Structure-Activity Studies of Antitumor Agents Based on Pyrrolo[1,2-a]benzimidazoles: New Reductive Alkylating DNA Cleaving Agents

Imadul Islam, Edward B. Skibo, Robert T. Dorr, David S. Alberts

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

Described herein are structure-activity studies of new antitumor agents based on the pyrrolo[1,2-α]benzimidazole (PBI) ring system. These compounds were designed as new DNA cross-linkers mimicking the mitomycin antitumor agents. Actually, the PBI derivatives were found to have anthracycline-like features: (i) shared cross resistance with doxorubicin in a human myeloma line, (ii) cardiotoxicity, and (iii) excellent DNA strand cleaving capability. The DNA strand cleavage is thought to result from reductive alkylation of DNA followed by the generation of reactive oxygen radicals. The best antitumor agent studied is 6-aziridinyl-3-hydroxy-7-methyl-2,3-dihydro-1H-pyrrolo- [1,2-α]benzimidazole-5,8-dione 3-acetate (PBI-A), which possesses nanomolar IC50values against various human ovarian and colon cancer cell lines.

Original languageEnglish (US)
Pages (from-to)2954-2961
Number of pages8
JournalJournal of Medicinal Chemistry
Volume34
Issue number10
DOIs
StatePublished - Oct 1 1991

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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