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Issue 2, 2013
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Total synthesis, stereochemical elucidation and biological evaluation of Ac2SGL; a 1,3-methyl branched sulfoglycolipid from Mycobacterium tuberculosis

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Abstract

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), continues to represent a challenging pathogen causing many deaths. A reason for the persistence of this pathogen is the cell-envelope composition, which consists of long-tailed (glyco)lipids, involved in the modulation of the host immune response. Diacylated sulfoglycolipid Ac2SGL (1), found in the cell envelope, is a potent antigen that stimulates the immune response towards TB. This observation suggests the application of 1 as part of a vaccine. Here, we report the first asymmetric total synthesis of 1. Two approaches were developed for the synthesis of hydroxyphthioceranic acid (4), its polypropionate part, thereby establishing the absolute stereochemistry of the C17 hydroxyl function to be of (R)-configuration. Subsequently, 4 was regioselectively connected to the trehalose core and after selective sulfation and a final fourfold deprotection step, pure 1 was obtained. The identity of synthetic and natural 1 was confirmed by NMR and mass analysis, Furthermore, synthetic 1 shows identical biological function to 1 and activates CD1b-restricted and Ac2SGL-specific T cells that are highly sensitive to minimal structural modifications of 1 with the same potency. A modeling study is presented to point out the structural features of 1 that are important for binding to the antigen-presenting molecule CD1b and to the T-cell receptor.

Graphical abstract: Total synthesis, stereochemical elucidation and biological evaluation of Ac2SGL; a 1,3-methyl branched sulfoglycolipid from Mycobacterium tuberculosis

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Publication details

The article was received on 28 Sep 2012, accepted on 01 Nov 2012 and first published on 01 Nov 2012


Article type: Edge Article
DOI: 10.1039/C2SC21620E
Citation: Chem. Sci., 2013,4, 709-716
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    Total synthesis, stereochemical elucidation and biological evaluation of Ac2SGL; a 1,3-methyl branched sulfoglycolipid from Mycobacterium tuberculosis

    D. Geerdink, B. T. Horst, M. Lepore, L. Mori, G. Puzo, A. K. H. Hirsch, M. Gilleron, G. de Libero and A. J. Minnaard, Chem. Sci., 2013, 4, 709
    DOI: 10.1039/C2SC21620E

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