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. 1994 Jul;120(7):409–414. doi: 10.1007/BF01240140

Antitumor activity of isomeric 1,2-diaminocyclohexane platinum(IV) complexes

Zahid H Siddik 1,✉, Salaam Al-Baker 1, Gerald Thai 1, Abdul R Khokhar 1
PMCID: PMC12201108  PMID: 8188734

Abstract

Acquired drug resistance is a major drawback of using cisplatin in the treatment of cancer; however, analogs containing the 1,2-diaminocyclohexane (DACH) ligand can overcome this resistance. DACH can exist as thetrans-1R,2R, trans-1S,2S orcis isomer, and we have examined whether specific isomers coordinated to a platinum(IV) center can modulate antitumor activities in murine tumor models in vivo. Ten isomeric series 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 theR,R andS,S configurations gave similar efficacies which were better than that of the correspondingcis analog. In three out of the ten series, the antitumor activities of theS,S andcis complexes were similar, in six thecis analogs were the least effective, and in the remaining one thecis analog was superior toS,S. One series of complexes with axial chloro ligands and an equatorial 1,1-cyclobutanedicarboxylato group, which had produced the efficacy rankingR,R>cis>S,S in the L1210/0 model, gaveS,S>R,R>cis against cisplatin-resistant L1210/DDP cells,R,R=S,S>cis against B16 melanoma cells, andR,R=S,S=cis against M5076 reticulosarcoma cells. The results demonstrate that profound variation can occur in antitumor activities among isomeric forms of the DACH-Pt(IV) complex. However, the (R,R)-DACH-Pt(IV) complexes appear to be of greater interest overall.

Key words: Platinum(IV) complexes, Diaminocyclohexane isomers, Tumor models, Efficacy

Abbreviations

DACH

1,2-diaminocyclohexane

CBDCA

1,1-cyclobutane-dicarboxylato

MTD

maximal tolerated dose

Footnotes

This work was supported by NIH Grants RO1 CA41581 and RO1 CA50380, and in part by NIH Cancer Center (Core) Support Grant PO30 CA16672

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