A new orally active antitumor 1R,2R-cyclohexanediamine-platinum(IV) complex: trans-(n-valerato)chloro(1R,2R-cyclohexanediamine)(oxalato)platinum(IV)

Purpose: The authors have previously reported that trans-bis(n-valerato)(1R ,2R-cyclohexanediamine) (oxalato)platinum(IV) (C5-OHP), an oxaliplatin deri vative, is an orally active antitumor agent in an intraperitoneal (i.p.) L1 210 murine leukemia model. In this study, several oxaliplatin derivatives o f the general formula trans-(carboxylato)chloro(1R,2R-cyclohexanediamine)(o xalato)platinum(IV) were synthesized in order to find new derivatives with greater oral activity than C5-OHP in a clinically predictive tumor model. I n the formula, the carboxylate and chloride ligands are situated in axial p ositions. Methods: Four complexes with the axial carboxylate ligands il-but yrate? n-valerate, n-caproate or n-heptanoate were synthesized and designat ed C4-OHP-Cl, C5-OHP-Cl, C6-OHP-Cl and C7-OHP-Cl, respectively. The oral an titumor activity of the complexes was evaluated against the murine reticulo sarcoma M5076 implanted subcutaneoulsy (s.c.) in to male BDF1 mice. The com plexes were administered orally daily for 5 days in two cycles initiated on days 5 and 12 postimplantation. The physicochemical properties were examin ed by measuring the concentrations of the complexes in test solutions at in tervals by HPLC. The pharmacokinetic behaviors of C5-OHP-Cl, C6-OHP-Cl and C5-OHP following a single oral administration were studied in non-tumor-bea ring male BDF1 mice. Results: Of the complexes synthesized in this study, C 5-OHP-Cl, which exhibited high activity in the i.p. L1210 model, was found to be orally active in the s.c. M5076 model while C5-OHP was not. The in vi tro reduction of the complexes by ascorbate was much more rapid than that o f C5-OHP, while the complexes were more stable than C5-OHP in HCl-acidic an d alkaline solutions. Pharmacokinetic study showed that C-max and AUC(0 24h ) values of plasma total and filterable platinum of C5-OHP-Cl were four to six times greater than those of C5-OHP, indicating that C5-OHP-Cl was absor bed more than C5-OHP. Conclusion: C5-OHP-Cl was found to be a superior 1-OH P derivative C5-OHP, exhibiting significant oral antitumor activity in the s.c. M5076 model. The enhanced activity of C5-OHP-Cl was considered to be d ue in part to increased susceptibility to reduction and increased gastroint estinal absorption. C5-OHP-Cl is a suitable candidate for further study as an oral cancer chemotherapy agent.