Document Detail


Synthesis of a glucuronic acid and glucose conjugate library and evaluation of effects on endothelial cell growth.
MedLine Citation:
PMID:  15261580     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Compounds that alter endothelial cell growth are of interest in the development of angiogenesis modulators. A structurally diverse series of saccharide derivatives (glycosylamide conjugates) have been synthesized and evaluated for their effects on bovine aortic endothelial cell (BAEC) growth. Heparin-albumin (HA) reduced BAEC growth by 32% at 10 microg/mL and a number of the novel saccharide conjugates from the library were found to mimic the effect of HA as they also inhibit endothelial cell survival under identical conditions. Two thiophene conjugates, thioglucamide (24% inhibition at 35 microM) and a related glucuronide (26% inhibition at 33 microM) were the most potent inhibitors of BAEC growth, as determined using a methylthiazol tetrazolium (MTT) assay. The effects of thioglucamide and HA on absolute cell number were also studied using cell counting experiments; thioglucamide (47% after 24 h) was more potent than indicated by the MTT assay and initially reduced the BAEC number to a greater extent than HA (30% after 24 h); however, its actions were over more rapidly than were HA's as cell growth had returned to levels of the control after 72 h where HA still caused 25% inhibition. The binding of the monosaccharide conjugates to fibroblast growth factor (FGF-2) in competition with heparin-albumin by ELISA was investigated to establish the possible mechanism by which glycoconjugates could alter growth but there was no general correlation between reduction in viable cell population and binding to FGF-2. No glycoconjugate reduced the proliferation of mouse mammary epithelial cells, nor did any alter gross cell morphology, supporting a proposal that the reduction in BAEC survival by monosaccharide conjugates such as thioglucamide is a result of the inhibition of cell proliferation rather than being an induction of cytotoxicity. These studies indicate that cell biological studies to determine the mechanism of action of the simple monosaccharide conjugates may be worthwhile.
Authors:
Nigel Pitt; Rhona M Duane; Alan O'Brien; Helena Bradley; Stephen J Wilson; Kathy M O'Boyle; Paul V Murphy
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Carbohydrate research     Volume:  339     ISSN:  0008-6215     ISO Abbreviation:  Carbohydr. Res.     Publication Date:  2004 Aug 
Date Detail:
Created Date:  2004-07-20     Completed Date:  2005-08-05     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0043535     Medline TA:  Carbohydr Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  1873-87     Citation Subset:  IM    
Affiliation:
Centre for Synthesis and Chemical Biology, Department of Chemistry, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
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MeSH Terms
Descriptor/Qualifier:
Animals
Carbohydrate Conformation
Carbohydrate Sequence
Cattle
Cell Division / drug effects
Cell Line
Combinatorial Chemistry Techniques
Endothelial Cells / drug effects*,  metabolism
Fibroblast Growth Factor 2 / pharmacology
Glucose / chemistry*
Glucosides / pharmacology
Glucuronic Acid / chemical synthesis*,  chemistry,  pharmacology*
Heparin / pharmacology
Mice
Molecular Sequence Data
Molecular Structure
Oligosaccharides / chemical synthesis*,  chemistry,  pharmacology*
Serum Albumin / pharmacology
Structure-Activity Relationship
Thiophenes / pharmacology
Chemical
Reg. No./Substance:
0/Glucosides; 0/Oligosaccharides; 0/Serum Albumin; 0/Thiophenes; 0/thioglucamide; 103107-01-3/Fibroblast Growth Factor 2; 50-99-7/Glucose; 576-37-4/Glucuronic Acid; 9005-49-6/Heparin

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


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