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.
Keywords: duocarmycins, nature prodrug, antitumor antibiotic, cc-1065
Current Pharmaceutical Design
Title: Duocarmycins - Natures Prodrugs?
Volume: 8 Issue: 15
Author(s): Mark Searcey
Affiliation:
Keywords: duocarmycins, nature prodrug, antitumor antibiotic, cc-1065
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.
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Cite this article as:
Searcey Mark, Duocarmycins - Natures Prodrugs?, Current Pharmaceutical Design 2002; 8 (15) . https://dx.doi.org/10.2174/1381612023394539
DOI https://dx.doi.org/10.2174/1381612023394539 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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