Advanced EPR spectroscopy applied to mechanistic studies on metallodrugs-biomolecules interactions

Abstract

In the present proposal, multidisciplinary studies are planned involving researchers with competence in complementary areas. We intend to go further on our studies at USP, about the reactivity of possible metallodrugs that we have been developing in the last 15 years. Complexes based on different essential metals, as copper(II), zinc(II), vanadium(IV), containing biologically active ligands, particularly derivatives of oxindoles, are the focus of extensive studies in our laboratory, with the aim of developing new antitumor and/or anti-parasite species. Those complexes have DNA and mitochondria as important intracellular targets that are significantly damaged by an oxidative process, producing reactive oxygen species. Additionally, these complexes are able to inhibit crucial enzymes as topoisomerase IB and cyclin-dependent kinases (CDK1/cyclin B, CDK2/cyclin A). Further, the studied ligands showed strongly binding to beta-amyloid peptides, inhibiting its aggregation, facilitated by copper or zinc ions. These peptides are implicated in Alzheimer's disease. Therefore, in collaboration with the EPR National Center at University of Manchester, we intend to better investigate the interactions of such metal complexes with molecules (nucleic acids, proteins, enzymes, peptides, organelles, etc.). Providing advanced spectroscopic methods (pulsed and time-resolved EPR), our partners in Manchester could help on the elucidation of possible mechanisms of action of such metal complexes as potential alternative pharmacological agents. (AU)