Pyrrolobenzimidazoles in cancer treatment

Abstract

This review presents a discussion of the design, chemistry, cytotoxicity and antitumour activity of agents based on the pyrrolobenzimidazole or azomitosene ring system. The focus is the 6-aziridinylquinone derivatives (PBIs) and 6-acetamidoquinone derivatives (APBIs) of this ring system (see Figure 1). Comparisons will be made with related benzimidazole and indole-based antitumour agent systems reported in the patent literature. The pyrrolobenzimidazoles will be shown to represent a new and useful class of antitumour agent with advantages over other such agents. The 6-aziridinyl derivatives (PBIs) alkylate and cleave DNA upon two-electron reduction as a result of phosphate alkylation by the protonated aziridine ring. In contrast, the 6-acetamido quinone derivatives (APBIs) do not require reductive activation to exert cytotoxicity. The 6-acetamido quinone derivatives act as DNA intercalating agents and inhibit the first step of topoisomerase II-mediated DNA relaxation. Some PBIs were found to exhibit high toxicity in mice with minimal antitumour activity while others exhibit a high degree of tumour selectivity. The APBIs showed significant increases in lifespans of mice as well as activity against tumours distant from the injection site.

• cancer chemotherapy
• DNA cleavage
• pyrrolobenzimidazole
• topoisomerase II