In vitro Metabolism and Cytotoxicity of Parthenolide: The Complete Identification of the Major Oxidative Product and the Evaluation of Trypanocidal and Leishmanicidal Activities

Author(s)

Maíra R. S. Silvério ^[1] ; Daniel Roberto Callejon ^[2] ; João M. Batista Jr. ^[3] ; Thalita B. Riul ^[4] ; Anderson Rodrigo M. de Oliveira ^[5] ; Norberto P. Lopes ^[6]

Affiliation

^[1] Universidade de São Paulo. Núcleo de Pesquisa de Produtos Naturais e Sintéticos. Departamento de Ciências BioMoleculares - Brasil

^[2] Yosen Nanotechnology - Brasil

^[3] Universidade Federal de São Paulo. Instituto de Ciência e Tecnologia - Brasil

^[4] Universidade Federal de Mato Grosso do Sul. Faculdade de Ciências Farmacêuticas - Brasil

^[5] Universidade de São Paulo. Departamento de Química. Faculdade de Filosofia - Brasil

^[6] Universidade de São Paulo. Núcleo de Pesquisa de Produtos Naturais e Sintéticos. Departamento de Ciências BioMoleculares - Brasil

• Document type: Journal article
• Source: Journal of the Brazilian Chemical Society; v. 36, n. 1 2024-06-17.

Abstract

Parthenolide (PTN) is a secondary metabolite of the plant Tanacetum parthenium (L.) Schulz Bip. and is considered the chemical marker of this species. This sesquiterpene lactone (germacrene skeleton) has been described as responsible for the biological activity of the leaf extract. In addition, several studies in the literature have demonstrated its antiparasitic and antineoplastic activity. However, there is a need for knowledge of other safety parameters, such as pharmacokinetic, pharmacodynamic and toxicity evaluations. Therefore, in this investigation, the in vitro metabolism of parthenolide was performed with rat liver microsomes and biomimetic metabolism (such as cytochrome P-450 system) using organometallic catalysts. The biomimetic procedure was validated since the major compound of biomimetic oxidative reaction with meta-chloroperbenzoic acid catalyzed by metalloporphyrin 5,10,15,20-tetrakis(pentafluorophenyl)-porphyrin iron(III) chloride was also observed with rat liver microsomes. Previous chemoenzymatic synthesis studies of PTN afforded the same epoxide formation, this major oxidative compound was isolated and fully characterized as (1 R,10R)-epoxyparthenolide based on experimental and theoretical calculations of infrared (IR) and vibrational circular dichroism (VCD) data at the B3PW91/6-311G. Furthermore, for the first time, this metabolite was evaluated for trypanocidal and leishmanicidal activity. The mean inhibitory concentration (IC50) values were lower for PTN than its metabolite and showed significant cytotoxic effects for both parasites. This finding holds promise for addressing neglected diseases. (AU)

• FAPESP's process: 16/07597-0 - Development of chromatographic/electrophoretic methods to be further used in in vitro enzymatic inhibition and drug interaction of chiral pesticides
• Grantee: Anderson Rodrigo Moraes de Oliveira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/25222-9 - Vibrational chiroptical spectroscopy for stereochemical characterization of small molecules and macromolecules
• Grantee: João Marcos Batista Junior
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 18/07534-4 - Development of chromatographic / electrophoretic methods to be further applied in in vitro enzymatic inhibition studies and prediction of drug interactions of chiral pesticides - Phase 2
• Grantee: Anderson Rodrigo Moraes de Oliveira
• Support Opportunities: Regular Research Grants