Toward Multi-Targeted Platinum and Ruthenium DrugsA New Paradigm in Cancer Drug Treatment Regimens?

• Published in: Chemical reviews 2019-01, Vol.119 (2), p.1058-1137
• Main Authors: Kenny, Reece G, Marmion, Celine J
• Format: Article
• Language: English
• Subjects: Anticancer properties; ATP-Binding Cassette Transporters - chemistry; ATP-Binding Cassette Transporters - metabolism; Biological activity; Biomedical materials; Cancer; Carcinogenesis; Carcinogens; Cells; Chemical compounds; Chemistry; Chemotherapy; Coordination Complexes - chemistry; Coordination Complexes - metabolism; Coordination Complexes - pharmacology; Coordination Complexes - therapeutic use; Coordination compounds; Deoxyribonucleic acid; Design; DNA; DNA Damage - drug effects; Enzymes - chemistry; Enzymes - metabolism; Heart; Humans; Inorganic chemistry; Medical research; Metal complexes; Mitochondria; Molecules; Natural products; Neoplasms - drug therapy; Organic chemistry; Peptides; Pharmacology; Platinum; Platinum - chemistry; Prodrugs - chemistry; Prodrugs - pharmacology; Prodrugs - therapeutic use; Proteins; Ruthenium; Ruthenium - chemistry; Toxicity
• ISSN: 0009-2665; 1520-6890
• DOI: 10.1021/acs.chemrev.8b00271

While medicinal inorganic chemistry has been practised for over 5000 years, it was not until the late 1800s when Alfred Werner published his ground-breaking research on coordination chemistry that we began to truly understand the nature of the coordination bond and the structures and stereochemistries of metal complexes. We can now readily manipulate and fine-tune their properties. This had led to a multitude of complexes with wide-ranging biomedical applications. This review will focus on the use and potential of metal complexes as important therapeutic agents for the treatment of cancer. With major advances in technologies and a deeper understanding of the human genome, we are now in a strong position to more fully understand carcinogenesis at a molecular level. We can now also rationally design and develop drug molecules that can either selectively enhance or disrupt key biological processes and, in doing so, optimize their therapeutic potential. This has heralded a new era in drug design in which we are moving from a single- toward a multitargeted approach. This approach lies at the very heart of medicinal inorganic chemistry. In this review, we have endeavored to showcase how a “multitargeted” approach to drug design has led to new families of metallodrugs which may not only reduce systemic toxicities associated with modern day chemotherapeutics but also address resistance issues that are plaguing many chemotherapeutic regimens. We have focused our attention on metallodrugs incorporating platinum and ruthenium ions given that complexes containing these metal ions are already in clinical use or have advanced to clinical trials as anticancer agents. The “multitargeted” complexes described herein not only target DNA but also contain either vectors to enable them to target cancer cells selectively and/or moieties that target enzymes, peptides, and intracellular proteins. Multitargeted complexes which have been designed to target the mitochondria or complexes inspired by natural product activity are also described. A summary of advances in this field over the past decade or so will be provided.