The Organic Chemistry of the Pyrrolo[1,2-a]benzimidazole Antitumor Agents. An Example of Rational Drug Design

Work in our laboratory has led to the development of the pyrrolo[1,2-a]benzimidazole-based antitumor agents. There are three structural classes of these agents: the 6-aziridinyl analogues (PBIs), the 6-acetamido analogues (APBIs), and the imino-6-acetamido analogues (imino-APBIs). These agents were prepared by multistep syntheses, all of which started with a pyrrolo[1,2-a]benzimidazole ring forming reaction utilizing the ”t-amino effect”. Enantiospecific synthesis were also carried out employing amino acids of known configuration and an ”internal” Phillips reaction. The chemistry of the rest of the steps leading to the PBIs, APBIs, and the imino-APBIs is presented. The aziridinyl ring of the PBIs is activated as an alkylating agent upon quinone reduction. In addition, the aziridinyl ring also traps a proton. This unprecedented reaction is very likely a [1,5]sigmatropic shift. Reductive alkylation of mononucleotides and DNA by PBIs result in alkylation of the phosphate oxygen anion. The reaction at this site is attributed to electronic factors as well as hydrogen bonding in the DNA major groove. The DNA alkylation reaction and resulting cleavage are likely responsible for the antitumor activity observed in the PBIs. The chemical events leading to APBI and imino-APBI antitumor activity are currently under study.

Quinone - iminoquinone - DNA Cleavage - pyrrolobenzimidazole - antitumor