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

J Med Chem. 2000 Feb 24;43(4):629-38. doi: 10.1021/jm990210q.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

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