Control of iron-dependent genotoxicity by desferrioxamine derivatives with high cell permeability

• Grant number: 19/21435-1
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2020
• End date: February 28, 2021
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Maria Teresa Machini
• Grantee: Lucas Henrique de Castro Ah-Time
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Iron overload is a debilitating condition for patients, leading to decreased 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 display several possibilities of clinical use: (I) reducing metal overload; (II) delivering toxic metals to selected targets; (III) scavenging essential metals from said targets. Desferrioxamine (DFO), a bacterial siderophore, was the first clinically approved iron chelator, displaying a high affinity for Fe(III). However, its use is hampered since it has low cell permeability and low gastrointestinal absorption. Our laboratory developed two DFO derivatives with high cell permeability, DFO-caffeine (DFCAF) and DFO-triphenylphosphonium (TPP-DFO), aimed at the blood-brain barrier and mitochondria, respectively. In this project, we intend to study the structure of the Fe(III) derivatives of both conjugates. Also, we plan to study the ability of the new chelators to mitigate iron-dependent genotoxicity.