title: Structure-activity studies of benzimidazole-based DNA-cleaving agents. Comparison of benzimidazole, pyrrolobenzimidazole, and tetrahydropyridobenzimidazole analogues.
abstract: The synthesis and cytotoxic properties of benzimidazole-based DNA-cleaving agents are presented herein. These agents include pyrrolo[1,2-a]benzimidazole (PBI), benzimidazole (BI), and tetrahydropyrido[1,2-a]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 in a system, TPBI, prone to decomposition. Another conclusion is that the 6-aziridinyl derivative of the PBI system is more potent than the 7-aziridinyl derivative. Comparative studies with known antitumor agents revealed that the benzimidazole-based DNA-cleaving agents possess a unique spectrum of activity. Noteworthy observations are the high level of cytotoxicity against melanoma cell lines and the complete absence of activity against leukemia cell lines. The reductive activation and DNA-cleavage properties of the most active analogue (BI-A) are also presented. Reduction of the quinone ring to the hydroquinone results in nucleophile and proton trapping 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.
authors.affiliation: Department of Chemistry and Biochemistry, Arizona State University, Tempe 85287-1604.
authors.forename: E B
authors.initials: EB
authors.lastname: Skibo
authors.forename: I
authors.initials: I
authors.lastname: Islam
authors.forename: M J
authors.initials: MJ
authors.lastname: Heileman
authors.forename: W G
authors.initials: WG
authors.lastname: Schulz
mesh_terms: D000478:Alkylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001483:Base Sequence; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D007938:Leukemia / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D008545:Melanoma / Q000188:drug therapy; D008969:Molecular Sequence Data; D015394:Molecular Structure; D008970:Molecular Weight; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D011725:Pyridines; D011758:Pyrroles; D004247:DNA