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Study of the genotoxicological potential and permeation assay with Caco-2 cells of metallic complexes with promising biological activities

Grant number: 17/16278-9
Support type:Regular Research Grants
Duration: August 01, 2018 - July 31, 2020
Field of knowledge:Biological Sciences - Genetics
Principal Investigator:Flávia Aparecida Resende Nogueira
Grantee:Flávia Aparecida Resende Nogueira
Home Institution: Universidade de Araraquara (UNIARA). Associação São Bento de Ensino. Araraquara , SP, Brazil

Abstract

This research project aims to evaluate the cytotoxic and mutagenic activities of metal complexes by different mechanisms of interaction with the genetic material, as well as permeation tests in colon carcinoma cells (Caco-2). Considering that medicinal inorganic chemistry represents a field of great promise, with potential for expansion due to chemical diversity and reactivity of metals, in addition to predict the safety and efficacy in a future therapeutic use, this project may also point to substances with positive mutagenicity at further studies, leading them to perform more specific and sophisticated tests, since the chemical agents used for the treatment of tumors, for example, are usually cytotoxic and mutagenic. Studies on the mechanism of action of these complexes become important so that their real clinical potential can be defined, contributing to the development of a new drug with selectivity, in order to minimize the side effects. The present study can be developed with an inter and multidisciplinary character, with collaborations that could result in great advances from the scientific point of view. Initially, complexes of copper (II), silver (I), platinum (II), palladium (II) and gold (I) with isoniazid, furosemide, indapamide, chlorthalidone and hydrochlorothiazide will be evaluated, some of them were included in project FAPESP (Proc: 2015 / 09833-0) under the coordination of Prof Dr Wilton Rogério Lustri, others produced and supplied by Prof Dr Antônio Carlos Massabni, professor at the University of Araraquara and by postdoctoral Dr Patrícia Bento Silva of the research group on Coordination Chemistry and Organometallic of the Institute of Chemistry of Araraquara - UNESP. These complexes were previously selected by show promising antibacterial or antitumor activity. In order to verify the safety for genetic material and human health, the objectives of this work are based on the study of cytotoxicity by the resazurin method (Alamar Blue), trypan blue and clonogenic survival in normal and tumor cells, in order to obtain the index of selectivity, and the ability to apoptosis induction. In addition, they will continue to analyze mutagenicity by Ames, Micronucleus and Comet in vitro tests and permeation tests on Caco-2 cell monolayers, due to the importance of pharmacokinetic knowledge of new drugs. (AU)