SYNTHESIS, CRYSTAL-STRUCTURE, ANTITUMOR-ACTIVITY, AND DNA-BINDING PROPERTIES OF THE NEW ACTIVE PLATINUM COMPOUND METHYLIMIDAZOL-2-YL)CARBINOL)DICHLOROPLATINUM(II), LACKING A NH MOIETY, AND OF THE INACTIVE ANALOG DICHLORO(N-1, N-1'-DIMETHYL-2,2'-BIIMIDAZOLE)PLATINUM(II)

To obtain insight into the structure-activity relationships of new ant itumor active platinum compounds the X-ray structure of the antitumor active Pt compound [Pt(bmic)Cl-2] (bmic = bis-(N-methylimidazol-2-yl)c arbinol) (1) and its interaction with short DNA fragments has been inv estigated using NMR spectroscopy, For comparison also the structurally related compound [Pt(bmi)Cl-2] (bmi = N-1,N-1'-dimethyl-2,2'-biimidaz ole) (2), which is not antitumor active, has been studied. The structu re of the compound [Pt(bmic)Cl-2] (1) was characterized by single-crys tal X-ray structure determination, Compound 1 crystallizes in the mono clinic space group P2(1)/n, with a = 10.055(3) Angstrom, b = 11.802(3) Angstrom, c = 10.620(3) Angstrom, beta = 103.78(2)degrees, V = 1224.0 (6) Angstrom(3) and Z = 4. Convergence was reached at wR2 = 0.1148 (al l data) and R1 = 0.0476 (I > 2 (I)) for 2433 independent reflections a nd 156 adjustable parameters, The platinum atom is coordinated by two nitrogen and two chlorine atoms, resulting in a square planar PtN2Cl2 coordination sphere. The two best least-squares planes through the two imidazole rings of the bmic ligand show a dihedral angle of 30.6 degr ees. The in vitro and in vive antitumor activity of 1 is significant w hereas for compound 2 no antitumor activity could be detected. In P388 mice leukemia an increase of lifespan of 56% was found for complex 1. The antitumor active Pt compound [Pt(bmic)Cl-2] binds to G bases in a similar fashion as cisplatin with a clear preference for N7, In react ion with d(GpG) two stereoisomers are formed, due to the unsymmetric b mic complex and the chiral d(GpG) molecule. Stereoisomer A, i.e. the i somer with the OH group of the bmic and the O6 of the G bases oriented on the same side of the Pt-N-4 plane, is preferentially formed. Model ing studies suggest that this preference is due to the presence of H b onds from the OH of the bmic moiety toward the O6 of the G bases. The presence of many conformers, present in solution, could also be due to these H bonds. For the inactive complex [Pt(bmi)Cl-2] only one GG-N7, N7 chelate is observed. Differences in reactivity toward G bases were also detected for the two platinum complexes. The inactive bmi complex proves to be the most reactive one, whereas the antitumor active bmic compound is less reactive. Thus both structural and kinetic propertie s may explain the different biological properties of these new platinu m compounds.