title: Jacobsen catalyst as a cytochrome P450 biomimetic model for the metabolism of monensin A.
abstract: Monensin A is a commercially important natural product isolated from Streptomyces cinnamonensins that is primarily employed to treat coccidiosis. Monensin A selectively complexes and transports sodium cations across lipid membranes and displays a variety of biological properties. In this study, we evaluated the Jacobsen catalyst as a cytochrome P450 biomimetic model to investigate the oxidation of monensin A. Mass spectrometry analysis of the products from these model systems revealed the formation of two products: 3-O-demethyl monensin A and 12-hydroxy monensin A, which are the same ones found in in vivo models. Monensin A and products obtained in biomimetic model were tested in a mitochondrial toxicity model assessment and an antimicrobial bioassay against Staphylococcus aureus, S. aureus methicillin-resistant, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Escherichia coli. Our results demonstrated the toxicological effects of monensin A in isolated rat liver mitochondria but not its products, showing that the metabolism of monensin A is a detoxification metabolism. In addition, the antimicrobial bioassay showed that monensin A and its products possessed activity against Gram-positive microorganisms but not for Gram-negative microorganisms. The results revealed the potential of application of this biomimetic chemical model in the synthesis of drug metabolites, providing metabolites for biological tests and other purposes.
authors.affiliation: Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14040-901 Ribeirão Preto, SP, Brazil.
authors.forename: Bruno Alves
authors.initials: BA
authors.lastname: Rocha
authors.affiliation: Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14040-901 Ribeirão Preto, SP, Brazil.
authors.forename: Anderson Rodrigo Moraes
authors.initials: AR
authors.lastname: de Oliveira
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, 14040-903 Ribeirão Preto, SP, Brazil.
authors.forename: Murilo
authors.initials: M
authors.lastname: Pazin
authors.affiliation: Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14040-901 Ribeirão Preto, SP, Brazil.
authors.forename: Daniel Junqueira
authors.initials: DJ
authors.lastname: Dorta
authors.affiliation: Laboratório de Pesquisa, Desenvolvimento e Inovação, Apis Flora Industrial e Comercial LTDA, 140120-670 Ribeirão Preto, SP, Brazil.
authors.forename: Andresa Piacezzi Nascimento
authors.initials: AP
authors.lastname: Rodrigues
authors.affiliation: Laboratório de Pesquisa, Desenvolvimento e Inovação, Apis Flora Industrial e Comercial LTDA, 140120-670 Ribeirão Preto, SP, Brazil.
authors.forename: Andresa Aparecida
authors.initials: AA
authors.lastname: Berretta
authors.affiliation: Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14040-901 Ribeirão Preto, SP, Brazil.
authors.forename: Ana Paula Ferranti
authors.initials: AP
authors.lastname: Peti
authors.affiliation: Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14040-901 Ribeirão Preto, SP, Brazil.
authors.forename: Luiz Alberto Beraldo
authors.initials: LA
authors.lastname: de Moraes
authors.affiliation: Núcleo de Pesquisas em Produtos Naturais e Sintéticos, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, 14040-903 Ribeirão Preto, SP, Brazil.
authors.forename: Norberto Peporine
authors.initials: NP
authors.lastname: Lopes
authors.affiliation: Institute of Microbiology, Academy of Sciences of the Czech Republic, Vídeňská, CZ-142 20 Prague, Czech Republic.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Pospíšil
authors.affiliation: School of Chemistry, University of Bristol, Bristol BS8 1TS, UK.
authors.forename: Paul Jonathan
authors.initials: PJ
authors.lastname: Gates
authors.affiliation: Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14040-901 Ribeirão Preto, SP, Brazil.
authors.forename: Marilda das Dores
authors.initials: Md
authors.lastname: Assis
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001419:Bacteria / Q000254:growth & development; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism*; D008954:Models, Biological; D008985:Monensin / Q000493:pharmacokinetics / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats
chemical_list: D000935:Antifungal Agents; D003577:Cytochrome P-450 Enzyme System; D008985:Monensin