title: Chemistry of the pyrrolo[1,2-alpha]benzimidazole antitumor agents: influence of the 7-substituent on the ability to alkylate DNA and inhibit topoisomerase II.
abstract: This study addresses the influence the 7-substituent on the cytotoxicity of pyrrolo[1,2-alpha]-benzimidazole quinones possessing a 6-aziridinyl group (PBIs) and a 6-acetamido group (APBIs). Reduction of a PBI to the aziridinyl hydroquinone results in both nucleophile trapping (alkylation) and 1,5-sigmatropic shift reactions. The latter process is essentially an internal redox reaction wherein the hydroquinone causes reductive opening of the aziridinyl ring. The 7-substituent controls the fate of the aziridinyl ring by means of steric and electronic effects. An electron-rich 7-substituent favors the 1,5-sigmatropic shift reaction. If the 7-substituent distorts the 6-aziridinyl group from the conformation required for the 1,5-sigmatropic shift, then nucleophile trapping occurs. The 7-methyl substituent results in significant nucleophilic trapping, and the 7-unsubstituted and 7-methoxy substituents favor the 1,5-sigmatropic reaction. Thus, the 7-methyl PBIs show the most cytotoxicity of the analogues studied. The APBIs are cytotoxic only as quinones, and reduction to the hydroquinone results in loss of activity. Consistent with this observation, the change from 7-methyl to the more electron-rich 7-methoxy results in a substantial loss of APBI cytotoxicity as well as decreased topoisomerase II inhibition. The mechanism of inhibition is thought to involve the interacalation of only electron deficient APBIs into DNA.
authors.affiliation: Department of Chemistry and Biochemistry, Arizona State University, Tempe 85287-1604, USA.
authors.forename: R
authors.initials: R
authors.lastname: Zhou
authors.forename: E B
authors.initials: EB
authors.lastname: Skibo
mesh_terms: D000478:Alkylation; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001388:Aziridines / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D004247:DNA / Q000378:metabolism*; D004331:Drosophila melanogaster; D006868:Hydrolysis; D007700:Kinetics; D013950:Thymus Gland / Q000737:chemistry; D059005:Topoisomerase II Inhibitors
chemical_list: D000970:Antineoplastic Agents; D001388:Aziridines; D001562:Benzimidazoles; D059005:Topoisomerase II Inhibitors; D004247:DNA