Ligand substitutions between ruthenium–cymene compounds can control protein versus DNA targeting and anticancer activity

Abstract

Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favourable toxicity and clearance properties. Nonetheless, their molecular targeting and mechanism of action are poorly understood. Here we study two prototypical ruthenium-arene agents—the cytotoxic antiprimary tumour compound [(η6-p-cymene)Ru(ethylene-diamine)Cl]PF6 and the relatively non-cytotoxic antimetastasis compound [(η6-p-cymene)Ru(1,3,5-triaza-7-phosphaadamantane)Cl2]—and discover that the former targets the DNA of chromatin, while the latter preferentially forms adducts on the histone proteins. Using a novel ‘atom-to-cell’ approach, we establish the basis for the surprisingly site-selective adduct formation behaviour and distinct cellular impact of these two chemically similar anticancer agents, which suggests that the cytotoxic effects arise largely from DNA lesions, whereas the protein adducts may be linked to the other therapeutic activities. Our study shows promise for developing new ruthenium drugs, via ligand-based modulation of DNA versus protein binding and thus cytotoxic potential, to target distinguishing epigenetic features of cancer cells.

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

“…29 While oxaliplatin was shown to preferentially interact with the oligonucleotide in this model system, 29 the organometallic ruthenium(arenes) turned out to be tuneable with respect to this property, depending on the inert ligands. 30 In the same setup, the drug candidate [chlorido(Z 6 -p-cymene)(N-(4-fluorophenyl)-2-pyridinecarbothioamide)ruthenium-(II)]chloride (plecstatin-1, Scheme 1A) was shown to exclusively coordinate to histidines 79 and 106 of histone 2B. 24 Then, an MS-based shotgun proteomics method was developed to identify potential protein targets of plecstatin-1 by a combination of affinity purification of cell lysates and in vitro treatment of cell cultures.…”

Fingerprinting the junctions of RNA structure by an open-paddlewheel diruthenium compound

“…1A, right panel) is higher than that of paddlewheel diruthenium species (Barral et al 2007(Barral et al , 2008, we decided to test the reactivity of the compound [Ru 2 Cl 2 (µ-DPhF) 3 (DMSO)] (designated OPW-Ru) (DPhF = N,N ′ -diphenylformamidinate) toward RNA. Numerous ruthenium compounds have been designed to interact with nucleic acid such as mononuclear ruthenium complexes with labile ligands (Busto et al 2013;Wu et al 2013;Adhireksan et al 2014) or tris(chelate)ruthenium(II) compounds (Song et al 2012;Li et al 2015). The existence of labile ligands in the first type of compounds allows establishing direct ruthenium-nucleic acid bonds; the coordination mode implies bond angles of 90°.…”

The versatile ruthenium(II/III) tetraazamacrocycle complexes and their nitrosyl derivatives

“…However, studies [242][243][244] with a series of ruthenium anticancer compounds revealed that DNA is not always the primary target and that these species were actually binding more strongly to proteins than to DNA. These findings clearly indicated the occurrence of significantly different modes of action, depending on the type of ruthenium complexes.…”