Electronic State of Sodium trans-[Tetrachloridobis(1H-indazole)ruthenate(III)] (NKP-1339) in Tumor, Liver and Kidney Tissue of a SW480-bearing Mouse

Abstract

Ruthenium complexes are promising candidates for anticancer agents, especially NKP-1339 (sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]), which is on the edge to clinical applications. The anticancer mechanism seems to be tightly linked to the redox chemistry but despite progress in human clinical trials the in vivo Ru oxidation state and the coordination of Ru remains unclear. The Ru-based anticancer drug NKP-1339 was studied applying XANES (Cl K- and Ru L2,3-edges) in tumor, kidney and liver tissue of a SW480 bearing mouse. Based on coordination charge and 3D XANES plots containing a series of model compounds as well as pre-edge analysis of the ligand Cl K-edge it is suggested that NKP-1339 remains in its +III oxidation state after 24 hours and at least one of the four chlorido ligands remain covalently bound to the Ru ion showing a biotransformation from RuIIIN2Cl4 to RuIIIClx(N/O)6−x (X = 1 or 2).

Anticancer Ruthenium(III) Complexes and Ru(III)-Containing Nanoformulations: An Update on the Mechanism of Action and Biological Activity

“…To the best of our knowledge, three Ru(III)-containing compounds entered in clinical trials: NAMI-A [45,46], KP1019 [47][48][49][50][51][52][53], as well as its sodium salt analogue named IT-139, formerly known as NKP-1339 [54][55][56][57][58]. Despite their structural similarities (Figure 1), these complexes dramatically differ in their bioactivity [59].…”

“…In contrast, KP1019 exhibited marked cytotoxic activity in vitro in cisplatin-resistant human colon carcinoma cell lines, as well as significant anti-tumour effects in vivo against a wide variety of tumour xenografts through induction of apoptosis [47][48][49][50][51][52][53]. NKP-1339 is the most recent compound entered in clinical trials against solid cancer forms, showing a manageable safety profile with absence of neurotoxicity and dose-limiting haematological toxicity [54][55][56][57][58].…”

A systematic assessment of chemical, genetic, and epigenetic factors influencing the activity of anticancer drug KP1019 (FFC14A)

“…Additionally, KP1019 is widely believed to be a ‘prodrug’ that gets activated by ‘reduction’ to highly reactive Ru (II) selectively in the hypoxic environment of cancer cells [ 6 ]. However, recent findings in contrast to the redox activation hypothesis, showed that ruthenium was present in its +III oxidation state (Ru 3+ ) after treatment with ruthenium complexes (KP1019 and KP1339) in yeast cells [ 20 ] and tissues (tumor/liver/kidney) of a mouse bearing tumors of SW480 colon cancer cells [ 21 ]. However, the redox potential of ruthenium was found to be reduced in the presence of biologically relevant reductants (ascorbic acid, glutathione) and thereby modulating the activity of KP1019 under physiological conditions [ 1 , 22 , 23 ].…”

On the binding modes of metal NHC complexes with DNA secondary structures: implications for therapy and imaging

“…This can even be extended by X-ray absorption near-edge spectroscopy (XANES) to study the composition of the first coordination sphere and the oxidation state of metallodrugs in tissues. 91 Notably, advanced mass spectrometric techniques emerge as promising tools to generate hypotheses on target identification 92 and mechanisms of action in the cellular context. 93 Furthermore, recent developments in the DNA targeted field of organometallic NHC anticancer agents show also a trend towards molecular and systems biology approaches in order to elucidate mechanisms of action or effective signal transduction pathways and in situ chemical affinity capture will presumably increase in popularity to validate binding of selected compounds to specific DNA secondary structures in vitro.…”