ANTITUMOR-ACTIVITY ISOMERIC 1,2-DIAMINOCYCLOHEXANE PLATINUM(IV) COMPLEXES

Acquired drug resistance is a major drawback of using cisplatin in the treatment of cancer; however, analogs containing the 1,2-diaminocyclo hexane (DACH) ligand can overcome this resistance. DACH can exist as t he trans-1R,2R, trans-1S,2S or cis isomer, and we have examined whethe r specific isomers coordinated to a platinum(IV) center can modulate a ntitumor activities in murine tumor models in vivo. Ten isomeric serie s of DACH-Pt(IV) complexes were synthesized, each series containing a different combination of axial and equatorial ligands and varying only by the isomeric form of the DACH ligand. Among the ten series, seven clearly indicated superiority of the (R,R)-DACH-Pt(IV) complex against leukemia L1210/0 cells, while in three the R,R and S,S configurations gave similar efficacies which were better than that of the correspond ing cis analog. In three out of the ten series, the antitumor activiti es of the S,S and cis complexes were similar, in six the cis analogs w ere the least effective, and in the remaining one the cis analog was s uperior to S,S. One series of complexes with axial chloro ligands and an equatorial 1,1-cyclobutanedicarboxylato group, which had produced t he efficacy ranking R,R>cis>S,S in the L1210/0 model, gave S,S>R,R>cis against cisplatin-resistant L1210/DDP cells, R,R=S,S>cis against B16 melanoma cells, and R,R=S,S=cis against M5076 reticulosarcoma cells. T he results demonstrate that profound variation can occur in antitumor activities among isomeric forms of the DACH-Pt(IV) complex. However, t he (R,R)-DACH-Pt(TV) complexes appear to be of greater interest overal l.