Document Detail

A strategy for tumor-selective chemotherapy by enzymatic liberation of seco-duocarmycin SA-derivatives from nontoxic prodrugs.
MedLine Citation:
PMID:  11425596     Owner:  NLM     Status:  MEDLINE    
Immuno-conjugates obtained by linking enzymes with appropriate monoclonal antibodies, which bind to tumor-associated antigens, can be employed in a tumor-selective antibody directed enzyme prodrug therapy (ADEPT). For this strategy the glycosides 17a--c were prepared as prodrugs of CI-TMI 14 which is a structurally simplified analogue of the highly potent antitumor agent duocarmycin SA 2. Exposure of 17a--c to cultured carcinoma cells of line A549 displayed a very low toxicity; however, after addition of the corresponding enzymes and exposure for 24 h at prodrug concentrations of <0.1 microM the proliferation of the carcinoma cells was inhibited almost completely with ED(50prodrug)/ED(50drug) of up to 270 in the presence and in the absence of the enzyme. The synthesis of 17a--c was achieved by transformation of nitroanisidine 6 into 12 which was glycosidated to give 16a--c. Removal of the silyl groups, introduction of a chlorine atom and solvolysis of the acetal groups led to 17a-c, of which 17a and 17c are promising candidates for further elaboration.
L F Tietze; M Lieb; T Herzig; F Haunert; I Schuberth
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Bioorganic & medicinal chemistry     Volume:  9     ISSN:  0968-0896     ISO Abbreviation:  Bioorg. Med. Chem.     Publication Date:  2001 Jul 
Date Detail:
Created Date:  2001-06-26     Completed Date:  2001-09-20     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9413298     Medline TA:  Bioorg Med Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  1929-39     Citation Subset:  IM    
Institut für Organische Chemie der Georg-August-Universität Göttingen, Tammannstrasse 2, D-37077 Göttingen, Germany.
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MeSH Terms
Antibiotics, Antineoplastic / chemistry,  isolation & purification*
Antibodies / chemistry
Bronchial Neoplasms / pathology
Magnetic Resonance Spectroscopy
Mass Spectrometry
Prodrugs / chemistry*
Pyrroles / chemistry,  isolation & purification*
Tumor Cells, Cultured
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Antibodies; 0/Indoles; 0/Prodrugs; 0/Pyrroles; 130288-24-3/duocarmycin SA

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