Crystal structure, solution chemistry, and antitumor activity of diastereomeric [1,2-bis(2-hydroxyphenyl)ethylenediamine]dichloroplatinum(II) complexes

Abstract

Complete 3-dimensional x-ray crystal structure analyses of meso- and S,S-PtCl2L (L = 1,2-bis(2-hydroxyphenyl)ethylenediamine] (I and II, resp.) were carried out. After anisotropic refinement of F-values by least squares, R is 0.098 for I and 0.048 for II. I and II crystallize with Z = 4, monoclinic symmetry and space group P21/n for I and space group P21 for II. I and II build dimeric units. The ethylenediamine ligand of I is puckered and exists in an envelope conformation, while the mols. of the dimeric units of II show both the envelope and the half-chair conformation. Both arom. rings of I are equatorially arranged and fixed by intramol. H bonds from the amino protons to the phenolic O. The hydroxy group of the axially standing ring of I is not involved in intramol. N-H...O bridges since it is oriented opposite to the NH2 groups. In soln., however, this OH group is oriented and builds H-H...O bonds, too. The influence of the 3-dimensional structure on the reactivity of the complexes was studied through the substitution of the Cl- leaving groups by I-. The substitution follows an associative mechanism, whereby the rate consts. are given by the equation kobs = ks + kI-[I-] in accordance with the possible reaction pathways. Ks is the rate const. for the I- coordination after hydrolysis and kI- the rate const. for the direct nucleophilic attack. Due to the shielding of the Pt by the axially oriented arom. ring, the reactivity of I is decreased compared to II. The reactivities correlate very well with the antitumor results in vivo on the P388 leukemia of the mouse and in vitro for the NIH-OVCAR 3 cell line. In accordance with the high reactivity the best antitumor effects were found for I. For the P388 leukemia of the mouse a dose of 6.6 micro mol/kg given on days 1-5 leads to survival of all the animals at the end of the test.