Chemical and biological studies on a series of novel (trans-(1R,2R)-, trans-(1S,2S)-, and cis-1,2-diaminocyclohexane)platinum(IV) carboxylate complexes.
A series of novel platinum(IV) complexes of the type DACH-PtIV-trans-(Y)2-cis-X (where DACH = trans-(1R,2R)-, trans-(1S,2S)-, or cis-1,2-diaminocyclohexane; X = diacetate, oxalate, malonate, methylmalonate, cyclobutanecarboxylate (CBCA), or 1,1-cyclobutanedicarboxylate (CB-DCA); and Y = acetate or trifluoroacetate) has been synthesized and characterized by elemental analysis, IR, and 195Pt-NMR spectroscopy. The compounds have been tested against cisplatin-sensitive L1210/0 leukemia, cisplatin-resistant L1210/DDP leukemia, and M5076 reticulosarcoma cell lines in vivo. Most of these analogs displayed reasonable activity against L1210/0 cells (%T/C = 135 to > 700). There were no gross differences in activity between analogs containing isomers of DACH. Selected compounds were evaluated against L1210/DDP tumor models in which they demonstrated reduced but significant activity compared with activity in the L1210/0 model. Interestingly, complex 20, PtIV(trans-1R,2R-DACH)-trans-(acetate)2-methylmalonate, was highly active against M5076, although it had no activity against the L1210 lines. The results demonstrate that specific combinations of axial and equatorial carboxylate ligands, together with the DACH carrier ligand, can favorably modulate the antitumor properties of platinum complexes and enhance circumvention of cisplatin resistance.
Khokhar
A R
AR
Department of Clinical Investigation, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
al-Baker
S
S
Shamsuddin
S
S
Siddik
Z H
ZH
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use; D002945:Cisplatin / Q000737:chemistry* / Q000627:therapeutic use; D003514:Cyclohexylamines; D018432:Drug Resistance, Multiple; D007536:Isomerism; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003514:Cyclohexylamines; D009944:Organoplatinum Compounds; C030435:1,2-cyclohexanediamine; D002945:Cisplatin; C049777:ormaplatin