A comparison of the cytotoxic and physical properties of aziridinyl quinone derivatives based on the pyrrolo[1,2-a]benzimidazole and pyrrolo[1,2-a]indole ring systems.
The cytotoxicity and physical properties of the pyrrolo[1,2-a] benzimidazole (PBI) and pyrrolo-[1,2-a]indole (PI) aziridinyl quinones were compared in order to assess the influence of the benzimidazole ring on antitumor activity and DNA reductive alkylation. Our studies show that the PI system possesses none of the cytotoxicity of the PBI systems. Unlike the PBIs, the PI system does not reductively alkylate DNA. Apparently, the benzimidazole ring favors reductive alkylation due to its electron deficient character compared to indole. In addition, the benzimidazole ring may provide the hydrogen bonding interactions required for the interaction with DNA. Our findings resulted in the elucidation of a PBI pharmacophore. Inspection of the literature revealed another drug sharing the PBI pharmacophore, 5-(1-aziridinyl)-3-(hydroxymethyl)- 2-(3-hydroxy-1-propenyl)-1-methyl-1H-indole-4,7-dione (EO9), which remarkably has cytotoxic properties similar to those of the PBIs.
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Department of Chemistry and Biochemistry, Arizona State University, Tempe 85287-1604.
Skibo
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D000478:Alkylation; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001388:Aziridines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects; D002417:Cattle; D004247:DNA / Q000187:drug effects; D005260:Female; D006860:Hydrogen Bonding; D006868:Hydrolysis; D045563:Indolequinones; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001388:Aziridines; D001562:Benzimidazoles; D045563:Indolequinones; D007211:Indoles; C087561:7-(1-azidirinyl)-2,3-dihydro-1-acetoxy-5,8-dihydroxy-6,9-dimethyl-1H-pyrrolo(1,2-a)indole; C087562:6-(1-aziridinyl)-2,3-dihydro-3-acetoxy-5,8-dihydroxy-7-methyl-1H-pyrrolo(1,2-a)benzimidazole; D004247:DNA; C060817:apaziquone