Duocarmycins - Natures prodrugs?

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Abstract

The duocarmycins and (+)-CC-1065 are amongst the most potent antitumour antibiotics discovered to date and yet have not progressed into the clinic. The natural products are extremely stable to nucleophilic attack until bound to their DNA target and are not substrates for any other biological nucleophile. The mechanism for this target activation of the duocarmycins is discussed with relation to both an acid-catalyzed activation and a binding-induced conformational change leading to ground state destabilization. It is suggested that targeting of the duocarmycins to their site of action in a tumour may be more important than introducing systemically-activated prodrugs as the natural product itself can be considered to be a type of prodrug, activated only on binding to its targets. Methods that have been used to target CC-1065 and the duocarmycins are reviewed as well as efforts towards systemically activated prodrugs. A simple analysis of the approaches that could be taken to vary the structure for targeting is suggested.
Original languageEnglish
Pages (from-to)1375-1389
Number of pages15
JournalCurrent Pharmaceutical Design
Volume8
Issue number15
Publication statusPublished - 2002

Keywords

  • CC-1065
  • FUNCTIONAL
  • DOUBLE-STRANDED DNA
  • ANTI-TUMOR AGENT
  • NONCOVALENT BINDING SELECTIVITY
  • ANALOGS
  • LEFT-HAND SUBUNIT
  • DNA-SEQUENCE SPECIFICITY
  • GROOVE ALKYLATING-AGENTS
  • ANTITUMOR ANTIBIOTIC
  • BIOLOGICAL-ACTIVITY
  • SECO-CBI-TMI

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