Document Detail


Design, synthesis, and biological evaluation of biotin conjugates of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid for the isolation of the protein targets.
MedLine Citation:
PMID:  15369396     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO, 1) and related compounds [for example, CDDO-Me (2) and CDDO-Im (3)] are potential anti-inflammatory, cancer chemopreventive, and chemotherapeutic agents. However, the mechanisms responsible for the multiple effects of CDDO are still unclear. Clarification of these mechanisms and particularly isolation of the protein targets are essential for the development of CDDO and its analogues as clinically useful drugs. Such knowledge would provide superior opportunities for designing new compounds with improved potency and selectivity. Therefore, to isolate protein targets using affinity chromatography with immobilized streptavidin as a carrier, we have designed and synthesized C-17 and C-23 biotin conjugates of CDDO (4, 5, and 6) on the basis of our established structure-activity relationships. For the synthesis of 6, a new important precursor, 23-hydroxy-CDDO-Me (29) was synthesized from 20 by a C-23 oxidation protocol, which involves cyclopalladation of the C-4 methyl group from a 3-one oxime. The inhibitory activity of C-23 conjugate 6 is only about 3 times less potent than the mother compound, CDDO, against the proliferation of MCF-7 breast cancer cells. Consequently, 6 may be a very promising tool for the isolation of the protein targets of CDDO.
Authors:
Tadashi Honda; Tomasz Janosik; Yukiko Honda; Jie Han; Karen T Liby; Charlotte R Williams; Robin D Couch; Amy C Anderson; Michael B Sporn; Gordon W Gribble
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  47     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2004 Sep 
Date Detail:
Created Date:  2004-09-16     Completed Date:  2004-11-01     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4923-32     Citation Subset:  IM    
Affiliation:
Department of Chemistry, Dartmouth College, 6128 Burke Laboratory, Hanover, New Hampshire 03755, USA.
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MeSH Terms
Descriptor/Qualifier:
Biochemistry / methods*
Biotin / chemistry*
Breast Neoplasms / drug therapy,  metabolism
Cell Division / drug effects
Chromatography, Affinity
Drug Design
Drug Evaluation, Preclinical
Female
Humans
Oleanolic Acid / analogs & derivatives*,  chemistry*,  pharmacology*
Proteins / drug effects,  isolation & purification*
Streptavidin / chemistry,  metabolism
Structure-Activity Relationship
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
1 R01-CA78814/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; 0/Proteins; 508-02-1/Oleanolic Acid; 58-85-5/Biotin; 9013-20-1/Streptavidin

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


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