Biomimetic Metabolism of Kaurenoic Acid Validated by Microsomal Reactions
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ORIGINAL ARTICLE
Biomimetic Metabolism of Kaurenoic Acid Validated by Microsomal Reactions Eduardo Felipe Alves Fernandes 1,2 Norberto Peporine Lopes 1
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Anderson R.M. de Oliveira 3
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Valeria Priscila Barros 4
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Thais Guaratini 2
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Received: 13 May 2020 / Accepted: 10 August 2020 / Published online: 27 August 2020 # Sociedade Brasileira de Farmacognosia 2020
Abstract The cytochrome P450 is a remarkable family of enzymes with widespread occurrence in animals and plants. In humans, they catalyze phase I metabolism reactions, such as oxidations and hydroxylations, playing a significant role in xenobiotics detoxification. Although mechanistic details of the catalytic cycle of cytochrome P450 are known, and human isoforms have their crystal structure solved, mimicking cytochrome P450 reactions using in vitro systems is still challenging. For this reason, biological assays using isolated enzymes or microsomal fractions are typically required to study the oxidative metabolism of new drugs before approval by regulatory agencies. Here we demonstrate that a series of metalloporphyrin catalysts generate the same oxidative product in vitro as a liver microsomal assay. The bioactive diterpene kaurenoic acid was chosen as a substrate model because it is a component of widely used phytomedicines in Brazil, such as guaco syrups and copaiba waxes. We evaluated the influence of reaction parameters such as catalyst type, oxygen donor type, solvent, and catalyst concentration on substrate consumption. Three products had their structures proposed by mass spectrometry, and among them, a dihydroxylated oxidation product was detected as a major metabolite after liver microsomal biotransformation and using porphyrin catalysts. We envision that the use of metalloporphyrins could be a useful strategy for biomimetic oxidation of kaurenic terpenes. Keywords Biomimetic oxidation . Metabolism . Microsomes . Kaurenoic acid . Terpenes
Introduction Despite the rapid development of synthetical and biological drugs, phytomedicines are still widely prescribed, especially Electronic supplementary material The online version of this article (https://doi.org/10.1007/s43450-020-00084-8) contains supplementary material, which is available to authorized users. * Norberto Peporine Lopes [email protected] 1
NPPNS, Departamento de Ciências Biomoleculares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto- Universidade de São Paulo, FCFRP-USP, Av. do Café s/n, Ribeirão Preto, SP 14040-903, Brazil
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Lychnoflora Pesquisa e Desenvolvimento em Produtos Naturais Ltda, Rua Ângelo Mestriner 263, Ribeirão Preto, SP, Brazil
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Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP 14040-901, Brazil
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Departamento de Química, Universidade Federal de Sergipe, Av. Vereador Olímpio Grande s/n, Itabaiana, SE 49500-000, Brazil
in the developing world (Robinson and Zhang 2011). Most of these medicines have not been subjected to pharmacokinetics studies, and their metabolism and
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