ABSTRACT
Heparan sulfate (HS) has multifaceted biological activities. To date, no libraries of HS oligosaccharides bearing systematically varied sulfation structures are available owing to the challenges in synthesizing a large number of HS oligosaccharides. To overcome the obstacles and expedite the synthesis, a divergent approach was designed, where 64 HS tetrasaccharides covering all possible structures of 2-O-, 6-O- and N-sulfation with the glucosamine-glucuronic acid-glucosamine-iduronic acid backbone were successfully produced from a single strategically protected tetrasaccharide intermediate. This extensive library helped identify the structural requirements for HS sequences to have strong fibroblast growth factor-2 binding but a weak affinity for platelet factor-4. Such a strategy to separate out these two interactions could lead to new HS-based potential therapeutics without the dangerous adverse effect of heparin-induced thrombocytopenia.
Subject(s)
Heparitin Sulfate , Oligosaccharides , Oligosaccharides/chemistry , Heparitin Sulfate/chemistry , Protein Binding , Glucuronic Acid/metabolism , GlucosamineABSTRACT
Stereoselective synthesis of S-linked trisaccharide glycal of angucycline antitumor antibiotic derhodinosylurdamycin A is described. The synthesis has been accomplished employing our previously reported umpolung S-glycosylation strategy - stereoselective sulfenylation of 2-deoxy glycosyl lithium. It was found that sugar-derived thiocyanate was a better electrophile than corresponding asymmetric disulfide in this type of stereoselective sulfenylation.
Subject(s)
Ethers/chemistry , Guanidines/chemistry , Guanidines/chemical synthesis , Lithium/chemistry , Oligosaccharides/chemistry , Oligosaccharides/chemical synthesis , Sulfur/chemistry , Thiocyanates/chemistry , Trisaccharides/chemistry , Alkylation , Chemistry Techniques, Synthetic , Electrons , Glycosylation , StereoisomerismABSTRACT
Stereoselective synthesis of carbohydrate mimics resistant toward acid-mediated or enzymatic hydrolysis is chemically challenging and biologically interesting. In this Letter, the first stereoselective synthesis of a "non-hydrolyzable" S-linked hexasaccharide of antitumor antibiotic landomycin A is described. This synthesis was accomplished through the utilization of our recently developed umpolung reactivity-based S-glycosylation-sulfenylation of stereochemically defined glycosyl lithium species with asymmetric sugar-derived disulfides.
Subject(s)
Aminoglycosides/chemical synthesis , Antibiotics, Antineoplastic/chemical synthesis , Aminoglycosides/chemistry , Antibiotics, Antineoplastic/chemistry , Glycosylation , Molecular Structure , Stereoisomerism , Streptomyces/chemistry , Structure-Activity RelationshipABSTRACT
An approach for direct synthesis of biologically significant 2-deoxy-ß-glycosides has been developed via O-alkylation of a variety of 2-deoxy-sugar-derived anomeric alkoxides using challenging secondary triflates as electrophiles. It was found a free hydroxyl group at C3 of the 2-deoxy-sugar-derived lactols is required in order to achieve synthetically efficient yields. This method has also been applied to the convergent synthesis of a 2-deoxy-ß-tetrasaccharide.
Subject(s)
Deoxy Sugars/chemistry , Glycosides/chemical synthesis , Alkylation , Molecular Structure , StereoisomerismABSTRACT
A mild and atom-economic rhenium(V)-catalyzed stereoselective synthesis of ß-D-digitoxosides from 6-deoxy-D-allals has been described. This ß-selective glycosylation was achieved probably because of the formation of corresponding α-digitoxosides disfavored by 1,3-diaxial interaction. In addition, this method has been successfully applied to the synthesis of digitoxin trisaccharide glycal for the direct synthesis of digitoxin and C1'-epi-digitoxin.