Synthesis, Characterization and Solution Chemistry of trans-Indazoliumtetrachlorobis(Indazole)Ruthenate(III), a New Anticancer Ruthenium Complex. IR, UV, NMR, HPLC Investigations and Antitumor Activity. Crystal Structures of trans-1-Methyl-Indazoliumtetrachlorobis-(1-Methylindazole)Ruthenate(III) and its Hydrolysis Product trans-Monoaquatrichlorobis-(1-Methylindazole)-Ruthenate(III).
Besides intensive studies into the synthesis of the complex trans-Hlnd[RuCl(4)(ind)(2)] (Ind = indazole) 1, which differs remarkably from the usual method for the complexes of the HL[RuCl(4)L(2)] - 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[RuCl(4)im(2)] (Im = imidaZole) ICR were examined by means of HPLC, UV and conductivity measurements (K(obs.)(1) = 1.55 x 10(-4) s(-1); K(obs.)(ICR) = 9.10 x 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)[RuCl(4)(1-Melnd)(2)] x 1H(2)O (1-Melnd = 1-methylindazole) 6 and its hydrolysis product in aqueous solution [RuCl(4)(H(2)O)(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 = 10.511A, b = 13.87A, c = 19.93A, and beta = 98.17 degrees and C2/c for 7 with a = 19.90A, b = 10.94A, c = 8.490A and beta = 96.74 degrees 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.
Lipponer
K G
KG
Institute of Inorganic Chemistry University of Heidelberg Im Neuenheimer Feld 270 Heidelberg D-69120 Germany.
Vogel
E
E
Keppler
B K
BK