Comparison of the protective effect of ICRF-187 and structurally related analogues against acute daunorubicin toxicity in Syrian golden hamsters

Abstract

Comparisons were made of the protective activity of ICRF-187 and a series of related bis-dioxopiperazine analogues against acute daunorubicin toxicity in Syrian golden hamsters. A single dose of daunorubicin (25 mg/kg) caused a marked decrease in body weight and was lethal to 84% of the animals within 1 to 4 weeks. Pretreatment with ICRF-187, the d-isomer of ICRF-159, ameliorated the lethal effects of daunorubicin. Over 70% of the animals given 50 to 200 mg of ICRF-187 before daunorubicin were alive at 8 weeks. Similar results were obtained with ICRF-186, the 1-isomer of ICRF-159, indicating that the protective activity is not stereospecific. Eighteen other analogues were also evaluated for protective activity; only bimolane, a central chain desmethyl analogue of ICRF-187 with N-morpholinomethyl substituents in each dioxopiperazine ring, was as effective as ICRF-187 in reducing the mortality of daunorubicin. The role of the N-morpholinomethyl groups in the biological activity of bimolane needs further study since ICRF-154, a similar compound without these substituents, exerted only minimal protective activity. Protection against daunorubicin lethality was minimal or absent when hamsters were pretreated with various doses of ICRF analogues in which slight changes had been made in dioxopiperazine rings (ICRF-158, ICRF-198) or in the central chain (ICRF-161, ICRF-192, ICRF-193, ICRF-197, ICRF-198, and ICRF-202). Similarly, animals pretreated with a number of conformationally constrained cyclopropane analogues of bis-dioxopiperazine compounds before receiving daunorubicin died at the same rates as those given only daunorubicin. These results confirm the effectiveness of ICRF-187 against daunorubicin toxicity and indicate that very little alteration can occur in the basic structure of ICRF-187 without loss of this protective activity.