Studies of the anticancer action and mechanism of new copper complexes using natural products ligands

Abstract

Copper is an essential element for the maintenance of life, being considered one of the most important micronutrients necessary for the perfect functioning of a living organism. Copper is present in the active site of numerous essential proteins in the cell, performing important functions in metabolism such as the electron transport chain in the mitochondria, the synthesis of amines, the oxidation of ascorbate, the protection against free radicals, among others. Although life is absolutely essential, copper is also involved in pathological processes when proteins that transport and control it are altered or mutated, such as ATP7A and B, CTR1, or cellular prion proteins. Due its very versatile redox capacity among the elements of the first transition series, copper can assume the most different geometric forms of coordination and consequently its high reactivity can be controlled in this way. So, being an endogenous element, whose cells have full regulation and transport capacity, and having a redox activity that can be controlled, copper can be used as a potential drug against cancer cells, and precisely that has been done for the past 30 years. Bioinorganic chemists understood that it is possible to regulate copper's ability to cause cellular damage in a controlled manner by merely changing its form of attachment with the most varied organic ligands. Our group has systematically made these changes in the sphere of copper coordination, either by changing the ligands when forming complexes or by altering the delicate balance of the metal inside the cell in order to simulate metabolic changes, pathologies related to oxidative stress and neurodegenerations. Following our line of work, this project proposes the synthesis, characterization, and biological study of new copper (II) complexes with plant-based binders obtained naturally from plant extracts. The ligands will be supplied by the group of natural products at UFABC, and the copper (II) complexes formed will be studied in cell cultures of glioma and neuroblastomas, in order to establish a mechanism of action for the most active of them against tumor cells. Tests in normal cell culture will also be carried out to verify the complexes' cytotoxicity for later study in vivo, in animals (type II phase). With this project, we seek to fill a gap in the variety of ligands used in the literature for the formation of copper (II) complexes, and we are also looking for new drug candidates in the treatment and co-treatment of cancer. (AU)