Isomers (R,R-, S,S-, and cis-) of 1,2-diaminocyclohexane (DACH) platinum(IV) complexes with selected axial and equatorial ligands were synthesized and evaluated for in vitro antitumor activity, cellular uptake, and total DNA-Pt adducts. L1210 cells, sensitive to cis-diamminedichloroplatinum(II) (CDDF) and tetraplatin (L1210/0), 160-fold resistant to CDDP [L1210/diamminedichloroplatinum (DDP)], or 70-foid resistant to tetraplatin (L1210/DACH), were used in conjunction with compounds having the general structure DACH-Pt(IV)-X2Y2, where X and Y are axial and equatorial ligands and X2Y2 are specifically CI2CI2, Ac2CI2, (TFA)2CI2, (OH)2CI2, and CI2CBDCA (CI, chloro; Ac, acetato; TFA, trifluoroacetato; OH, hydroxo; CBDCA, 1,1-cyclobutanedicarboxylato). Comparison of cytotoxicities between isomers of CI2CI2, Ac2CI2, or CI2CBDCA indicated that R,R-isomers were the most effective against all three cell lines. The relatively lower activity of the S,S- and cis-isomers was cell line dependent: against L1210/DACH, both isomers of CI2CI2 were only 2- to 3-fold less effective, and this contrasted with 7- and 26-fold lower cytotoxicities, respectively, against L1210/DDP. Cross-resistance factors in the L1210/ DDP and L1210/DACH lines depended on both isomeric form and the nature of axial or equatorial ligand. The L1210/DDP cells were 6- to 9-fold cross-resistant to the R,R-isomer, 8- to 15-fold to S,S-isomer, and 13- to 38-fold to cis-isomer. The L1210/DACH line was only 4- to 7-fold cross-resistant to the three isomers of Ac2CI2, but cross-resistance to the isomers was 47- to 79-fold for CI2CI2 and 22- to 56-fold for CI2CBDCA complexes. Compared with CDDP, accumulation (2 h at 100 µm drug concentration) of Ac2CI2 in the three L1210 cell lines was 26–50%, while uptake of CI2CI2 and (TFA)2CI2 was 100–170% and 320–570%, respectively. The greatest DNA binding was seen with CI2CI2 in all cell lines, followed by (TFA)2CI2, CDDP, and Ac2CI2. DNA binding correlated directly with potency (1/ concentration producing 50% inhibition) in the L1210/0 model (r = 0.973, P < 0.016) but not in the L1210/DDP and L1210/DACH models. Accumulation and DNA-binding studies indicated that binding efficiency to DNA was: CI2CI2 > Ac2CI2 > CDDP > (TFA)2CI2. In a nonreducing environment, the Pt(IV) complexes (20 µm) did not react with salmon sperm DNA. Reduced glutathione (100 µm), as a reducing agent, rendered full binding capacity to CI2CI2; binding was 25–30% of the expected maximum for (TFA)2CI2, while Ac2CI2 remained inert. These data indicate profound effects of axial and equatorial ligands in Pt(IV) complexes on the antitumor activity and cellular pharmacology of the compounds. The investigations also identified Ac2CI2 as of particular interest because of its low cross-resistance in the L1210/DDP and L1210/DACH cells.

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This work was supported in part by grants R01 CA-41581 and R01 CA-50380 from the National Institutes of Health.

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