RESUMO
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.
Assuntos
Proteínas de Bactérias/síntese química , Parede Celular/química , Manosídeos/síntese química , Mycobacterium tuberculosis/química , Fosfatidilinositóis/síntese química , Acilação , Adjuvantes Imunológicos/farmacologia , Animais , Proteínas de Bactérias/farmacologia , Parede Celular/imunologia , Interferon gama/efeitos dos fármacos , Interferon gama/imunologia , Interleucina-4/imunologia , Manosídeos/farmacologia , Camundongos , Mycobacterium tuberculosis/imunologia , Ovalbumina/farmacologia , Fosfatidilinositóis/farmacologia , Ácidos Esteáricos/química , Toxoide Tetânico/farmacologiaRESUMO
Oligosaccharide syntheses are an important source of well-defined sugar constructs particularly needed for the evaluation of structure-activity relationships. The chemical assembly of oligosaccharides requires several building blocks, that is, glycosyl donors and acceptors, which are prepared in multistep processes and in a generally tedious and time-consuming manner. Having developed one-pot procedures meant to minimise the effort in sugar building block preparation, we tackled herein the one-pot preparation of fully protected and 2-, 3-, 4-, and 6-alcohol derivatives of d-mannose, a widely distributed monosaccharide. As a consequence of the hydroxyl group pattern of D-mannose, regioselective and stereoselective benzylidenations were developed and later seamlessly utilised as the first transformation in the one-pot procedure.
Assuntos
Álcoois/química , Compostos de Benzilideno/química , Manose/análogos & derivados , Álcoois/síntese química , Compostos de Benzilideno/síntese química , Glicosilação , Manose/síntese química , Oligossacarídeos/síntese química , EstereoisomerismoRESUMO
A seven-step synthesis of triacylated phosphatidylinositol dimannoside is described from myo-inositol 1,3,5-orthoformate. It proceeded in 31% overall yield via a highly regioselective and stereoselective 2,6-di-O-D-mannosylation as the key step.