Document Detail


Duocarmycins--natures prodrugs?
MedLine Citation:
PMID:  12052214     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Mark Searcey
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Current pharmaceutical design     Volume:  8     ISSN:  1381-6128     ISO Abbreviation:  Curr. Pharm. Des.     Publication Date:  2002  
Date Detail:
Created Date:  2002-06-07     Completed Date:  2002-11-04     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9602487     Medline TA:  Curr Pharm Des     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  1375-89     Citation Subset:  IM    
Affiliation:
Department of Pharmaceutical and Biological Chemistry, University of London School of Pharmacy, 29/39 Brunswick Square, London, WC1N 1AX, UK. mark.searcey@ams1.ulsop.ac.uk
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibiotics, Antineoplastic / chemistry*,  pharmacology
Antineoplastic Agents, Alkylating / chemistry*,  pharmacology
Cell Survival / drug effects
DNA / chemistry*
Drug Stability
Indoles*
Leucomycins / chemistry,  pharmacology
Leukemia L1210
Prodrugs / chemistry*,  pharmacology
Pyrroles / chemistry,  pharmacology
Pyrrolidinones / chemistry,  pharmacology
Structure-Activity Relationship
Tumor Cells, Cultured
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Antineoplastic Agents, Alkylating; 0/Indoles; 0/Leucomycins; 0/Prodrugs; 0/Pyrroles; 0/Pyrrolidinones; 118292-34-5/duocarmycin A; 118292-35-6/pyrindamycin B; 118292-36-7/pyrindamycin A; 124325-93-5/duocarmycin B1; 124325-94-6/duocarmycin B2; 130288-24-3/duocarmycin SA; 69866-21-3/CC 1065; 9007-49-2/DNA

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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