Synthesis, characterization, and biological evaluation of platinum IV complexes exhibiting anticancer properties

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Montana State University - Bozeman, College of Letters & Science


The chemotherapeutic agent cisplatin is widely used in the treatment of head, neck, ovarian, testicular and bladder cancers. The major disadvantages in using cisplatin are its low solubility and high toxicity, in particular nephrotoxicity. These two limitations prevent cisplatin from being administrated at higher concentrations than 1.0 mg/Kg. Fifteen platinum IV compounds were synthesized and characterized by NMR. Nine of the 15 were soluble enough in Fetal Bovine Serum to be evaluated in a tissue culture assay using murine B-16 melanoma and Lewis Lung carcinoma cells. Toxicity and chemotherapeutic activity in tumor bearing mice was used to evaluate those compounds showing high solubility and chemotherapeutic activity in tissue culture. Only one of the nine compounds showed high solubility and chemotherapeutic activity in the assay. The toxicity of this compound,11, using C57B1 mice was determined to be LD50 >41 mg/Kg, compared to cisplatins' LD50 of 13-14 mg/Kg. The compound was evaluated for its chemotherapeutic effects in tumor bearing mice and it was found to give a dose response against the B-16 melanoma tumor. Of the other compounds tested in the tissue culture assay one in particular showed significant activity, 20. The LD100 was 29 μM while cisplatin and dichloro-(ethylenediamine)Pt(II) were 15 microns and 75 microns respectively. It was discovered that dicarboxylates substituents increased the solubility of platina(IV)cylcobutanes more so than alcohols, ethers and aldehydes. Amine platinum ligands influenced the chemotherapeutic activity, with ethylenediamine complexes showing more activity than either pyridine or 2,2'-dipyridine complexes.




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