Mechanism of antitumoral action of goniothalamin di-metoxy derivative and its mutagenicity and genotoxicity evaluation

Abstract

The emergence of cancer is a complex process that usually takes decades, where normal cells progressively gain a neoplastic phenotype through the process of carcinogenesis. Being inevitable contact with agents that promote this process, currently, new therapeutic agents that prevent the action of these carcinogens are sought. And in this search, natural products have traditionally been a common target of research, especially when efforts are joined to the strategies of Synthetic Organic Chemistry. In this context, a few years our laboratory has work in collaboration to evaluate the biological activity of several compounds obtained by synthesis, and goniothalamin (GTN) is the main representative of this effort. Previous studies developed by our group showed that GTN has antiproliferative activity on human tumor cells, in addition to presenting antitumor activity and anti-inflammatory in vivo, apparently with no signs of toxicity. Therefore, in order to continue their studies with goniothalamin, we propose the synthesis of the racemic form of 2,4-dimethoxy-goniothalamin (diOMe-GTN) and evaluation of in vivo activity against Ehrlich solid tumor and breast cancer cells (MCF-7) implanted in fiber semipermeable (Hollow fiber). We also propose the evaluation of antiproliferative activity on MCF-7 strain incubated with 17 b-estradiol, using the methodology of E-screen, to evaluate the influence of treatment on hormonal stimuli. It is also proposed to evaluate the expression of genes related to cell cycle, apoptosis, necrosis, promotion and progression of cancer in breast tumor cells (MCF-7), to identify the possible mechanisms of action of the test compound. Finally, the mutagenic and genotoxic activity, using Ames test and Micronucleus Assay, will be evaluated. All these trials together should provide crucial information about the biological activity of the racemic form of diOMe-GTN, allowing us to compare these results with those obtained previously by GTN in order to identify the mechanisms by which these molecules act. This project has several collaborations such as the Department of Organic Chemistry at the Institute of Chemistry - UNICAMP, Institute of Biology - Unicamp and other groups allocated in CPQBA-Unicamp, and it is part of the thematic research project "Biologia Química: Novos Alvos Moleculares Naturais e Sintéticos contra o Câncer. Estudos Estruturais, Avaliação Biológica e Modo de Ação", Fapesp nº 2009/51602-5, coordinated by Dr. Ronaldo A. Pilli.