Binding mechanisms of half-sandwich Rh(III) and Ru(II) arene complexes on human serum albumin: a comparative study

During the development of metal compounds for medicinal purposes, organometallics have been shown to exhibit promising activity in various diseases [ 1 , 2 , 3 , 4 , 5 ]. In particular, half-sandwich Ru(II)-arene complexes have attracted attention, since some representatives show significant anticancer activity and non-cross resistance with cisplatin. [ 3 , 6 , 7 , 8 ]. The interest for organoruthenium compounds in cancer treatment became more pronounced as the clinically relevant Ru(III) drug candidates NKP1339 and NAMI-A were reported to exert their anticancer effect in the reduced Ru(II) forms [ 9 ]. Among Ru(II) compounds [Ru(II)(4,4′-dimethyl-2,2″-bipyridine)(2-((2′,2′’:5′’,2′’’-terthiophene)-imidazo[4,5-f] [1,10] phenanthroline))] (TLD1433) has completed a phase 1 clinical trial for treating bladder cancer with photodynamic therapy [ 10 ]. [Ru(II)(η 6 - p -cymene)(PTA)Cl 2 ] (RAPTA-C; PTA = 1,3,5-triaza-7-phosphaadamantane) and the RAED type [Ru(II)(η 6 -biphenyl)(ethylenediamine)Cl] + (RM175) are considered the lead structures for antitumor half-sandwich Ru(II)-arene compounds [ 1 , 5 , 11 , 12 ]. Complexes of the isoelectronic congener Rh(III)(η 5 -C 5 Me 5 ) showing promising in vitro anticancer activity have also been intensively investigated [ 13 , 14 ]. Early reports on the mechanism of action of anticancer Ru(III) complexes suggested interaction with DNA, similar to cisplatin, which was believed to be ultimately responsible for the anticancer activity. Even in the case of Ru(II)-arene complexes, DNA nucleobases were primary suspects in their cytotoxic activity [ 15 , 16 , 17 , 18 ]. Although the actual mechanisms of action of these complexes are still not clarified, in recent years, more studies evidenced that DNA is not necessarily the only and/or primary target for ruthenium organometallics. Currently, the role of intra and extracellular proteins as possible targets of organoruthenium and related complexes is widely investigated [ 19 ].