Reactions of potent antitumor complex trans-[RuIIICl 4(indazole)2]- with a DNA-relevant nucleobase and thioethers: Insight into biological action

Author(s)

Alexander Egger, Vladimir Arion, Erwin Reisner, Berta Cebrian, Sergiu Shova, Günter Trettenhahn, Bernhard Keppler

Abstract

Reactions of the complex trans-[RuCl4(Hind)2]- (Hind ) indazole), which is of clinical relevance today, with both

the DNA model nucleobase 9-methyladenine (made) and the thioethers R2S (R ) Me, Et), as models of the

methionine residue in biological molecules possibly acting as nitrogen-competing sulfur-donor ligands for ruthenium

atom, have been investigated to get insight into details of mechanism leading to antitumor activity. Three novel

ruthenium complexes, viz., [RuIIICl3(Hind)2(made)], 1, [RuIICl2(Hind)2(Me2S)2], 2, and [RuIICl2(Hind)2(Et2S)2], 3, have

been isolated as solids. Oxidation of 2 and 3 with hydrogen peroxide in the presence of 12 M HCl in chloroform

afforded the monothioether adducts, viz., [RuIIICl3(Hind)2(Me2S)], 4, and [RuIIICl3(Hind)2(Et2S)], 5. By dissolution of

2 or 3 in DMSO, replacement of both R2S ligands by DMSO molecules occurred with isolation of trans,trans,trans-

[RuIICl2(Hind)2(DMSO)2], 6. The products were characterized by elemental analysis, IR, UV-vis, electrospray mass

spectrometry, cyclic voltammetry, and X-ray crystallography (1âCH2Cl2âCH3OH and 1â1.1H2Oâ0.9CH3OH, 2, and

5). The first crystallographic evidence for the monofunctional coordination of the 9-methyladenine ligand to ruthenium

via N7 and the self-pairing of the complex molecules via H-bonding, using the usual Watson-Crick pairing donor

and acceptor sites of two adjacent 9-methyladenine ligands, is reported. The electrochemical behavior of 1-5 has

been studied in DMF and DMSO by cyclic voltammetry. The redox potential values have been interpreted on the

basis of the Lever¿s parametrization method. The EL parameter was estimated for 9-methyladenine at 0.18 V,

showing that this ligand behaves as a weaker net electron donor than imidazole (EL ) 0.12 V). The kinetics of the

reductively induced stepwise replacement of chlorides by DMF in 4 and 5 were studied by digital simulation of the

cyclic voltammograms. The rate constant k1 has been determined as 0.9 ± 0.1 s-1, which obeys the first-order rate

law, while k2 is concentration dependent (0.2 ± 0.1 M1-nâs-1 with n > 1 for 4 mM solutions of 4 and 5), indicating

higher-order reactions mechanism.

Organisation(s)

Department of Inorganic Chemistry, Department of Physical Chemistry

Journal

Inorganic Chemistry

Volume

Pages

122-132

No. of pages

ISSN

0020-1669

Publication date

2005

Peer reviewed

Yes

Austrian Fields of Science 2012

1040 Chemistry

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