ScienceDirect - Bioorganic & Medicinal Chemistry : Synthesis of lipid A monosaccharide analogues containing acidic amino acid: Exploring the structural basis for the endotoxic and antagonistic activities

Bioorganic & Medicinal Chemistry
Volume 14, Issue 19, 1 October 2006, Pages 6759-6777

Font Size:

Abstract - selected

Article Toolbox

E-mail Article

Add to my Quick Links

Bookmark and share in 2collab (opens in new window)

Request permission to reuse this article

Cited By in Scopus (4)

Related Articles in ScienceDirect

Synthesis of neoglycoproteins containing O-methylated t...
Carbohydrate Research

2-Nitro and 4-nitro-quinone-methides are not irreversib...
Carbohydrate Research

Arabinofuranose disaccharide analogs as inhibitors of M...
Tetrahedron

Regioselective formation of 6-O-acylsucroses and 6,3'-d...
Carbohydrate Research

Syntheses of a series of lacto-N-neotetraose clusters u...
Carbohydrate Research

View More Related Articles

View Record in Scopus

doi:10.1016/j.bmc.2006.05.051

Synthesis of lipid A monosaccharide analogues containing acidic amino acid: Exploring the structural basis for the endotoxic and antagonistic activities

References and further reading may be available for this article. To view references and further reading you must purchase this article.

Masao Akamatsu^a, Yukari Fujimoto^a, Mikayo Kataoka^a, Yasuo Suda^b, Shoichi Kusumoto^a^,^† and Koichi Fukase^a^,^,

^aDepartment of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan

^bDepartment of Nanostructure and Advanced Materials, Graduate School of Science and Engineering, Kagoshima University, Kagoshima 890-0065, Japan

Received 23 March 2006;

revised 25 May 2006;

accepted 25 May 2006.

Available online 7 July 2006.

Abstract

For elucidation of the structural and conformational requirements on the endotoxic and antagonistic activity of lipid A derivatives, we designed and synthesized lipid A analogues containing acidic amino acid residues in place of the non-reducing end phosphorylated glucosamine. Definite switching of the endotoxic or antagonistic activity was observed depending on the difference of the acidic groups (phosphoric acid or carboxylic acid) in the lipid A analogues.

Graphical abstract

Lipid A monosaccharide analogues possessing acidic amino acid were synthesized. Aspartic acid-substituted analogues exhibited endotoxicity, and in contrast phosphoserine-substituted ones behaved as antagonists.

Full-size image (18K)

