Repositioning of anti-resorptives to treat iron overload

Abstract

Iron overload is a harmful condition for patients, who have a significant decrease in quality of life. At the same time, iron is a crucial nutrient also for parasites and tumor cells. Iron chelators are high-affinity molecules that present several possibilities for clinical use: (i) metal overload attenuators; (ii) hijackers of essential metals of those same targets; (iii) metalloenzyme inhibitors essential to tumor growth. Considering the coordination environments with characteristics favorable to the coordination of Fe (III) present in anti-resorptives, more specifically, etidronate, tiludronate, alendronate, zoledronate and ranelate, this project aims to reposition anti-resorptives to treat iron overload in order to expand the range of chelation therapy. For this, it is intended to synthesize complexes of the binders with iron and characterize them by UV-visible electronic spectroscopy, mass spectrum and FT-IR spectroscopy; evaluate the affinity of anti-resorptives against ferric calcein, iron-transferrin and hemin; to study its iron-mediated antioxidant activity in extra and intracellular media; evaluate their ability to penetrate cells and complement them with free cytosolic iron; to study the antitumor activity of anti-resorptives and their complexes with iron; and simulate the interaction of iron complexes with mineral forms of apatite and / or bone matrix.