Structure–activity relationships for ruthenium and osmium anticancer agents – towards clinical development

Abstract

Anticancer metallodrugs based on ruthenium and osmium are among the most investigated and advanced non-platinum metallodrugs. Inorganic drug discovery with these agents has undergone considerable advances over the past two decades and has currently two representatives in active clinical trials. As many ruthenium and osmium metallodrugs are prodrugs, a key question to be addressed is how the molecular reactivity of such metal-based therapeutics dictates the selectivity and the type of interaction with molecular targets. Within this frame, this review introduces the field by the examples of the most advanced ruthenium lead structures. Then, global structure-activity relationships are discussed for ruthenium and osmium metallodrugs with respect to in vitro antiproliferative/cytotoxic activity and in vivo tumor-inhibiting properties, as well as pharmacokinetics. Determining and validating global mechanisms of action and molecular targets are still major current challenges. Moreover, significant efforts must be invested in screening in vivo tumor models that mimic human pathophysiology to increase the predictability for successful preclinical and clinical development of ruthenium and osmium metallodrugs.

Time-dependent shotgun proteomics revealed distinct effects of an organoruthenium prodrug and its activation product on colon carcinoma cells

“…1 While DNA was revealed as the main target of platinum anticancer agents already in the 1970s, 28 it was unclear until recently, whether derivatives of the ruthenium class would target DNA or rather proteins. Indications on the DNA versus protein binding preference were obtained from crystal soaking experiments with the nucleosome core particle, which is the basic chromatin structure consisting of a histone octamer surrounded by double-stranded DNA.…”

“…1 RomeroCanelón and Sadler suggested the use of systems pharmacology approaches to assess metallodrug effects in 2015 2 and proteomics [3][4][5][6] or transcriptomics 7,8 approaches are being reported with increasing frequency. Such cell-level investigations are still challenging because metallodrugs are considered to be rather unspecific and the detailed modes of action are indeed elusive in most cases.…”

“…Such cell-level investigations are still challenging because metallodrugs are considered to be rather unspecific and the detailed modes of action are indeed elusive in most cases. 1 Additionally, metallodrugs may change their binding properties in time due to ligand exchange reactions. 9 For example, these compounds may be prodrugs that hydrolyse a labile metal-halido bond.…”

Retracted: Studies of proteasome inhibition and antitumor activity by novel amino acid‐polypyridine‐copper complexes

“…However, their negative side‐effects and the risk of resistance remain a pressing matter in their clinical use. These issues drive the research and development of new metallotherapeutics, in many cases, divergent from the platinum‐based complexes . Copper is biocompatible and less toxic that non‐endogenous heavy metals, furthermore, copper is an interesting candidate for the treatment of cancers because of its bioavailability and the observation of increased copper level in cancer tissue .…”

Recent Considerations in the Application of RAPTA‐C for Cancer Treatment and Perspectives for Its Combination with Immunotherapies

“…Although RAPTA-C will bind to DNA ex vivo, [90] preferential binding to the histone core of chromatin dominates. [92] Studies in pre-clinical models reveal that RAPTA-C treatment leads to a 50% reduction of the number of lung metastases in CBA mice bearing mucin-like carcinoma-associated antigen (MCa) mammary carcinoma compared to the control group. [92] Studies in pre-clinical models reveal that RAPTA-C treatment leads to a 50% reduction of the number of lung metastases in CBA mice bearing mucin-like carcinoma-associated antigen (MCa) mammary carcinoma compared to the control group.…”