol and possibly also of other bioactive natural compounds. (C) 2012 Elsevier Masson SAS. All rights reserved.
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