Synthesis and cytotoxicity of 2-methyl-4,9-dihydro-1-substituted-1H-imidazo[4,5-g]quinoxaline-4,9-dion es and 2,3-disubstituted-5,10-pyrazino[2,3-g]quinoxalinediones

Abstract

Series of 2-methyl-4,9-dihydro-1H-imidazo[4,5-g]quinoxaline-4,9-diones and 5,10-pyrazino[2,3g]quinoxalinediones have been synthesized from 6,7-dichloro-5,8-quinoxalinedione for developing new anticancer drugs. Intercalation complex of 2-methyl-4,9-dihydro-1-methyl-1H-imidazo-[4,5-g]quinoxaline-4,9-dione with GC/GC base pairs by a computer graphics-aided method was parallel to the axis of the helix. The interaction energies of synthetic compounds were low. 2-Methyl-4,9-dihydro-1-(4-bromophenyl)-1H-imidazo[4,5-g]quinoxaline-4,9-dione, which has the lowest interaction energy of the test compounds, was identified as being more cytotoxic against human gastric adenocarcinoma cells (MKN 45) than adriamycin and cis-platin in vitro using the MTT assay. The IC50 value of this compound was 1.30 mu M, whereas those of adriamycin and cis-platin were 3.13 and 86.5 mu M, respectively. The cytotoxicity of 2,3-diethyl-5,10-pyrazino-[2,3-g]quinoxalinedione was comparable to that of adriamycin in the in vitro assay. However these compounds showed loss of activity on human lung adenocarcinoma cells (PC 14) and human colon adenocarcinoma cells (colon 205). These results suggest that 2-methyl-4,9-dihydrol-(4-bromophenyl)-1H-imidazo[4,5-g]quinoxaline-4,9-dione, with the lowest interaction energy, might be an excellent and selective antitumor agent against MKN 45.