STRUCTURE-ACTIVITY STUDIES OF BENZIMIDAZOLE-BASED DNA-CLEAVING AGENTS- COMPARISON OF BENZIMIDAZOLE, PYRROLOBENZIMIDAZOLE, AND TETRAHYDROPYRIDOBENZIMIDAZOLE ANALOGS

The synthesis and cytotoxic properties of benzimidazole-based DNA-clea ving agents are presented herein. These agents include pyrrolo[1,2-alp ha]benzimidazole (PBI), benzimidazole (BI), and tetrahydropyrido[1,2-a lpha]benzimidazole (TPBI) analogues. As a result of these studies, it is concluded that the pyrrolo ring is not necessary for cytotoxicity ( PBI is only slightly more cytotoxic than BI) but that homologation of the pyrrolo ring by one carbon results ins system, TPBI, prone to deco mposition. Another conclusion is that the 6-aziridinyl derivative of t he PBI system is more potent than the 7-aziridinyl derivative. Compara tive studies with known antitumor agents revealed that the benzimidazo le-based DNA-cleaving agents possess a unique spectrum of activity. No teworthy observations are the high level of cytotoxicity against melan oma cell lines and the complete absence of activity against leukemia c ell lines. The reductive activation and DNA-cleavage properties of the most active analogue (BI-A) are also presented. Reduction of the quin one; ring to the hydroquinone results in nucleophile and proton trappi ng by the aziridinyl group. Documented nucleophiles include water and the oxygen anion of 5'-dAMP. In addition, reduced BI-A reacts with DNA to form a stable adduct, which cleaves at G + A bases upon heating in basic gel-loading solution.