Repositioning of antiresorptive agents for the treatment of iron overload

Author(s)

Julia Tiemy Leal Konno

• Document type: Master's Dissertation
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ)
• Defense date: 2023-08-29

Examining board members

Breno Pannia Esposito; Adelino Vieira de Godoy Netto; Cristina Helena dos Reis Serra

• Advisor: Breno Pannia Esposito

Abstract

Iron is the most abundant transition metal in the human body and without its presence in several cellular processes, life would not be possible. However, iron overload is a harmful condition for patients, who experience a significant decrease in quality of life. As a treatment, chelation therapy has only three approved drugs, which have strong adverse effects that hinder therapeutic adherence. The search for new chelators may benefit from drug repositioning, a strategy that aims to identify new applications for drugs already approved in clinical trials for another indication. Antiresorptives are drugs that act by inhibiting bone resorption, used in the treatment of osteoporosis and Paget\'s disease. For this work, four drugs of the bisphosphonate class (etidronate, alendronate, tiludronate, and zoledronate) and strontium ranelate were chosen. Considering the coordination environments with characteristics favorable to the coordination of Fe(III) present in their molecules, we aimed to study the iron-binding properties, antioxidant effect, cell permeation, and antiproliferative activity with a view to repositioning for use in iron overload chelation therapy. The antiresorptive-iron complexes were synthesized and characterized by UV-visible electron spectroscopy, in which their formation was verified by the appearance of a proper band at 260 nm with all ligands except tiludronate and strontium ranelate. Cyclic voltammetry tests were performed to complement the characterization of the complexes, which showed unique reduction and oxidation profiles. Competition test between the antiresorptives and ferric calcein demonstrated a moderate ability to sequester iron. Bisphosphonates were able to sequester a small part of the iron bound to transferrin but were not able to transfer it from their complex to the protein. The reaction with hemin indicated that the antiresorptives did not chelate iron from porphyrin and kept its structure intact. Bisphosphonates showed antioxidant activity against reactive species generated by the reaction between iron and ascorbate. In cellular assays with HeLa and HepG2 cell lines, the antiresorptive agents showed little cell permeation capacity, however, in the extracellular medium, the bisphosphonates etidronate and tiludronate helped to prevent death by iron-dependent oxidative stress. At the concentrations tested (5 - 160 M), no antiproliferative activity was observed with HeLa. Bisphosphonates form soluble complexes and have antioxidant activity in physiological medium. Calcium did not significantly alter iron-dependent reactions. Although they are not permeable to these cells, they can be used to prevent death due to oxidative stress in situations of iron overload. (AU)

• FAPESP's process: 21/02165-3 - Repositioning of anti-resorptives to treat iron overload
• Grantee: Julia Tiemy Leal Konno
• Support Opportunities: Scholarships in Brazil - Master