Síntese e caracterização de complexos de pentacianoferrato(II) como possíveis ativadores da guanilato ciclase solúvel

Abstract

The enzyme soluble guanylate cyclase (sGC) is a nitric oxide receptor in the human body, which upon NO binding increases from 200 up to 400 times its enzymatic activity, leading to the production of cGMP from GTP. This enzyme is involved many important biological events in the body, which has made sGC a molecular target for the investigation and treatment of various cardiovascular, endothelial, pulmonary diseases among others. Thus, reaching a better understanding of the structure-reactivity of compounds that can act as sGC activators-, inhibitors or stimulators is of great importance to have treat those conditions. Based on this, we have synthesized and studied the chemical reactivity of pentacyanoferrate(II) compounds with N-heterocyclic ligands as potential agents to activate, stimulate or inhibit sGC. First of all, iron complexes were synthesized using pentacyanoferrate (II) moiety bound to the ligands: indazole (FOR112), 7-azaindole (FOR117), 1H-indazol-6-carboxaldehyde (FOR112A) and 4-benzoylpyiridine (FOR119). These compounds were characterize by cyclic voltammetry, spectroscopy in the infrared and the ultraviolet-visible region, high-performance liquid chromatography and hydrogen nuclear magnetic resonance measurements. Cytotoxicity assays were conducted with the complexes FOR112, FOR117 and FOR119 using three tumor cell lines, HCT116 (human colon), OVCAR-8 (human ovary) and SF-295 (human glioblastoma). These complexes exhibited very little cytotoxicity across the three cell lines. Furthermore, vasodilation assays were carried out in aorta of male Wistar rats. Two compounds were selected based on that screen, FOR112 (IC50 = 1.72 μM and Emax = 127.00 ± 6.88) and FOR119 (IC50 = 2.08 μM and Emax = 186.16 ± 23.26). However, all complexes have improved vasodialtaion IC50 values if compared to their free N-heterocyclic ligands. So, for the two most potent compounds it was preliminarily investigated the mechanism of vasodilation, which has showed both complexes activate sGC in a heme-dependent manner, and requires of endogenous NO. These exciting results open up new avenues for the quick development of new non NO-based agents and the understanding of their structure-activity.