Pyrrolo(l ,4)benzodiazepine Antitumor Antibiotics: Chemistry, Interaction with DNA, and Biological Implications

Laurence H. Hurley, David E. Thurston

Research output: Contribution to journalReview article

58 Scopus citations

Abstract

The pyrrolo(l,4)benzodiazepine (P(1,4)B) antitumor antibiotics, anthramycin, tomaymycin, sibiromycin and the neothramycins A and B, are potent anticancer agents that form covalent adducts through the exocyclic amino group of guanine in DNA. This review describes the chemistry important for both the DNA reactivity and synthesis of the carbinolamine containing drugs and the strategy for elucidation of the three-dimensional form of the adduct with DNA. The high DNA sequence specificity as well as some of the observed biological consequences of DNA damage caused by these agents in human and yeast cells are rationalized through the proposed structure of the drug-DNA adducts. Parallel toxicological studies have led to a proposal for the underlying mechanism for the cardiotoxicity of certain members of this group of agents. A rationale for designing drugs which should retain their potent antitumor activity without the associated cardiotoxicity is also proposed. Lastly, the application of the P(l,4)B's as probes for monitoring drug binding to DNA and drug-induced conformational changes is described.

Original languageEnglish (US)
Pages (from-to)52-59
Number of pages8
JournalPharmaceutical Research: An Official Journal of the American Association of Pharmaceutical Scientists
Volume1
Issue number2
DOIs
StatePublished - Mar 1984
Externally publishedYes

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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