title: 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.
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D001835:Body Weight / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy; D002460:Cell Line; D002945:Cisplatin / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004351:Drug Resistance; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy / Q000235:genetics; D007941:Leukemia P388 / Q000188:drug therapy / Q000235:genetics; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D009154:Mutation; D009944:Organoplatinum Compounds / Q000032:analysis / Q000138:chemical synthesis / Q000627:therapeutic use*; D051381:Rats; D012513:Sarcoma, Experimental / Q000188:drug therapy; D013237:Stereoisomerism
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D002945:Cisplatin; C049777:ormaplatin