Chemical synthesis and proinflammatory responses of monophosphoryl lipid a adjuvant candidates

Maiti, Kaustabh K., DeCastro, Michael, El-Sayed, Abu-Baker M Abdel-Aal, Foote, Matthew I, Wolfert, Margreet A. and Boons, Geert-Jan (2010) Chemical synthesis and proinflammatory responses of monophosphoryl lipid a adjuvant candidates. European Journal of Organic Chemistry, 2010 1: 80-91. doi:10.1002/ejoc.200900973

Author Maiti, Kaustabh K.
DeCastro, Michael
El-Sayed, Abu-Baker M Abdel-Aal
Foote, Matthew I
Wolfert, Margreet A.
Boons, Geert-Jan
Title Chemical synthesis and proinflammatory responses of monophosphoryl lipid a adjuvant candidates
Journal name European Journal of Organic Chemistry   Check publisher's open access policy
ISSN 1434-193X
Publication date 2010-01-01
Year available 2009
Sub-type Article (original research)
DOI 10.1002/ejoc.200900973
Volume 2010
Issue 1
Start page 80
End page 91
Total pages 12
Editor Kar
Place of publication Weinheim, Germany
Publisher Wiley - V C H Verlag GmbH & Co. KGaA
Language eng
Subject C1
Formatted abstract
Lipopolysaccharides (LPS), which are structural components of the outer-surface membrane of Gram-negative bacteria, trigger innate immune responses through activation of Toll-like receptor 4 (TLR4). Such responses may be exploited for the development of adjuvants and in particular monophosphoryl lipid A (MPLA) obtained by controlled hydrolysis of LPS of Salmonella minnesota, exhibits low toxicity yet possesses beneficial immuno-stimulatory properties. We have developed an efficient synthetic approach for the preparation of a major component of MPLA (1), which has as a key feature the use of allyloxycarbonates (Alloc) as permanent protecting groups for the C-3 and C-4 hydroxy groups of the proximal glucosamine unit. The latter protecting groups greatly facilitated deprotection of the fully assembled compound. Furthermore, the amino functions were protected as N-2,2,2-trichloroethoxycarbamates (Troc), which performed efficient neighboring-group participation to give selectively 1,2-trans-glycosides and could easily be removed under mild conditions without affecting the permanent Alloc carbonates and anomeric dimethylthexylsilyl (TDS) ether. The synthetic methodology was also employed for the preparation of a monophosphoryl lipid A (2) derivative that has the anomeric center of the proximal sugar modified as a methyl glycoside. Compound 1 was not able to induce cytokine production in mouse macrophages whereas methyl glycoside 2 displayed activity, however it has a lower potency and efficacy than lipid A obtained by controlled hydrolysis S. minnesota. This indicates compound 2 is an attractive candidate for adjuvant development and that 1 is not the active substance of MPLA obtained by controlled hydrolysis of LPS.
Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Keyword Carbohydrates
Protecting groups
Tumor necrosis factor
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article first published online: 18 Nov 2009

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
School of Chemistry and Molecular Biosciences
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Citation counts: TR Web of Science Citation Count  Cited 14 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 15 times in Scopus Article | Citations
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Created: Sun, 07 Feb 2010, 10:06:38 EST