Dihydropyrazine derivatives as a new type of DNA strand breaking agent.

The DNA strand-breaking activity of some dihydropyrazine derivatives, 2,3-dihydro-5,6-dimethylpyrazine (3), 2,3-dihydro-2,5,6-trimethylpyrazine (4), 2,3-dihydro-2,2,5,6-tetramethylpyrazine (5), trans-2,3-dimethyl-5,6,7,8,9, 10-hexahydroquinoxaline (6), its cis-compound (7) and the mixture of 6 and 7 (8) was tested by agarose gel electrophoresis using plasmid pBR322 ccc-DNA as a substrate. The order of DNA strand-breaking activity in the presence of Cu2+ was (7) > (8) > or = (5) > (2) > (6) > (4) > or = (1) > or = (3). 2,5-Bis(D-arabino-tetrahydroxybutyl)-2,5-dihydropyrazine (1) and 2,5-dihydro-3,6-dimethylpyrazine (2) have already been described in terms of DNA breaking activity in a previous paper. The activity was suggested to be due to the dihydropyrazine skeleton, in addition to active oxygen radicals formed in an aqueous solution. The introduction of a methyl group to the dihydropyrazine skeleton enhanced the activities of dihydropyrazine derivatives. The possible chemical basis for DNA strand breakage by dihydropyrazine derivatives, especially in the presence of Cu2+, was discussed.