Keywords: Innate immunity; Lipid A; Cytokine induction; IL-6; Endotoxin

Article Outline

1. Introduction
2. Results and discussion 2.1. Design of the monosaccharide analogues of lipid A 2.2. Synthesis of the monosaccharide analogues of lipid A 2.3. Biological study
3. Conclusion
4. Experimental
4.1. General methods
4.2. Computational analysis
4.3. Biological assay
4.4. Allyl 4,6-O-benzylidene-3-O-((R)-3-benzyloxytetradecanoyl)-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-α-d-glucopyranoside (13)
4.5. Allyl 4,6-O-benzylidene-3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-2-deoxy-α-d-glucopyranoside (14)
4.6. Formylmethyl 4,6-O-benzylidene-3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-2-deoxy-α-d-glucopyranoside (15)
4.7. Benzyloxycarbonylmethyl 4,6-O-benzylidene-3-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-2-deoxy-2-α-d-glucopyranoside (16)
4.8. Benzyloxycarbonylmethyl 3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-2-deoxy-α-d-glucopyranoside (17)
4.9. Benzyloxycarbonylmethyl 3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-2-deoxy-6-O-(N-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-d-seryl)-α-d-glucopyranoside (19a)
4.10. Benzyloxycarbonylmethyl 3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-2-deoxy-6-O-(N-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-l-seryl)-α-d-glucopyranoside (19b)
4.11. Benzyloxycarbonylmethyl 3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-6-O-(N-((R)-3-benzyloxytetradecanoyl)-O-tert-butyl-d-seryl)-2-deoxy-α-d-glucopyranoside (20a)
4.12. Benzyloxycarbonylmethyl 3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-2-deoxy-6-O-(N-((R)-3-(tetradecanoyloxy)tetradecanoyl)-O-tert-butyl-d-seryl)-α-d-glucopyranoside (20b)
4.13. Benzyloxycarbonylmethyl 3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-2-deoxy-6-O-(N-((R)-3-(tetradecanoyloxy)tetradecanoyl)-O-tert-butyl-d-seryl)-α-d-glucopyranoside (21a)
4.14. Benzyloxycarbonylmethyl 3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-2-deoxy-6-O-(N-((R)-3-(tetradecanoyloxy)tetradecanoyl)-O-tert-butyl-l-seryl)-α-d-glucopyranoside (21b)
4.15. Benzyloxycarbonylmethyl 4-O-benzyloxycarbonyl-3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-6-O-(N-((R)-3-benzyloxytetradecanoyl)-O-tert-butyl-d-seryl)-2-deoxy-α-d-glucopyranoside (22a)
4.16. Benzyloxycarbonylmethyl 4-O-benzyloxycarbonyl-3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-6-O-(N-((R)-3-benzyloxytetradecanoyl)-O-tert-butyl-l-seryl)-2-deoxy-α-d-glucopyranoside (22b)
4.17. Benzyloxycarbonylmethyl 4-O-benzyloxycarbonyl-3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-2-deoxy-6-O-(N-((R)-3-(tetradecanoyloxy)tetradecanoyl)-O-tert-butyl-d-seryl)-α-d-glucopyranoside (23a)
4.18. Benzyloxycarbonylmethyl 4-O-benzyloxycarbonyl-3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-2-deoxy-6-O-(N-((R)-3-(tetradecanoyloxy)tetradecanoyl)-O-tert-butyl-l-seryl)-α-d-glucopyranoside (23b)
4.19. Benzyloxycarbonylmethyl 4-O-benzyloxycarbonyl-3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-6-O-(N-((R)-3-benzyloxytetradecanoyl)-d-seryl)-2-deoxy-α-d-glucopyranoside (24a)
4.20. Benzyloxycarbonylmethyl 4-O-benzyloxycarbonyl-3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-6-O-(N-((R)-3-benzyloxytetradecanoyl)-l-seryl)-2-deoxy-α-d-glucopyranoside (24b)
