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Synthetic analogs of sialyl Lewis x

Ellervik, Ulf LU (1998)
Abstract
The sialyl Lewis x (SLex) tetrasaccharide is the smallest recognizable ligand for selectins. The selectins constitute a vital part of the inflammatory cascade for recruitment of leukocytes to a site of tissue damage or microbial infection. If too many leukocytes are recruited, normal, not injured, cells can be damaged; a process known from chronic inflammatory diseases such as reumatoid arthritis, psoriasis, and from septic shock and reperfusion damage. Sialyl Lewis x saccharides were originally identified as human tumor-associated antigens and are found on all highly malignant types of cancer cells. The identification of the SLex tetrasaccharide and later synthetic efforts have elucidated the biologically important features of the... (More)
The sialyl Lewis x (SLex) tetrasaccharide is the smallest recognizable ligand for selectins. The selectins constitute a vital part of the inflammatory cascade for recruitment of leukocytes to a site of tissue damage or microbial infection. If too many leukocytes are recruited, normal, not injured, cells can be damaged; a process known from chronic inflammatory diseases such as reumatoid arthritis, psoriasis, and from septic shock and reperfusion damage. Sialyl Lewis x saccharides were originally identified as human tumor-associated antigens and are found on all highly malignant types of cancer cells. The identification of the SLex tetrasaccharide and later synthetic efforts have elucidated the biologically important features of the molecule. A large number of analogs and mimics have been designed in order to get simpler and more stable compounds for use as anti-inflammatory drugs.



Sialic acid-containing oligosaccharides, such as sialyl Lewis x, can form lactones under slightly acidic conditions. These lactones are generally more immunogenic due to their increased rigidity and it has been proposed that the lactones are the actual immunogens. The lactones are however not hydrolytically stable and are therefore difficult to investigate and to raise antibodies against.



Lactams were introduced as analogs to lactones and were found to be structurally similar and more stable against hydrolysis. Lactam analogs of a number of monosialylated gangliosides (GM2, GM3, GM4) were synthesized and used with success.



This thesis describes the synthesis of the sialyl Lewis x tetrasaccharide, the Lewis x trisaccharide, the 1’’’-2’-, 1’’’-4’-lactam- and 2-acetamido analogs of the sialyl Lewis x tetrasaccharide, the 2- and 4-acetamido- and 2- and 4-lactam analogs of the Lewis x trisaccharide. The key-steps in the syntheses were regio- and stereoselective galactosylations of one common monosaccharide diol acceptor, stereoselective fucosylation and regio- and stereoselective sialylations to yield the oligosaccharidic products in 10-62% over-all yield from monosaccharidic starting materials. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Dr Boons, Geert-Jan, University of Birmingham, England
organization
publishing date
type
Thesis
publication status
published
subject
keywords
stereoselective synthesis, regioselective synthesis, lactam analogs, lactone, Selectin, Sialyl Lewis x, SLex, Organic chemistry, Organisk kemi
pages
110 pages
publisher
Organic Chemistry, Lund University
defense location
Center for Chemistry and Chemical Engineering, Lecture Hall C
defense date
1998-10-02 13:15
external identifiers
  • Other:ISRN: LUTKDH/(TKOK-1046)/1-110/(1998)
ISBN
91-628-3105-4
language
English
LU publication?
yes
id
5d0d0245-c583-4a15-b68c-e39a554c8053 (old id 38957)
date added to LUP
2007-06-20 12:50:26
date last changed
2016-09-19 08:45:06
@phdthesis{5d0d0245-c583-4a15-b68c-e39a554c8053,
  abstract     = {The sialyl Lewis x (SLex) tetrasaccharide is the smallest recognizable ligand for selectins. The selectins constitute a vital part of the inflammatory cascade for recruitment of leukocytes to a site of tissue damage or microbial infection. If too many leukocytes are recruited, normal, not injured, cells can be damaged; a process known from chronic inflammatory diseases such as reumatoid arthritis, psoriasis, and from septic shock and reperfusion damage. Sialyl Lewis x saccharides were originally identified as human tumor-associated antigens and are found on all highly malignant types of cancer cells. The identification of the SLex tetrasaccharide and later synthetic efforts have elucidated the biologically important features of the molecule. A large number of analogs and mimics have been designed in order to get simpler and more stable compounds for use as anti-inflammatory drugs.<br/><br>
<br/><br>
Sialic acid-containing oligosaccharides, such as sialyl Lewis x, can form lactones under slightly acidic conditions. These lactones are generally more immunogenic due to their increased rigidity and it has been proposed that the lactones are the actual immunogens. The lactones are however not hydrolytically stable and are therefore difficult to investigate and to raise antibodies against.<br/><br>
<br/><br>
Lactams were introduced as analogs to lactones and were found to be structurally similar and more stable against hydrolysis. Lactam analogs of a number of monosialylated gangliosides (GM2, GM3, GM4) were synthesized and used with success.<br/><br>
<br/><br>
This thesis describes the synthesis of the sialyl Lewis x tetrasaccharide, the Lewis x trisaccharide, the 1’’’-2’-, 1’’’-4’-lactam- and 2-acetamido analogs of the sialyl Lewis x tetrasaccharide, the 2- and 4-acetamido- and 2- and 4-lactam analogs of the Lewis x trisaccharide. The key-steps in the syntheses were regio- and stereoselective galactosylations of one common monosaccharide diol acceptor, stereoselective fucosylation and regio- and stereoselective sialylations to yield the oligosaccharidic products in 10-62% over-all yield from monosaccharidic starting materials.},
  author       = {Ellervik, Ulf},
  isbn         = {91-628-3105-4},
  keyword      = {stereoselective synthesis,regioselective synthesis,lactam analogs,lactone,Selectin,Sialyl Lewis x,SLex,Organic chemistry,Organisk kemi},
  language     = {eng},
  pages        = {110},
  publisher    = {Organic Chemistry, Lund University},
  school       = {Lund University},
  title        = {Synthetic analogs of sialyl Lewis x},
  year         = {1998},
}