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
synthesis, Mycobacterium tuberculosis, Ac2PIM6, phosphatidylinositolmannoside
NCBI PubMed ID: 26037164Publication DOI: 10.1038/ncomms8239Journal NLM ID: 101528555Publisher: London: Nature Publishing Group
Correspondence: Hung SC
Institutions: Genomics Research Center, Academia Sinica, Taipei, Taiwan
Methods: ELISA, chemical synthesis, biological assays, immunological assays, cytokine production
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