DEVELOPMENT OF RHENIUM, PLATINUM, AND RUTHENIUM METALLODRUG CANDIDATES

Abstract

243 pagesThe clinical success of cisplatin and other platinum-based chemotherapeutics has inspired extensive research efforts to develop alternative metallodrugs with improved pharmacological properties. The first section of this dissertation focuses on design of novel metallodrugs for cytotoxic anticancer applications. Recently, rhenium(I) tricarbonyl complexes have attracted significant attention as novel anticancer agents, because their mechanisms of action are distinct from the DNA-binding pathways that are operative for platinum(II) complexes. Chapter 1 is a comprehensive review of the recent developments of multimetallic rhenium(I) tricarbonyl complexes for therapeutic and diagnostic applications. Chapter 2 describes the development of the first Pt(IV)Re(I) molecular conjugates as photoactivated anticancer agents. The second section of this dissertation explores the use of metal complexes as cytoprotective agents targeting the mitochondrial calcium uniporter (MCU), a transmembrane protein that is responsible for shuttling cytosolic Ca2+ into mitochondria. Dysregulation of the MCU can trigger an overload of mitochondrial Ca2+, which is implicated in the progression of cardiovascular and neurodegenerative diseases. As such, the chemical inhibition of MCU represents a promising therapeutic strategy. Chapter 3 summarizes recent advances in metal-based MCU inhibitors and highlights a diruthenium coordination complex, Ru265, as the state-of-the-art MCU inhibitor due to its excellent potency, selectivity, and cellular permeability. Chapter 3 also outlines the structure-activity relationship of Ru265-based MCU inhibitors. Chapter 4 describes a ferrocene-functionalized analogue of Ru265 and demonstrates that the cellular permeability of this class of MCU inhibitors can be rationally improved through ligand functionalization. Finally, Chapter 5 details the development of the first fluorogenic MCU inhibitor, a coumarin-functionalized analogue of Ru265. Collectively, these results demonstrate the potential of metal complexes for cytotoxic and cytoprotective applications and provide strategies for the rational design of metallodrug candidates