title: Total synthesis of tetraacylated phosphatidylinositol hexamannoside and evaluation of its immunomodulatory activity.
abstract: Tuberculosis, aggravated by drug-resistant strains and HIV co-infection of the causative agent Mycobacterium tuberculosis, is a global problem that affects millions of people. With essential immunoregulatory roles, phosphatidylinositol mannosides are among the cell-envelope components critical to the pathogenesis and survival of M. tuberculosis inside its host. Here we report the first synthesis of the highly complex tetraacylated phosphatidylinositol hexamannoside (Ac2PIM6), having stearic and tuberculostearic acids as lipid components. Our effort makes use of stereoelectronic and steric effects to control the regioselective and stereoselective outcomes and minimize the synthetic steps, particularly in the key desymmetrization and functionalization of myo-inositol. A short synthesis of tuberculostearic acid in six steps from the Roche ester is also described. Mice exposed to the synthesized Ac2PIM6 exhibit increased production of interleukin-4 and interferon-γ, and the corresponding adjuvant effect is shown by the induction of ovalbumin- and tetanus toxoid-specific antibodies.
authors.affiliation: Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 115, Taiwan.
authors.forename: Pratap S
authors.initials: PS
authors.lastname: Patil
authors.affiliation: Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 115, Taiwan.
authors.forename: Ting-Jen Rachel
authors.initials: TJ
authors.lastname: Cheng
authors.affiliation: Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 115, Taiwan.
authors.forename: Medel Manuel L
authors.initials: MM
authors.lastname: Zulueta
authors.affiliation: Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 115, Taiwan.
authors.forename: Shih-Ting
authors.initials: ST
authors.lastname: Yang
authors.affiliation: Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 115, Taiwan.
authors.forename: Larry S
authors.initials: LS
authors.lastname: Lico
authors.affiliation: Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 115, Taiwan.
authors.forename: Shang-Cheng
authors.initials: SC
authors.lastname: Hung
mesh_terms: D000215:Acylation; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001426:Bacterial Proteins / Q000138:chemical synthesis* / Q000494:pharmacology; D002473:Cell Wall / Q000737:chemistry* / Q000276:immunology; D007371:Interferon-gamma / Q000187:drug effects / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008362:Mannosides / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000276:immunology; D010047:Ovalbumin / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000138:chemical synthesis* / Q000494:pharmacology; D013229:Stearic Acids / Q000737:chemistry; D013745:Tetanus Toxoid / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D001426:Bacterial Proteins; D008362:Mannosides; D010716:Phosphatidylinositols; D013229:Stearic Acids; D013745:Tetanus Toxoid; C000606357:tetraacylated phosphatidylinositol hexamannoside; D015847:Interleukin-4; C031183:stearic acid; C026082:tuberculostearic acid; D007371:Interferon-gamma; D010047:Ovalbumin