Synthesis and reactivity of the aquation product of the antitumor complex trans-[Ru(III)Cl4(indazole)2]-

Aquation of the investigational anticancer drug trans-Ru(III)Cl4(Hind)2](-) (1, KP1019) results in the formation of mer,trans-Ru(III)Cl3(Hind)2(H2O)] (2), which was isolated in high yield (85%) and characterized by spectroscopic methods and X-ray crystallography. Dissolution of 2 in acetone, led to its dimerization into Ru(III)2(mu-Cl)2Cl4(Hind)4] x 2 (Me)2CO (3) in 79% yield, with release of two water molecules. Complex 2 reacts readily with nucleophilic organic molecules, viz., methanol or dimethyl sulfide, at room temperature by replacement of the aqua ligand to give mer,trans-Ru(III)Cl3(Hind)2(MeOH)] (4) and mer,trans-Ru(III)Cl3(Hind)2(Me2S)] (5) in 58 and 64% yield, respectively. By reaction of 2 with DMSO at room temperature or dimethyl sulfide at elevated temperatures trans,trans,trans-Ru(II)Cl2(Hind)2(Me2S)2] (6) and trans,trans,trans-Ru(II)Cl2(Hind)2(S-DMSO)2] (7) were prepared in 64 and 75% yield, respectively. Dissolution of 2 in acetonitrile or benzonitrile gave rise to mer,trans-Ru(III)Cl3(Hind)(HNC(Me)ind)] (8a), mer,trans-Ru(III)Cl3(Hind)(HNC(Ph)ind)] (8b), and trans,trans-Ru(III)Cl2(HNC(Me)ind)2]Cl (9) in 67, 50, and 23% yield, respectively, upon metal-assisted iminoacylation of indazole, which is unprecedented for ruthenium(III). Furthermore, complex 2 reacts with the DNA-model bases 9-methyladenine (9-meade) and N6,N6-dimethyladenine (6-me2ade) to yield mer,trans-Ru(III)Cl3(Hind)2(9-meade)] (10) and mer,trans-Ru(III)Cl3(Hind)2(6-me2ade)] (11) with the purine bases bound to the Ru(III) center via N7 and N3, respectively. Complex 11 represents the first ruthenium complex in which the coordination of the purine ligand N6,N6-dimethyladenine occurs via N3. In addition, the polymer Na(EtOAc)2Ru(III)(mu-Cl)4(Hind)2]n (12) was crystallized from ethyl acetate/diethyl ether solutions of Natrans-Ru(III)Cl4(Hind)2] x 1.5 H2O (1a). The reported complexes were characterized by elemental analysis, IR and UV-vis spectroscopy, ESI mass spectrometry, cyclic voltammetry, and X-ray crystallography. Electrochemical investigations give insight into the mechanistic details of the solvolytic behavior of complex 2. The lability of the aqua ligand in 2 suggests that this complex is a potential active species responsible for the high antitumor activity of trans-Ru(III)Cl4(Hind)2](-).