Genotoxic activity of four newly synthesized pyrrolin-2-one derivatives.

PURPOSE: To study the genotoxic activity of 4 newly synthesized derivatives of pyrrolin-2-one by means of the micronucleus (MN) assay both in vivo and in vitro, and the DNA-damaging activity of these substances by means of the comet assay on murine cells in vitro. MATERIALS AND METHODS: The following compounds were studied: [3-(imidazolyl-1)-propylamide-4,5,5-trimethyl- pyrrolin-2-one] (IPA-TP); [3-cyclohexylamide-4,5,5 -trimethyl- pyrrolin-2-one](CH-TP); [3-piperonylamide-4,5,5- trimethyl-pyrrolin-2-one] (PA-TP); and [3-phenethylamide- 4,5,5-trimethyl-pyrrolin-2-one] (PHA-TP). L5178Y mouse lymphoma cells were used to study the activity of the compounds by the MN and the comet assays. The acute toxicity and MN-inducing activity of the 4 compounds was assessed on Swiss albino mice. RESULTS: IPA-TP, PA-TP, and PHA-TP were very weak MN inducers in mouse lymphoma cells, which induced MN only at toxic for lymphoma cells concentrations. No doseeffect relationship was registered. CH-TP was tested at low concentration because of bad solubility and was not MNinducer. IPA-TP and CH-TP were not active in the comet assay, while both PA-TP and PHA-TP were active. The study of acute toxicity showed the following results: LD(50) of IPATP, CH-TP, PA-TP and PHA-TP were 460 mg/kg, 650 mg/kg, 370 mg/kg, and 350 mg/kg, respectively. The substances were studied using the MN assay on mouse bone marrow polychromatic erythrocytes (PCEs), and all of them were active only at doses equal to 1/2 of LD(50). The increase of bone marrow cells with MN was 2.5-5.8-fold compared with the background MN level. Lower doses (1/5 of LD(50)) of all substances were not effective. CONCLUSION: A good agreement between in vivo and in vitro genotoxicity was obtained. IPA-TP, PA-TP, PHA-TP with potential antitumor activity, comparatively low acute toxicity and genotoxicity are good candidates for in vivo studies of antitumor activity.