Design of highly active analogues of the pyrrolo[1,2-a]benzimidazole antitumor agents

The pyrrolo[1,2-a]benzimidazole (PBI) reductive alkylating agents have been investigated in this laboratory since their discovery in the late 1980s. O f all the structural modifications of the PBIs investigated so far, the var iation of the 3-substituent has the greatest influence on cytotoxicity, tox icity, and in vivo antitumor activity. In the present study, we prepared bo th the R and S enantiomers of nitrogen-containing 3-substituents possessing hydrogen-bonding capability as well as varying basicity. The rationale was to take advantage of stereoselective DT-diaphorase reductive activation as well as hydrogen bonding in the DNA major groove. As a result of these stu dies, analogues were discovered possessing among the highest hollow fiber t umor assay scores observed in hundreds of natural and synthetic antitumor a gents. Our findings indicate that a relatively basic 3-substituent is requi red for outstanding PBI cytotoxicity but that the importance of using pure enantiomers is still open to study.