Role of metallomic strategies in developing ruthenium anticancer drugs

There is still high anticipation among oncology metallodrug developers that a real breakthrough can be gained due to substituting platinum, as a principal component of all approved metal-based chemotherapeutics, with another metal such as arguably second in importance ruthenium. Such expectations have directed research activities to improvements in the molecular design, with varying the ruthenium oxidation state and bonding type, and to the better understanding of the basic underlying chemistry and biochemical mechanisms of cytotoxicity. It is the latter issue where the metallomic approaches have received growing attention as indispensable to decipher the metabolic pathways, to shed light on modes of delivery and action, and to identify active, toxic species and potential cell targets of metallodrugs. Therefore, there is obviously a need to critically evaluate recent progress due to using metallomic strategies and techniques to advance the preclinical development of anticancer ruthenium agents. Being aware that the rate of failure for ruthenium compounds is no less than for other molecular entities tested and tending to be overwhelming, the author places the focus of this review on merely (H(2)ind)[(RuCl4)-Cl-III(Hind)(2)] (Hind = 1H-indazole) and Na[(RuCl4)-Cl-III(Hind)(2)], often referred to as KP1019 and NKP-1339, respectively, the only ruthenium drug candidates presently in clinical trials, (H(2)im)[(RuCl4)-Cl-III(DMSO)(Him)] (Him = 1H-imidazole), NAMIA, which has though been recently suspended of clinical testing, as well as on Ru(eta(6)-toluene)(pta)Cl-2 and Ru-II(eta(6)-p-cymene)(pta)Cl-2 (pta = 1,3,5-triaza-7-phosphaadamantane), or RAPTA-T and RAPTA-C, respectively, the lead investigational compounds of the RAPTA family. (C) 2016 Elsevier B.V. All rights reserved.