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)

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-orderrate constant under physiological conditions of complex 1 in comparison with the analogous imidazolecomplex trans-Hlm[RuCl4im2] (Im = imidaZole) ICR were examined by means of HPLC, UVand conductivity measurements (Kobs.(1) = 1.55 × 10-4 s-1; Kobs.(ICR) = 9.10 × 10-4 s-1). An attemptwas made to elucidate the bonding conditions in 1 by studying the reactions of Ru(lll) and the twoN-methyl isomers of indazole. It can be expected that bonding in the unsubstituted ligand shouldoccur 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 Fvalues 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 dimensionsa = 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 dissolving6 in a water/acetone solution confirmed the theory of many Ru(lll) complexes being initiallytransformed, under physiological conditions, into aqua complexes in a first and often rate-determininghydrolysis step. Compounds 1 and ICR are potent antitumor agents which exhibit activityagainst a variety of tumor cells and experimental tumor models in animals, including autochthonouscolorectal tumors. Clinical studies with 1 are in preparation.