CRYSTAL-STRUCTURE, SOLUTION CHEMISTRY, AND ANTITUMOR-ACTIVITY OF DIASTEREOMERIC HYDROXYPHENYL)ETHYLENEDIAMINE]DICHLOROPLATINUM(II) COMPLEXES

Complete three-dimensional X-ray crystal structure analyses of meso- a nd S,S-configurated ydroxyphenyl)-ethylenediamine]dichloroplatinum(II) complexes (meso-3-PtCl2 and (-)-3-PtCl2) have been carried out. Data were collected at room temperature. After anisotropic refinement of F- values by least squares, R is 0.098 for the meso-configurated complex and 0.048 for the S,S-configurated complex. meso- and (-)-3-PtCl2 crys tallize with 4 molecules in a unit cell of monoclinic symmetry. The sp ace group is P2(1)/n for meso-3-PtCl2 with cell dimensions a = 11.032 Angstrom, b = 11.671 Angstrom, c = 12.347 Angstrom, and beta = 111.17 degrees and P2(1) for (-)-3-PtCl2 with a = 9.969 Angstrom, b = 11.263 Angstrom, c = 14.560 Angstrom, and beta = 107.73 degrees. meso-3-PtCl2 and (-)-3-PtCl2, respectively, build dimeric units. The ethylenediami ne ligand of meso-3-PtCl2 is puckered and exists in an envelope confor mation, while the molecules of the dimeric units of (-)-3-PtCl2 show b oth the envelope and the half-chair conformation. Both aromatic rings of (-)-3-PtCl2 are equatorially arranged and fixed by intramolecular h ydrogen bonds from the amino protons to the phenolic oxygen. The hydro xy group of the axially standing ring of meso-3-PtCl2 is not involved in intramolecular N-H...O bridges since it is oriented opposite to the NH2 groups. In solution, however, this OH group is reoriented and bui lds H-H...O bonds, too. The influence of the 3D structure on the react ivity of the complexes was investigated through the substitution of th e cl(-) leaving groups by I-. - The substitution follows an associativ e mechanism, whereby the rate constants are given by the equation k(ob s) = k(s) + k(I-)[I-] in accordance with the possible reaction pathway s. K-s is the rate constant for the I- coordination after hydrolysis a nd k(I-) the rate constant for the direct nucleophilic attack. Due to the shielding of the platinum by the axially oriented aromatic ring, t he reactivity of meso-3-PtCl2 (k(1,s), = 3.06 X 10(-5) s(-1), k(1,I-) = 383.5 L/mol.s, k(2,s) = 1.26 X 10(-5) s(-1), k(2,I-) = 120.2 L/mol.s ) is decreased compared to (-)-3-PtCl2 (k(1,s) = 5.05 x 10(-5) s(-1), k(1,I-) = 543.9 L/mol.s, k(2,s) = 1.64 x 10(-5) s(-1), k(2,I-) = 191.6 L/mol.s). The reactivities correlate very well with the antitumor res ults in vivo on the P388 leukemia of the mouse and in vitro for the NI H-OVCAR 3 cell line. In accordance with the high reactivity the best a ntitumor effects were found for (-)-3-PtCl2. For the P388 leukemia of the mouse a dose of 6.6 mu mol/kg given on days 1-5 leads to survival of all the animals at the end of the test.