Synthesis Characterization and Solution Chemistry oftrans-Indazoliumtetrachlorobis(Indazole)Ruthenate(III) a NewAnticancer Ruthenium Complex. IR UV NMR HPLC Investigations andAntitumor Activity. Crystal Structures of trans-1-Methyl-Indazoliumtetrachlorobis-(1-Methylindazole)Ruthenate(III)and its Hydrolysis Product trans-Monoaquatrichlorobis-(1-Methylindazole)-Ruthenate(III)

摘要

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 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 autochthonouscolorectal tumors. Clinical studies with >1 are in preparation.