SYNTHESIS OF 6-AZIRIDINYLBENZIMIDAZOLE DERIVATIVES AND THEIR IN-VITROANTITUMOR ACTIVITIES

In search for new antitumor agents, twelve 6-aziridinylbenzimidazole d erivatives were synthesized and their cytotoxicities were tested again st three cancer cell lines (mouse lymphocytic leukemia P388 and B16, a nd human gastric carcinoma SNU-16). From 4-amino-3-nitrotoluene as the starting material, 2-(acetoxymethyl)benzimidazoles (5a-d) were obtain ed by Phillips reaction. These benzimidazoles were then reacted with F remyls salt to give a mixture of three 2-(acetoxymethyl) (8a-c) and fo ur 2-(hydroxymethyl)benzimidazole-4,7-diones (9a-d). Addition of these quinones with aziridine afforded 6-aziridinyl-2-(acetoxymethyl) (10a- c) and 6-aziridinyl-2-(hydroxymethyl)benzimidazole-4, 7-diones (11a-d) . Utilizing 2-(hydroxymethyl)benzimidazole-4,7-diones (9b,d), esters 1 0d and 13e-h were prepared by the sequential reactions of esterificati on and addition. The synthesized compounds show potent cytotoxicity ag ainst all of three cell lines tested. The cytotoxicities of 10a-d or 1 1a-d against SNU-16 were superior to those of 13e-h, and were equal to or slightly higher than that of mitomycin C. Compounds 11a-d were sli ghtly more cytotoxic than 10a-d in all cell lines tested.