ASAP Inorg. Chem., ASAP Article, 10.1021/ic800506g
Web Release Date: June 14, 2008

Copyright © 2008 American Chemical Society

Synthesis and Reactivity of the Aquation Product of the Antitumor Complex trans-[RuIIICl4(indazole)2]−

Berta Cebrián-Losantos,† Erwin Reisner,†‡ Christian R. Kowol,† Alexander Roller,† Sergiu Shova,§ Vladimir B. Arion,*† and Bernhard K. Keppler*†

Institute of Inorganic Chemistry, University of Vienna, Währingerstr. 42, A-1090 Vienna, Austria, Inorganic Chemistry Laboratory, University of Oxford, South Parks Road, OX1 3QR Oxford, U.K., and Department of Chemistry, Moldova State University, A. Mateevici Street 60, 2009 Chisinau, Moldova

Received March 20, 2008

Abstract:

Aquation of the investigational anticancer drug trans-[RuIIICl4(Hind)2]− (1, KP1019) results in the formation of mer,trans-[RuIIICl3(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 [RuIII2(µ-Cl)2Cl4(Hind)4]·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-[RuIIICl3(Hind)2(MeOH)] (4) and mer,trans-[RuIIICl3(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-[RuIICl2(Hind)2(Me2S)2] (6) and trans,trans,trans-[RuIICl2(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-[RuIIICl3(Hind)(HNC(Me)ind)] (8a), mer,trans-[RuIIICl3(Hind)(HNC(Ph)ind)] (8b), and trans,trans-[RuIIICl2(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-[RuIIICl3(Hind)2(9-meade)] (10) and mer,trans-[RuIIICl3(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)2RuIII(µ-Cl)4(Hind)2]n (12) was crystallized from ethyl acetate/diethyl ether solutions of Na[trans-RuIIICl4(Hind)2]·1.5H2O (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-[RuIIICl4(Hind)2]−.

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