Ruthenium Anticancer Agents—From Cisplatin Analogues to Rational Drug Design

Abstract

The discovery of cisplatin has triggered research in metal‐based anticancer agents. Ruthenium complexes have been investigated as chemotherapeutics for more than 30 years. In this article, we review the early steps of Ru‐based drug development, which was often based on the structural similarity to cisplatin, and led eventually to the clinical trials of KP1019/KP1339 and NAMI‐A and the emergence of the organometallic RAPTA and RAED compound series. The unique modes of action of Ru compounds equip them with their special pharmacological properties. Especially in the past decades, many rationally designed Ru complexes have been reported to expand the range of compound types, and therewith the modes of action these compounds follow. This article covers many of the reported novel approaches and newer developments in the field, demonstrating in some cases properties advantageous to that of platinum anticancer agents and opening the route to new generations of metal‐based anticancer agents.

Coumarin‐Tagged Dinuclear Trithiolato‐Bridged Ruthenium(II)⋅Arene Complexes: Photophysical Properties and Antiparasitic Activity

“…The use of ruthenium complexes as potential chemotherapeutics has been an active area of research for almost two decades. [1][2][3] Developed initially as a potential alternative to platinum-based anticancer drugs, [4,5] ruthenium(II)•arene complexes were also considered for other pharmacological properties, particularly as antiparasitic [6][7][8][9][10][11][12][13] and antibacterial compounds. [14][15][16][17] A special class of ruthenium(II)•arene complexes is constituted by symmetric [18,19] and "mixed" [20] cationic trithiolato-bridged dinuclear ruthenium(II)•arene complexes (general formulae [(η 6 -arene) 2 Ru 2 (μ 2 -SR) 3 ] + and [(η 6 -arene) 2 Ru 2 (μ 2 -SR 1 ) 2 (μ 2 -SR 2 )] + , respectively).…”

Diiron Complexes with a Bridging Functionalized Allylidene Ligand: Synthesis, Structural Aspects, and Cytotoxicity

“…Nevertheless, although cisplatin and the second generation of platinum drugs are widely applied in the clinic, they exhibit certain limitations: i.e., severe side effects due to limited drug selectivity and progressive resistance acquisition . Considerable efforts have been devoted to the development of new metal drugs overcoming such limitations; thus, compounds based on several, alternative transition metals have been proposed as possible anticancer agents. ,, Notably, iron has emerged as an attractive metal for drug design, being bioessential and substantially nontoxic in many forms . Following the discovery of ferrocene in organometallic chemistry, diverse ferrocene derivatives have been investigated for their anticancer behavior, such as compounds functionalized with hydroxytamoxifen-type substituents (ferrocifens), which have promising properties .…”

Ruthenium Complex HB324 Induces Apoptosis via Mitochondrial Pathway with an Upregulation of Harakiri and Overcomes Cisplatin Resistance in Neuroblastoma Cells In Vitro

“…Due to tissue toxicity, side effects, and the development of resistance, there is a strong interest in the development of new effective complexes with other metals. Ruthenium compounds may be a possible alternative due to lower toxicity and different mechanisms of action [ 16 , 17 , 18 ]. Therefore, we investigated two different ruthenium complexes and their non-metallic (non-ruthenium) ligands ( Figure 1 ) for their antiproliferative, apoptosis-inducing, and resistance-breaking properties.…”