Synthesis and TNF-α inducing activities of mycoloyl-arabinan motif of mycobacterial cell wall components

• Published in: Bioorganic & medicinal chemistry 2006-05, Vol.14 (9), p.3049-3061
• Main Authors: Ishiwata, Akihiro, Akao, Hiroko, Ito, Yukishige, Sunagawa, Makoto, Kusunose, Naoto, Kashiwazaki, Yasuo
• Format: Article
• Language: English
• Subjects: Animals; BCG-CWS; Biological and medical sciences; Carbohydrate Conformation; Cell Line; Cell Wall - chemistry; Cell Wall - metabolism; Cell Wall - secretion; Esterification; Immunomodulators; Mass Spectrometry; Medical sciences; Mice; Mycobacterium bovis; Mycobacterium bovis - chemistry; Mycobacterium bovis - metabolism; Mycolic Acids - chemistry; Mycoloyl-arabinan; Pharmacology. Drug treatments; Polysaccharides - biosynthesis; Polysaccharides - chemistry; Stereoselective arabinofuranosylation; TNF-α secretion-inducer; Tumor Necrosis Factor-alpha - secretion
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.12.037

The aim of this study was to synthesize a series of mono- ( 1), di- ( 2, 3, 4) and tetramycolated ( 5) arabinans, which constitute the terminal region of BCG-CWS. In addition, their activities to induce TNF-α were evaluated. The extract of the cell wall skeleton of Bacillus Calmette–Guérin (BCG-CWS) from Mycobacterium bovis is known to be an activator of innate immunity. Synthesis of pentaarabinofuranoside as part of the arabinan moiety of BCG-CWS was achieved by double α-arabinofuranosylation followed by double β-arabinofuranosylation with orthogonally protected donors. Mycolic esters of the arabinan in the terminal lipo-arabinan motif of BCG-CWS were synthesized through alkylation of unprotected mycolic acid with bis- and tetra-tosylates of pentaarabinofuranoside. A series of compounds were subjected to a tumor necrosis factor alpha (TNF-α) secretion-inducing assay, disclosing aspects of the structure–activity relationship which should be useful in finding the site of the activity.