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Some New Methods in Sialic Acid Chemistry

Ercegovic, Teddy LU (2001)
Abstract
Gangliosides (G) are sialic acid-containing cell surface glycosphingolipids capable of forming lactones, i.e. inner esters. Some gangliosides are tumor-associated antigens, and they may serve as immunogens in their lactone form, where the latter is comparatively more abundant on the surface of malignant cells. Due to improved hydrolytic stability, lactam (inner amide) analogues of gangliosides should be better immunogens than the corresponding lactones while still being conformationally nearly identical. Hence, a lactam-specific antibody which cross-reacts with the corresponding lactone is possible to prepare. As target molecule for this work was chosen an [8,9]-lactam analogue of GD3, a tumor-associated antigen for human malignant... (More)
Gangliosides (G) are sialic acid-containing cell surface glycosphingolipids capable of forming lactones, i.e. inner esters. Some gangliosides are tumor-associated antigens, and they may serve as immunogens in their lactone form, where the latter is comparatively more abundant on the surface of malignant cells. Due to improved hydrolytic stability, lactam (inner amide) analogues of gangliosides should be better immunogens than the corresponding lactones while still being conformationally nearly identical. Hence, a lactam-specific antibody which cross-reacts with the corresponding lactone is possible to prepare. As target molecule for this work was chosen an [8,9]-lactam analogue of GD3, a tumor-associated antigen for human malignant melanoma.



The alfa-2-8 coupling of two sialic acid residues proved to be the critical and most difficult step in the synthesis, and a novel potent tetra-O-acetylated-3-(S)-phenylthio ethylthioglycoside sialyl donor was therefore developed (Papers I-II).



Sialylation of a 9-azido acceptor was accomplished in 28% yield with the novel donor, and the subsequently prepared bis-sialic acid lactam was shown to be conformationally nearly identical with a lactone analogue, where the latter was also prepared by means of the novel sialyl donor (Paper III).



Removal of the auxiliary 3-(S)-phenylthio group was however difficult in some instances, and a 3-(S)-phenylseleno phosphite donor was therefore prepared. Although the 3-(S)-phenylseleno group was easily removable, it did not confer any powerful sialylation capability in terms of yield, albeit the stereoselectivity was excellent. Both the weak C-Se bond and a conformational phenomena explained this result (Paper IV).



Two 3-(S)-(2-methoxyphenyl)thio methylthioglycoside sialyl donors were also prepared, and they provided good yields in bis-sialo couplings, albeit the stereoselectivity was unsatisfactory. The removal of the 3-(S)-(2-methoxyphenyl)thio group was also unexpectedly difficult.



Many promoter systems of thioglycosides are available, such as NIS/TfOH and MeSBr/AgOTf, but they all have some practical disadvantages. In order to overcome this, the novel promoter system ICl/AgOTf was developed, and it proved to be both versatile and especially convenient to use (Paper V). (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Professor Boons, Gert-Jan, Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602, USA
organization
publishing date
type
Thesis
publication status
published
subject
keywords
thioglycoside promoter, ganglioside, Tumor-associated antigen, lactam, lactone, sialic acid, N-acetylneuraminic acid, Neu5Ac, sialyl donor, auxiliary group, 3-(S)-phenylthio, bis-sialic acid lactam, 3-(S)-phenylseleno, silver trifluoromethanesulfonate, iodine monochloride, Organic chemistry, Organisk kemi
pages
64 pages
publisher
Organic Chemistry, Lund University
defense location
Sal B Center for Chemistry and Chemical Engineering, University of Lund
defense date
2001-03-23 10:15
ISBN
91-628-4623-X
language
English
LU publication?
yes
id
57c8ab99-dcb7-4b33-914e-3acf1f89a991 (old id 41336)
date added to LUP
2007-06-20 12:56:29
date last changed
2016-09-19 08:45:10
@misc{57c8ab99-dcb7-4b33-914e-3acf1f89a991,
  abstract     = {Gangliosides (G) are sialic acid-containing cell surface glycosphingolipids capable of forming lactones, i.e. inner esters. Some gangliosides are tumor-associated antigens, and they may serve as immunogens in their lactone form, where the latter is comparatively more abundant on the surface of malignant cells. Due to improved hydrolytic stability, lactam (inner amide) analogues of gangliosides should be better immunogens than the corresponding lactones while still being conformationally nearly identical. Hence, a lactam-specific antibody which cross-reacts with the corresponding lactone is possible to prepare. As target molecule for this work was chosen an [8,9]-lactam analogue of GD3, a tumor-associated antigen for human malignant melanoma.<br/><br>
<br/><br>
The alfa-2-8 coupling of two sialic acid residues proved to be the critical and most difficult step in the synthesis, and a novel potent tetra-O-acetylated-3-(S)-phenylthio ethylthioglycoside sialyl donor was therefore developed (Papers I-II).<br/><br>
<br/><br>
Sialylation of a 9-azido acceptor was accomplished in 28% yield with the novel donor, and the subsequently prepared bis-sialic acid lactam was shown to be conformationally nearly identical with a lactone analogue, where the latter was also prepared by means of the novel sialyl donor (Paper III).<br/><br>
<br/><br>
Removal of the auxiliary 3-(S)-phenylthio group was however difficult in some instances, and a 3-(S)-phenylseleno phosphite donor was therefore prepared. Although the 3-(S)-phenylseleno group was easily removable, it did not confer any powerful sialylation capability in terms of yield, albeit the stereoselectivity was excellent. Both the weak C-Se bond and a conformational phenomena explained this result (Paper IV).<br/><br>
<br/><br>
Two 3-(S)-(2-methoxyphenyl)thio methylthioglycoside sialyl donors were also prepared, and they provided good yields in bis-sialo couplings, albeit the stereoselectivity was unsatisfactory. The removal of the 3-(S)-(2-methoxyphenyl)thio group was also unexpectedly difficult.<br/><br>
<br/><br>
Many promoter systems of thioglycosides are available, such as NIS/TfOH and MeSBr/AgOTf, but they all have some practical disadvantages. In order to overcome this, the novel promoter system ICl/AgOTf was developed, and it proved to be both versatile and especially convenient to use (Paper V).},
  author       = {Ercegovic, Teddy},
  isbn         = {91-628-4623-X},
  keyword      = {thioglycoside promoter,ganglioside,Tumor-associated antigen,lactam,lactone,sialic acid,N-acetylneuraminic acid,Neu5Ac,sialyl donor,auxiliary group,3-(S)-phenylthio,bis-sialic acid lactam,3-(S)-phenylseleno,silver trifluoromethanesulfonate,iodine monochloride,Organic chemistry,Organisk kemi},
  language     = {eng},
  pages        = {64},
  publisher    = {ARRAY(0x9b621a0)},
  title        = {Some New Methods in Sialic Acid Chemistry},
  year         = {2001},
}