4.21. Benzyloxycarbonylmethyl 4-O-benzyloxycarbonyl-3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-2-deoxy-6-O-(N-((R)-3-(tetradecanoyloxy)tetradecanoyl)-d-seryl)-α-d-glucopyranoside (25a)
4.22. Benzyloxycarbonylmethyl 4-O-benzyloxycarbonyl-3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-2-deoxy-6-O-(N-((R)-3-(tetradecanoyloxy)tetradecanoyl)-l-seryl)-α-d-glucopyranoside (25b)
4.23. Benzyloxycarbonylmethyl 4-O-benzyloxycarbonyl-3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-6-O-(N-((R)-3-benzyloxytetradecanoyl)-O-(1,5-dihydro-3-oxo-3H-2,4,3-λ⁵-benzodioxaphosphepin-3-yl)-d-seryl)-2-deoxy-α-d-glucopyranoside (26a)
4.24. Benzyloxycarbonylmethyl 4-O-benzyloxycarbonyl-3-O-((R)-3-benzyloxytetradeca-noyl)-2-((R)-3-benzyloxytetradecanoylamino)-6-O-(N-((R)-3-benzyloxytetradecanoyl)-O-(1,5-dihydro-3-oxo-3H-2,4,3-λ⁵-benzodioxaphosphepin-3-yl)-l-seryl)-2-deoxy-α-d-glucopyranoside (26b)
4.25. Benzyloxycarbonylmethyl 4-O-benzyloxycarbonyl-3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-2-deoxy-6-O-(N-((R)-3-(tetradecanoyloxy)tetradecanoyl)-O-(1,5-dihydro-3-oxo-3H-2,4,3-λ⁵-benzodioxaphosphepin-3-yl)-d-seryl)-α-d-glucopyranoside (27a)
4.26. Benzyloxycarbonylmethyl 4-O-benzyloxycarbonyl-3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-2-deoxy-6-O-(N-((R)-3-(tetradecanoyloxy)tetradecanoyl)-O-(1,5-dihydro-3-oxo-3H-2,4,3-λ⁵-benzodioxaphosphepin-3-yl)-l-seryl)-α-d-glucopyranoside (27b)
4.27. Carboxymethyl 3-O-((R)-3-hydroxytetradecanoyl)-2-((R)-3-hydroxytetradecanoylamino)-6-O-(N-((R)-3-hydroxytetradecanoyl)-O-phospho-d-seryl)-2-deoxy-α-d-glucopyranoside (d-Ser(P)1011 (5a))
4.28. Carboxymethyl 3-O-((R)-3-hydroxytetradecanoyl)-2-((R)-3-hydroxytetradecanoylamino)-6-O-(N-((R)-3-hydroxytetradecanoyl)-O-phospho-l-seryl)-2-deoxy-α-d-glucopyranoside (l-Ser(P)1011 (5b))
4.29. Carboxymethyl 3-O-((R)-3-hydroxytetradecanoyl)-2-((R)-3-hydroxytetradecanoylamino)-6-O-(N-((R)-3-(tetradecanoyloxy)tetradecanoyl)-O-phospho-d-seryl)-2-deoxy-α-d-glucopyranoside (d-Ser(P)2011 (6a))
4.30. Carboxymethyl 3-O-((R)-3-hydroxytetradecanoyl)-2-((R)-3-hydroxytetradecanoylamino)-6-O-(N-((R)-3-(tetradecanoyloxy)tetradecanoyl)-O-phospho-l-seryl)-2-deoxy-α-d-glucopyranoside (l-Ser(P)2011 (6b))
4.31. Benzyloxycarbonylmethyl 3,4-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-6-O-(N-((R)-3-benzyloxytetradecanoyl)-O-tert-butyl-d-seryl)-2-deoxy-α-d-glucopyranoside (28a)
4.32. Benzyloxycarbonylmethyl 3,4-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-6-O-(N-((R)-3-benzyloxytetradecanoyl)-O-tert-butyl-l-seryl)-2-deoxy-α-d-glucopyranoside (28b)
4.33. Benzyloxycarbonylmethyl 3,4-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-6-O-(N-((R)-3-benzyloxytetradecanoyl)-d-seryl)-2-deoxy-α-d-glucopyranoside (29a)
4.34. Benzyloxycarbonylmethyl 3,4-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-6-O-(N-((R)-3-benzyloxytetradecanoyl)-l-seryl)-2-deoxy-α-d-glucopyranoside (29b)
4.35. Benzyloxycarbonylmethyl 3,4-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-6-O-(N-((R)-3-benzyloxytetradecanoyl)-O-(1,5-dihydro-3-oxo-3H-2,4,3-λ⁵-benzodioxaphosphepin-3-yl)-d-seryl)-2-deoxy-α-d-glucopyranoside (30a)
4.36. Benzyloxycarbonylmethyl 3,4-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-6-O-(N-((R)-3-benzyloxytetradecanoyl)-O-(1,5-dihydro-3-oxo-3H-2,4,3-λ⁵-benzodioxaphosphepin-3-yl)-l-seryl)-2-deoxy-α-d-glucopyranoside (30b)
