Abstract
Besides intensive studies into the synthesis of the complex trans-Hlnd[RuCl4(ind)2] (Ind = indazole) 1, which differs remarkably from the usual method for the complexes of the HL[RuCl4L2] - type, competitive products and hydrolysis of this species are described. Stability and pseudo-first-order rate constant under physiological conditions of complex 1 in comparison with the analogous imidazole complex trans-Hlm[RuCl4im2] (Im = imidaZole) ICR were examined by means of HPLC, UV and conductivity measurements (Kobs.(1) = 1.55 × 10-4 s-1; Kobs.(ICR) = 9.10 × 10-4 s-1). An attempt was made to elucidate the bonding conditions in 1 by studying the reactions of Ru(lll) and the two N-methyl isomers of indazole. It can be expected that bonding in the unsubstituted ligand should occur via the N2 nitrogen. The molecular structures of the complex trans-H(1-Melnd)[RuCl4(1-Melnd)2] × 1H2O (1-Melnd = 1-methylindazole) 6 and its hydrolysis product in aqueous solution [RuCl4(H2O)(1-Melnd)2] 7 were determined crystallographically. After anisotropic refinement of F values by least squares, R is 0.053 for 6 and 0.059 for 7. Both complexes crystallize with four molecules in a unit cell of monoclinic symmetry. The space group is P2.1/n for 6 with cell dimensions a = 10.511Å, b = 13.87Å, c = 19.93Å, and β = 98.17° and C2/c for 7 with a = 19.90Å, b = 10.94Å, c = 8.490Å and β = 96.74 ° The fact that the aqua species 7 could be isolated after dissolving 6 in a water/acetone solution confirmed the theory of many Ru(lll) complexes being initially transformed, under physiological conditions, into aqua complexes in a first and often rate-determining hydrolysis step. Compounds 1 and ICR are potent antitumor agents which exhibit activity against a variety of tumor cells and experimental tumor models in animals, including autochthonous colorectal tumors. Clinical studies with 1 are in preparation.
Highlights
Extensive studies have been made into the fact that ruthenium complexes with good antitumor effects undergo numerous conversions in vivo and are transformed into the species which is active at the affected area by metabolic processes Ru(lll) complexes are better handled as "prodrugs", which are converted in situ into the corresponding, more labile, species
Considering the antitumor activity of the complex ICR against tumors of the colon and rectum, which has already been tested with good success, the analogous indazole complex 1 is of major interest for clinical use because of its even higher activity
The composition of the reaction mixture measured by HPLC after 24 h showed that three ruthenium complexes are formed in different shares: A (10 %), B (57 %) and C (33 %)
Summary
. Extensive studies have been made into the fact that ruthenium complexes with good antitumor effects undergo numerous conversions in vivo and are transformed into the species which is active at the affected area by metabolic processes Ru(lll) complexes are better handled as "prodrugs", which are converted in situ into the corresponding, more labile, species. These complexes are able to dissociate one or more non-nitrogen ligands, which in our case are the reactive CI leaving groups, to undergo bonding with the target molecule.
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