Biochemical studies on growth‐inhibitory bisdioxopiperazines. I. Effect on dna, rna and protein synthesis in mouse‐embryo fibroblasts

A number of bisdioxopiperazines have recently been shown to possess marked growth-inhibitory activity against a range of experimental tumours in mice and rats. These compounds were originally designed as potential intracellularly activated chelating agents. In the present investigation, two of these compounds (±)-1,2-bis (3,5-dioxopiperazin-1-yl) propane (ICRF 159) and meso -2,3-bis (3,5-dioxopiperazin-1-yl) butane (ICRF 193) have been shown to be potent inhibitors of DNA synthesis in growing mouse-embryo fibroblasts while having relatively little effect on RNA and protein synthesis. In this respect, their behaviour strongly resembles that of radiomimetic drugs and ionizing radiation. X-rays and both ICRF 159 and ICRF 193 exhibit a very similar pattern for the time-course of the inhibition of 3H-thymidine uptake into DNA. They all show a recovery taking place about 4 h after the initial treatment (presumably due to repair and/or stimulation of unscheduled DNA synthesis) followed later by a more substantial and permanent inhibition. In view of the structure of these compounds, it is possible that they may be exerting a radiomimetic effect by acting as mono- or bi-functional acylating agents.