title: Synthesis and biological investigation of PIM mimics carrying biotin or a fluorescent label for cellular imaging.
abstract: Phosphatidyl inositol mannosides (PIMs) are constituents of the mycobacterial cell wall; these glycolipids are known to exhibit potent inhibitory activity toward the LPS-induced production of cytokines by macrophages, and therefore have potential as anti-inflammatory agents. Recently, heterocyclic analogues of PIMs in which the inositol is replaced by a piperidine (aza-PIM mimics) or a tetrahydropyran moiety (oxa-PIM mimics) have been prepared by short synthetic sequences and shown to retain the biological activity of the parent PIM structures. In this investigation, the aza-PIM analogue was used as a convenient scaffold to link biotin or a fluorescent label (tetramethyl-rhodamine) by way of an aminocaproyl spacer, with the goal of using these conjugates for intracellular localization and for the study of the mechanism of their antiinflammatory action. The synthesis of these compounds is reported, as well as the evaluation of their activities as inhibitors of LPS-induced cytokine production by macrophages (TNFα, IL12p40); preliminary investigations by FACS and confocal microscopy indicated that PIM-biotin conjugate binds to macrophage membranes with rapid kinetics.
authors.affiliation: Institut de Chimie Organique et Analytique, Université d'Orléans, CNRS UMR 7311, Rue de Chartres, 45067 Orléans, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Front
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Bourigault
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Rose
authors.forename: Ségueni
authors.initials: S
authors.lastname: Noria
authors.forename: Valérie F J
authors.initials: VF
authors.lastname: Quesniaux
authors.forename: Olivier R
authors.initials: OR
authors.lastname: Martin
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000032:analysis / Q000737:chemistry* / Q000494:pharmacology*; D001372:Aza Compounds / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology; D001710:Biotin / Q000737:chemistry; D019921:Biotinylation; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology*; D005456:Fluorescent Dyes / Q000032:analysis; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D010716:Phosphatidylinositols / Q000032:analysis / Q000737:chemistry* / Q000494:pharmacology*; D012235:Rhodamines / Q000032:analysis
chemical_list: D000893:Anti-Inflammatory Agents; D001372:Aza Compounds; D016207:Cytokines; D005456:Fluorescent Dyes; D008070:Lipopolysaccharides; D010716:Phosphatidylinositols; D012235:Rhodamines; C034154:phosphatidylinositol mannoside; C005358:tetramethylrhodamine; D001710:Biotin