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

Abstract

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.

Five‐Coordinate Platinum(II) Compounds as Potential Anticancer Agents

“…Cisplatin was the first metal-based anticancer drug to be approved, and today it is of great importance in the treatment of many tumours. [1] Over the years, cisplatin has been flanked by new-generation drugs, with the aim of reducing side effects and increasing performance in terms of activity and selectivity. In particular, modern Pt-based drugs have been designed to increase their specificity and stability, so that they can be internalized only in cancer cells without undesired structural changes.…”

“…In this context, platinum(IV) complexes have been proposed as efficient pro-drugs because the coordinative saturation enhances their stability, and the octahedral geometry allows the generous introduction of tailored groups. [1] Once in the cellular environment, they are supposed to be reduced to species of Pt(II), which are recognized as the actual drugs. [1] On these bases, platinum(II) complexes with the number of coordination five do already combine the features of reliable agents: (i) the active oxidation state (II); (ii) the coordinative saturation; (iii) an appropriate number of ligands, useful for a straightforward tuning of their physical-chemical properties.…”

Conjugating Biotin to Ruthenium(II) Arene Units via Phosphine Ligand Functionalization

“…The development of metal-based anticancer drugs that overcome the limitations of platinum compounds currently used in chemotherapy continues to receive considerable attention. [1] In this respect, ruthenium compounds have emerged as promising alternatives, with [indazoleH][trans-Ru(N-indazole) 2 Cl 4 ] (KP1019) and [imidazoleH][trans-Ru(N-imidazole)(S-DMSO)Cl 4 ] (NAMI-A), having undergone clinical evaluation. [2] These Ru(III) compounds exhibit lower toxicities and side-effects than the clinically approved Pt(II) drugs, attributed to in situ reduction and activation of Ru(III) to Ru(II) species in the tumour environment.2 , [3] However, a key limitation of all of these drugs is that they do not efficiently target tumours.…”

Microwave assisted synthesis of disubstituted benzyltin arylformylhydrazone complexes: anticancer activity and DNA‐binding properties

“…This compound inspired the development of subsequent small molecule metal complexes as anticancer drugs. Because of this breakthrough, researchers have considered whether other metal complexes have anticancer effects . In 1972, Brown found that Ph 3 SnOOCCH 3 can inhibit the growth of mouse tumors, and scientists have reported the in vitro anticancer activity of organotin compounds .…”