ABSTRACT
Heparan sulfate (HS) glycosaminoglycans participate in critical biological processes by modulating the activity of a diverse set of protein binding partners. Such proteins include all known members of the chemokine superfamily, which are thought to guide the migration of immune cells through their interactions with HS. Here, we describe an expedient, divergent synthesis to prepare defined HS glycomimetics that recapitulate the overall structure and activity of HS glycosaminoglycans. Our approach uses a core disaccharide precursor to produce a variety of differentially sulfated glycopolymers. We demonstrate that a specific trisulfated mimetic antagonizes the chemotactic activity of the proinflammatory chemokine RANTES with potency similar to that of heparin, without inhibiting serine proteases in the blood coagulation cascade. Our work provides a general strategy for modulating chemokine activity and dissecting the pleiotropic functions of HS/heparin through the presentation of defined sulfation motifs within polymeric scaffolds.
Subject(s)
Biomimetic Materials/chemistry , Biomimetic Materials/pharmacology , Chemokine CCL5/metabolism , Heparitin Sulfate/chemistry , Animals , Cell Line , Cell Movement/drug effects , MiceABSTRACT
[reaction: see text] An asymmetric synthesis of the heavily oxygenated inner sector of amphidinol 3 constituted of C31-C52 is described. The successful pathway highlights construction of the pair of identical tetrahydropyran subunits from a common intermediate.
Subject(s)
Alkenes/chemical synthesis , Antifungal Agents/chemical synthesis , Dinoflagellida/chemistry , Pyrans/chemical synthesis , Aldehydes/chemistry , Alkenes/pharmacology , Animals , Antifungal Agents/pharmacology , Epoxy Compounds/chemistry , Hydrocarbons, Iodinated/chemistry , Models, Chemical , Oxygen/chemistry , Pyrans/chemistry , Pyrans/pharmacology , Stereoisomerism , Vinyl Compounds/chemistryABSTRACT
[structure: see text] The richly oxygenated C(1)-C(30) polyol segment of amphidinol 3 has been synthesized in protected form. Incorporated in this long chain are 10 of the 25 stereogenic centers housed in the target. The asymmetric pathway that has been developed is based on the efficient union of three independently prepared subunits.
