Metal Coordination Complexes as Therapeutic Agents for Ischemia-Reperfusion Injury

Abstract

Ischemia-reperfusion injury (IRI), which describes the cell damage and death that occurs after blood and oxygen are restored to ischemic or hypoxic tissue, is a significant factor within the mortality rates of heart disease and stroke patients. At the cellular level, the return of oxygen triggers an increase in reactive oxygen species (ROS) and mitochondrial calcium ( m Ca 2+ ) overload, which both contribute to cell death. Despite the widespread occurrence of IRI in different pathological conditions, there are currently no clinically approved therapeutic agents for its management. In this Perspective, we will briefly discuss the current therapeutic options for IRI and then describe in great detail the potential role and arising applications of metal-containing coordination and organometallic complexes for treating this condition. This Perspective categorizes these metal compounds based on their mechanisms of action, which include their use as delivery agents for gasotransmitters, inhibitors of m Ca 2+ uptake, and catalysts for the decomposition of ROS. Lastly, the challenges and opportunities for inorganic chemistry approaches to manage IRI are discussed.

Chemical Structure Elucidation in the Development of Inorganic Drugs: Evidence from Ru‐, Au‐, As‐, and Sb‐based Medicines

“…[35][36][37][38][39][40][41] These developments, including the extension to Os complexes, have been reviewed recently. [42][43][44] It is currently suspected that these compounds function by inhibiting the mitochondrial calcium uniporter, but efforts to continue to elucidate their mechanism of action are ongoing. [42] The story of ruthenium red provides a prototypical example of a substance that was erroneously thought to be active, when the activity was in fact conferred by a small amount of a contaminant (Figure 1c).…”

“…Armed with the knowledge of the structure of the active agent, it was possible for medicinal inorganic chemists to reproducibly confirm Ru360 activity, [27] to probe its mechanism of action, [28–31] to develop improved syntheses of the multinuclear pharmacophore, [32–34] and to derivatize this scaffold to improve activity (Figure 3). [35–41] These developments, including the extension to Os complexes, have been reviewed recently [42–44] . It is currently suspected that these compounds function by inhibiting the mitochondrial calcium uniporter, but efforts to continue to elucidate their mechanism of action are ongoing [42]…”

Structure-Based Identification of Organoruthenium Compounds as Nanomolar Antagonists of Cannabinoid Receptors

“… , The role of metals in these drugs could be classified into three modes: (1) metal complexes undergo ligand exchange, and the metals coordinately bind to biomolecules (Pt-, Au-, and Bi-based metallodrugs); , (2) Fe­(II) in sodium nitroprusside acts as a carrier to deliver NO, which can rapidly lower blood pressure in hypertensive emergencies; (3) metals in photosensitizers can enhance the physicochemical properties and photodynamic activity . Moreover, the mechanisms of action of many metal complexes under therapeutic study can be attributed to these three modes. − …”

Novel Re(I) Complexes as Potential Selective Theranostic Agents in Cancer Cells and In Vivo in Caenorhabditis elegans Tumoral Strains

“…Cancer stands as the second leading cause of death worldwide, contributing to a significant global disease burden with approximately 10 million annual deaths. , Conventional cancer treatments, such as surgery, radiotherapy, and chemotherapy, have notable limitations, including severe side effects on healthy organs and drug resistance . Consequently, discovering of alternative and more selective anticancer drugs is a highly desirable goal and remains to be an active field of research, where metallopharmaceuticals are playing a significant role. − Smart drugs that provide a combination of diagnostics and therapy, “theranostic agents”, are of recent origin and have also received a surge of research interest. , Radioactive 186 Re and 188 Re have been extensively used in clinical treatment of cancer, , and in the past decade, there has been an enormous interest in the exploitation of the rich photophysical properties of rhenium complexes for diverse imaging modalities and therapeutic biomedical applications. − In particular, rhenium carbonyl complexes have been shown to be novel anticancer agents, , inhibitors of the SARS-CoV-2 main protease, , and more recently therapeutic agents for schemia-reperfusion injury (IRI) . In general, the mechanisms of action of Re(I) anticancer complexes containing the fac -[Re(CO) 3 ] + core are quite distinct from that of conventional platinum agents, ,− that is dependent on covalent bond formation to DNA .…”