4.37. Carboxymethyl 3,4-O-((R)-3-hydroxytetradecanoyl)-2-((R)-3-hydroxytetradecanoylamino)-6-O-(N-((R)-3-hydroxytetradecanoyl)-O-phospho-d-seryl)-2-deoxy-α-d-glucopyranoside (d-Ser(P)1111 (7a))
4.38. Carboxymethyl 3,4-O-((R)-3-hydroxytetradecanoyl)-2-((R)-3-hydroxytetradecanoylamino)-6-O-(N-((R)-3-hydroxytetradecanoyl)-O-phospho-l-seryl)-2-deoxy-α-d-glucopyranoside (l-Ser(P)1111 (7b))
4.39. Benzyloxycarbonylmethyl 3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-6-O-(N-tert-butoxycarbonyl-O⁴-benzyl-d-aspartyl)-2-deoxy-α-d-glucopyranoside (31a)
4.40. Benzyloxycarbonylmethyl 3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-6-O-(N-tert-butoxycarbonyl-O⁴-benzyl-l-aspartyl)-2-deoxy-α-d-glucopyranoside (31b)
4.41. Benzyloxycarbonylmethyl 3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-6-O-(N-((R)-3-benzyloxytetradecanoyl)-O⁴-benzyl-d-aspartyl)-2-deoxy-α-d-glucopyranoside (32a)
4.42. Benzyloxycarbonylmethyl 3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-6-O-(N-((R)-3-benzyloxytetradecanoyl)-O⁴-benzyl-l-aspartyl)-2-deoxy-α-d-glucopyranoside (32b)
4.43. Benzyloxycarbonylmethyl 3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-2-deoxy-6-O-(N-((R)-3-(tetradecanoyloxy)tetradecanoyl)-O⁴-benzyl-d-aspartyl)-α-d-glucopyranoside (33a)
4.44. Benzyloxycarbonylmethyl 3-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-2-deoxy-6-O-(N-((R)-3-(tetradecanoyloxy)tetradecanoyl)-O⁴-benzyl-d-aspartyl)-α-d-glucopyranoside (33b)
4.45. Carboxymethyl 3-O-((R)-3-hydroxytetradecanoyl)-2-((R)-3-hydroxytetradecanoylamino)-6-O-(N-((R)-3-hydroxytetradecanoyl)-d-aspartyl)-2-deoxy-α-d-glucopyranoside (d-Asp1011 (8a))
4.46. Carboxymethyl 3-O-((R)-3-hydroxytetradecanoyl)-2-((R)-3-hydroxytetradecanoylamino)-6-O-(N-((R)-3-hydroxytetradecanoyl)-d-aspartyl)-2-deoxy-α-l-glucopyranoside (l-Asp1011 (8b))
4.47. Carboxymethyl 3-O-((R)-3-hydroxytetradecanoyl)-2-((R)-3-hydroxytetradecanoylamino)-6-O-(N-((R)-3-(tetradecanoyloxy)tetradecanoyl)-d-aspartyl)-2-deoxy-α-d-glucopyranoside (d-Asp2011 (9a))
4.48. Carboxymethyl 3-O-((R)-3-hydroxytetradecanoyl)-2-((R)-3-hydroxytetradecanoylamino)-6-O-(N-((R)-3-(tetradecanoyloxy)tetradecanoyl)-l-aspartyl)-2-deoxy-α-l-glucopyranoside (l-Asp2011 (9b))
4.49. Benzyloxycarbonylmethyl 3,4-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-2-deoxy-6-O-(N-((R)-3-(tetradecanoyloxy)tetradecanoyl)-O⁴-benzyl-d-aspartyl)-α-d-glucopyranoside (34a)
4.50. Benzyloxycarbonylmethyl 3,4-O-((R)-3-benzyloxytetradecanoyl)-2-((R)-3-benzyloxytetradecanoylamino)-2-deoxy-6-O-(N-((R)-3-(tetradecanoyloxy)tetradecanoyl)-O⁴-benzyl-l-aspartyl)-α-d-glucopyranoside (34b)
4.51. Carboxymethyl 3,4-O-((R)-3-hydroxytetradecanoyl)-2-((R)-3-hydroxytetradecanoylamino)-6-O-(N-(R)-3-hydroxytetradecanoyl-d-aspartyl)-2-deoxy-α-l-glucopyranoside (d-Asp1111 (10a))
4.52. Carboxymethyl 3,4-O-((R)-3-hydroxytetradecanoyl)-2-((R)-3-hydroxytetradecanoylamino)-6-O-(N-(R)-3-hydroxytetradecanoyl-l-aspartyl)-2-deoxy-α-l-glucopyranoside (l-Asp1111 (10b))
Acknowledgements
References

Corresponding author. Fax: +81 6 6850 5419.
^† Present address: Suntory Institute for Bioorganic Research, Shimamoto-cho, Mishima-gun, Osaka 618-8503, Japan

Bioorganic & Medicinal Chemistry
Volume 14, Issue 19, 1 October 2006, Pages 6759-6777

About ScienceDirect | Contact Us | Information for Advertisers | Terms & Conditions | Privacy Policy