Inhibitors of topoisomerase II based on the benzodiimidazole and dipyrroloimidazobenzimidazole ring systems: controlling DT-diaphorase reductive inactivation with steric bulk.

Abstract

Described herein are the synthesis, cytotoxic properties, and topoisomerase II inhibition assays of benzodiimidazole and dipyrroloimidazobenzimidazole structural variants of the pyrrolo[1, 2-a]benzimidazole or APBI ring system. These ring variants were designed to inhibit topoisomerase II, much as the APBIs are able to do. Since only the quinone form of the APBIs can intercalate DNA, two-electron reduction to the hydroquinone by DT-diaphorase is known to deactivate these compounds. Indeed, the APBIs possess a high inverse correlation with the cellular concentration of DT-diaphorase. Therefore one feature of the ABPI structural variants is the excessive bulk about the quinone ring, which was predicted to diminish DT-diaphorase substrate activity. Another feature is the presence of one or two alkylating centers, which would permit alkylation of DNA and/or topoisomerase II. Inhibition assays for topoisomerase II-mediated relaxation of supercoiled DNA indicate that the benzodiimidazole and dipyrroloimidazobenzimidazole quinone ring systems are catalytic inhibitors of topoisomerase II. Both quinone systems exhibit cytotoxicity perhaps due to the lack of inactivation by DT-diaphorase as well as topoisomerase II inhibition. One quinone displayed the novel feature of cytotoxicity selectively against melanoma cell lines. In conclusion, the benzodiimidazole and dipyrroloimidazobenzimidazole quinone ring systems will be subjected to future analogue development and structure-activity studies.

• Authors: W G Schulz, E B Skibo
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 43 Issue 4 Pg. 629-38 (Feb 24 2000) ISSN: 0022-2623 [Print] United States
• PMID: 10691689 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Benzimidazoles
• Enzyme Inhibitors
• Imidazoles
• Topoisomerase II Inhibitors
• DNA
• NAD(P)H Dehydrogenase (Quinone)

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Benzimidazoles (chemical synthesis, chemistry, pharmacology)
• DNA (chemistry)
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Imidazoles (chemical synthesis, chemistry, pharmacology)
• Inhibitory Concentration 50
• NAD(P)H Dehydrogenase (Quinone) (antagonists & inhibitors, chemistry)
• Rats
• Structure-Activity Relationship
• Substrate Specificity
• Topoisomerase II Inhibitors
• Tumor Cells, Cultured