ACTIVATION OF THE TRANS GEOMETRY IN PLATINUM ANTITUMOR COMPLEXES - SYNTHESIS, CHARACTERIZATION, AND BIOLOGICAL-ACTIVITY OF COMPLEXES WITH THE PLANAR LIGANDS PYRIDINE, N-METHYLIMIDAZOLE, THIAZOLE, AND QUINOLINE - CRYSTAL AND MOLECULAR-STRUCTURE OF TRANS-DICHLOROBIS(THIAZOLE)PLATINUM(II)

The presence of planar ligands in trans-[PtCl2(py)2] (py = pyridine) greatly enhances the cytotoxicity of such species, with respect both to their corresponding cis isomer and also to trans-[PtCl2(NH3)2]. The cytotoxicity of trans-[PtCl2(py)2] in murine tumor cell lines is equivalent to the anticancer drug cisplatin, cis-[PtCl2(NH3)2] (J. Med. Chem. 1989, 32, 2240). The generality of this effect has been studied for a range of structures with planar ligands of formula trans-[PtCl2(L)(L')]. Three distinct series have been examined-(i) L = L' = pyridine (py), N-methylimidazole (N-MeIm), and thiazole (Tz), (ii) L = quinoline (quin) and L' = substituted sulfoxide R'R''SO, where R' = Me and R'' = Me, CH2Ph, and Ph, and (iii) L = quinoline and L' = NH3. The synthesis and chemical characterization of all new complexes are described. An X-ray crystal structure determination for trans-[PtCl2(Tz)2] confirmed the geometry with N-bond thiazole. The crystals are monoclinic, space group C2/c, with cell dimensions a = 8.088 (3) angstrom, b = 14.964 (4) angstrom, c = 8.847 (2) angstrom, and Z = 4. Platinum has the expected square planar coordination with l(Pt-Cl) = 2.300 (5) angstrom and l(Pt-N) = 2.024 (18) and 2.077 (17) angstrom. Bond angles are normal with N(1)-Pt-N(2) = 180.0 (1)-degrees, N(1)-Pt-Cl(1) = 904 (1)-degrees, and N(2)-Pt-Cl(1A) = 89.6 (1)-degrees. The intensity data were collected with Mo K-alpha radiation with lambda = 0.71073 angstrom. Refinement was by full-matrix least-squares methods to a final R value of 5.45%. The thiazole rings are not coplanar but slightly tilted to each other at an angle of 14.3-degrees. The dihedral angles between the Pt coordination plane and the thiazole rings are 119.3 and 105.0-degrees. The biological studies confirm the generality of activation of the trans geometry using planar ligands. Cytotoxicity tests in murine leukemia (L1210) cell lines both sensitive and rendered resistant to cisplatin show that the complexes show equivalent cytostatic activity to that of cisplatin. Thus the activity is an order of magnitude greater than trans-[PtCl2(NH3)2]. The cytotoxicity is further marked by consistent activity in the cisplatin-resistant cell line. Contrary to the well-established but empirical structure-activity relationships, the trans geometry can give platinum complexes with cytotoxicity equivalent to that of the analogous cis isomer. The results point to a further source of platinum antitumor complexes acting by a different molecular mechanism to cisplatin with potential for antitumor activity complementary to that of the clinically used drug.