Synthesis, physical properties, and antitumor activity of tetraplatin and related tetrachloroplatinum(IV) stereoisomers of 1,2-diaminocyclohexane.

Abstract

The synthesis, physical properties, and antitumor activity of the cis-, d,l-trans-, d-trans-, and l-trans- stereoisomers of 1,2-diaminocyclohexane tetrachloroplatinum(IV) are described. The objective of the study was to produce a platinum complex with activity against cisplatin-resistant tumor cells and with suitable pharmaceutical properties for formulation development. The isomers had the following solubilities in saline: cis-, 2 mg/ml; d,l-trans-, 6.5 mg/ml; and d-trans- and l-trans-, 15-16 mg/ml. The four complexes showed slightly better activity than cisplatin against the ip implanted murine L1210 leukemia. In contrast to cisplatin, all complexes produced significant increases in life span against L1210/cisplatin, a subline of L1210 with acquired resistance to cisplatin. However, the cis- isomer was less active against L1210/cisplatin. The d,l-trans- isomer (tetraplatin) was selected for further studies based on greater ease for large-scale synthesis. It showed superior activity to cisplatin against P388/cisplatin and like cisplatin showed significant and reproducible activity against the ip implanted B16 melanoma, ip implanted M5076 sarcoma, ip implanted P388 leukemia, and MX-1 human breast xenograft implanted under the renal capsule. Purity and stability (greater than 24 hours in saline) were evaluated by high-performance liquid chromatography and found to be suitable for development of a parenteral dosage form. Preliminary studies in a rat model (to be reported elsewhere) showed it to be less nephrotoxic than cisplatin on a molar basis and worthy of further study.

• Authors: W K Anderson, D A Quagliato, R D Haugwitz, V L Narayanan, M K Wolpert-DeFilippes
• Journal: Cancer treatment reports (Cancer Treat Rep) Vol. 70 Issue 8 Pg. 997-1002 (Aug 1986) ISSN: 0361-5960 [Print] United States
• PMID: 3731155 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Organoplatinum Compounds
• Cisplatin
• ormaplatin

Topics

• Animals
• Antineoplastic Agents
• Body Weight (drug effects)
• Breast Neoplasms (drug therapy)
• Cell Line
• Cisplatin (therapeutic use)
• Drug Evaluation, Preclinical
• Drug Resistance
• Humans
• Leukemia L1210 (drug therapy, genetics)
• Leukemia P388 (drug therapy, genetics)
• Melanoma (drug therapy)
• Mice
• Mutation
• Organoplatinum Compounds (analysis, chemical synthesis, therapeutic use)
• Rats
• Sarcoma, Experimental (drug therapy)
• Stereoisomerism