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.

Design of Highly Active Analogues of the Pyrrolo[1,2-a]benzimidazole Antitumor Agents

“…Thus 3-unsubstituted PBI and the 3-hydroxy PBI are devoid of activity, while the lipophilic 3-propanoate derivative showed animal toxicity (100% drug deaths) at doses as low as 5 mg/kg without any significant antitumor activity. 8,3,4 The acetate and the carbamate, PBI-A and PBI-B, respectively, appear to have a suitable balance of polarity and lipophilicity in the 3-substituent for antitumor activity. These findings prompted the investigation of 1, which bears a nitrogen instead of an oxygen bound to the 3-position.…”

“…The preparation of the new PBIs is outlined in Schemes and . Previous synthetic studies led to the preparation of racemic 4 employing 3-bromo-4-nitrotoluene and either racemic or S (−)-2,4-diaminobutanoic acid. ,, Acetylation of S (−)- 4 to S (−)- 5 was followed by conversion to S (−)- 1 , Scheme . The previously unknown R (+) enantiomer was prepared from racemic 4 employing an acyltransferase (ALTUS 20 CLEC catalyst), which afforded R (+)- 5 as the major product.…”

“…Work in this laboratory − has been involved in the design of a new class of DNA cleaving agent based on the pyrrolo[1,2- a ]benzimidazole (PBI) ring system. These agents were designed to alkylate the phosphate backbone upon DT-diaphorase-mediated reduction resulting in a hydrolytically labile phosphotriester; the reductive activation to the hydroquinone form is shown in the inset of Chart .…”

Facile Synthesis of Novel Aminopyrrolobenzimidazole System via Regioselective Amination

“…Pyrrolobenzimidazoles, on the other hand, posses well‐documented and significant therapeutic activities with anticancer . Figure shows representative biologically active compounds as anti‐inflammatory and antioxidant derivatives that contain the pyrrolobenzimidazole moiety.…”

Rational Design of Pyrrolo[1,2-a]benzimidazole-Based Antitumor Agents Targeting the DNA Major Groove

“…Work in this laboratory (1,2) has been involved in the design of a new class of antitumor agent based on the pyrrolo[1,2-a]benzimidazole (PBI) ring system shown in Chart 1. These agents were designed to possess a number of novel features:…”