Recent developments in ruthenium anticancer drugs

Abstract

Interest in Ru anticancer drugs has been growing rapidly since NAMI-A ((ImH(+))[Ru(III)Cl(4)(Im)(S-dmso)], where Im = imidazole and S-dmso = S-bound dimethylsulfoxide) or KP1019 ((IndH(+))[Ru(III)Cl(4)(Ind)(2)], where Ind = indazole) have successfully completed phase I clinical trials and an array of other Ru complexes have shown promise for future development. Herein, the recent literature is reviewed critically to ascertain likely mechanisms of action of Ru-based anticancer drugs, with the emphasis on their reactions with biological media. The most likely interactions of Ru complexes are with: (i) albumin and transferrin in blood plasma, the former serving as a Ru depot, and the latter possibly providing active transport of Ru into cells; (ii) collagens of the extracellular matrix and actins on the cell surface, which are likely to be involved in the specific anti-metastatic action of Ru complexes; (iii) regulatory enzymes within the cell membrane and/or in the cytoplasm; and (iv) DNA in the cell nucleus. Some types of Ru complexes can also promote the intracellular formation of free radical species, either through irradiation (photodynamic therapy), or through reactions with cellular reductants. The metabolic pathways involve competition among reduction, aquation, and hydrolysis in the extracellular medium; binding to transport proteins, the extracellular matrix, and cell-surface biomolecules; and diffusion into cells; with the extent to which individual drugs participate in various steps along these pathways being crucial factors in determining whether they are mainly anti-metastatic or cytotoxic. This diversity of modes of action of Ru anticancer drugs is also likely to enhance their anticancer activities and to reduce the potential for them to develop tumour resistance. New approaches to metabolic studies, such as X-ray absorption spectroscopy and X-ray fluorescence microscopy, are required to provide further mechanistic insights, which could lead to the rational design of improved Ru anticancer drugs.

Solution equilibrium studies of anticancer ruthenium(II)-η6-p-cymene complexes of pyridinecarboxylic acids

“…The mode of action and the intracellular targets of Ru(III) complexes are not exactly known. There are many investigations suggesting that the intravenously injected drugs can be transported mainly by the serum albumin and/or transferrin in the blood plasma [14][15][16][17][18]. Reduction of Ru (III) compounds in the cytosol leads to the kinetically more labile and more reactive Ru (II) compounds.…”

Conjugation of a Ru(II) Arene Complex to Neomycin or to Guanidinoneomycin Leads to Compounds with Differential Cytotoxicities and Accumulation between Cancer and Normal Cells

“…63 Accumulation ratio 59 cell lines, including cisplatin-resistant cells. [6][7][8][9][10][11][12] In medicinal chemistry terms, their "piano-stool" structure allows the optimization of lead compounds through structureactivity relationship studies by modifying ligands around the metallic center. [15][16] Among such modifications, derivatization of non-leaving ligands with a carrier molecule has tremendous potential to generate selective, less toxic metallodrugs.…”

“…[1][2][3][4][5] Among them, ruthenium(II) complexes bearing a π-bonded arene ligand are particularly interesting since they have shown promising anticancer activities, [6][7][8] even in cells that had become resistant to cisplatin, such as Sadler's compounds containing N,N-chelating ligands. 1,9,10 In addition, some of the Dyson's RAPTA compounds containing pta ligand have shown antimetastatic activity.…”

Lightening up Ruthenium Complexes to Fight Cancer?

“…Ruthenium compounds are nowadays considered as the potential successors to Pt-based anticancer drugs. [ 29,30] Indeed, two complexes (NAMI-A and NKP1339) are currently in phase II clinical trials and a third one (RAPTA-C) is currently in pre-clinical evaluation. [31][32][33][34] Ru complexes are characterized by a very versatile chemistry, a generally lower systemic toxicity than Pt-based compounds and a higher tumor accumulation.…”