title: Synthesis and Toll-like receptor 4 (TLR4) activity of phosphatidylinositol dimannoside analogues.
abstract: A series of five PIM(2) analogues were synthesized and tested for their ability to activate primary macrophages and modulate LPS signaling. Structural changes included replacement of the fatty acid esters of the phosphatidyl moiety of PIM(2) with the corresponding ether or amide. An AcPIM(2) analogue possessing an ether linkage was also prepared. The synthetic methodology utilized an orthogonally protected chiral myo-inositol starting material that was conveniently prepared from myo-inositol in just two steps. Important steps in the synthetic protocols included the regio- and α-selective glycosylation of inositol O-6 and introduction of the phosphodiester utilizing phosphoramidite chemistry. Replacement of the inositol core with a glycerol moiety gave compounds described as phosphatidylglycerol dimannosides (PGM(2)). Biological testing of these PIM compounds indicated that the agonist activity was TLR4 dependent. An ether linkage increased agonist activity. Removal of the inositol ring enhanced antagonist activity, and the presence of an additional lipid chain enhanced LPS-induced cytokine production in primary macrophages. Furthermore, the interruption of the LPS-induced 2:2 TLR4/MD-2 signaling complex formation by PIM(2) represents a previously unidentified mechanism involved in the bioactivity of PIM molecules.
authors.affiliation: Carbohydrate Chemistry Team, Industrial Research Limited, P.O. Box 31-310, Lower Hutt, New Zealand.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Ainge
authors.forename: William John
authors.initials: WJ
authors.lastname: Martin
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Compton
authors.forename: Colin M
authors.initials: CM
authors.lastname: Hayman
authors.forename: David S
authors.initials: DS
authors.lastname: Larsen
authors.forename: Sung-Il
authors.initials: SI
authors.lastname: Yoon
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.forename: Jacquie L
authors.initials: JL
authors.lastname: Harper
authors.forename: Gavin F
authors.initials: GF
authors.lastname: Painter
mesh_terms: D000818:Animals; D004952:Esters; D004987:Ethers; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008074:Lipoproteins; D051218:Lymphocyte Antigen 96 / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010716:Phosphatidylinositols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D055503:Protein Multimerization; D015398:Signal Transduction; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004952:Esters; D004987:Ethers; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008074:Lipoproteins; D051218:Lymphocyte Antigen 96; D010716:Phosphatidylinositols; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C054977:phosphatidylinositol dimannoside