Synthesis and Evaluation of Anticancer Vaccine Candidates, C

Chapter 10

Synthesis and Evaluation of Anticancer Vaccine Candidates, C-Glycoside Analogs of STn and PSA Downloaded by PENNSYLVANIA STATE UNIV on May 21, 2013 | http://pubs.acs.org Publication Date: September 1, 2008 | doi: 10.1021/bk-2008-0990.ch010

1

1

1

1

Michel Weïwer , Fei Huang , Chi-Chang Chen , Xuejun Yuan , Kazuo Tokuzaki , Hiroshi Tomiyama, and Robert J. Linhardt * 2

2

1,

1

Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, NY 12180 Kotobuki Pharmaceutical Company, LTD, Oaza Sakaki, Sakaki-machi, Hanishina-gun, Nagano, 389-0697 Japan 2

Neuraminic acids are biologically important and occupy the terminal position of the glycoconjugate glycans on the outside of cells. Sialyl-Tn (sTn) is found on tumor-associated glycoprotein antigens present on the surface of cancer cells, including those associated with carcinomas of the breast, prostate, pancreas, colon, ovary, lung, and stomach. The sTn antigen is well known as a prognostic indicator and has proven to be an effective target for cancer therapy. Conjugate vaccines of sTn-KLH show remarkable immunogenicity, resulting in the production of both IgM and IgG type antibodies. The sTn C -glycoside was designed and synthesized and its KLH-conjugate was evaluated for immunogenicity in mice. Neuraminic acid C -glycosides such as sTn and polysialic acid (PSA) might be useful in preparing immunogens for active immunization against neuraminic acid containing glycoconjugates in the design and preparation of anti-cancer vaccines.

216

© 2008 American Chemical Society In Chemical Glycobiology; Chen, X., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.

217

Downloaded by PENNSYLVANIA STATE UNIV on May 21, 2013 | http://pubs.acs.org Publication Date: September 1, 2008 | doi: 10.1021/bk-2008-0990.ch010

Introduction Ulosonic acids, or sialic acids (Figure 1), constitute a unique family of complex monosaccharides that are involved in many important biological functions (1-4). Their biological roles include facilitating cell-cell interactions (5), aggregation (6, 7) and development (8). Ulosonic acids are 8- and 9-carbon monosaccharides that contain an anomeric carboxylate, a deoxygenated methylene C-3 ring carbon, an hydroxylated 2- or 3-carbon side chain at C-6 and are differentiallyfimctionalizedat C-5. Neuraminic acid (5-amino-3,5-dideoxyD-glycero-D-galacto-non-2-ulosonic acid) does not occur naturally, but many of its derivatives (Neu5Ac, KDN, KDO, Figure 1) are found widely distributed in animal tissues and in bacteria, especially in glycoproteins and gangliosides (2, 3). These sugars can be found in a wide variety of glycosidic linkages, mainly oc(2,3) and oc(2,6) to galactose or lactose but also as cc(2,8) and ct(2,9) in polysialic acids (2, 5). The most common sialic acid, Af-acetylneuraminic acid (Neu5Ac), is a constituent of a large number of glycoconjugates (glycoproteins, glycopeptides, glycolipids, etc.) and is always found at the non-reducing termini of oligosaccharide chains. Neu5 Ac represents an important biological receptor domain that interacts with enzymes, hormones, toxins, microbes, viruses and cells (9-11). For example, cell-cell recognition between circulating leukocytes in blood vessels and endothelial cells is believed to occur through the interaction between mammalian lectins (selectins) and Neu5Ac containing oligosaccharides ligands (10). Moreover, many pathogens employs Neu5Ac or other sialic acids to promote infection. Some viruses use hemagglutinin, a sialic acid binding lectin, others utilize neuraminidases, hydrolase-type enzymes that cleaves sialic acid glycosidic linkage, to gain entry into the cells they infect (12-15). Neisseria meningitides, a pathogenic bacteria, biosynthesizes an extracellular capsule composed of Neu5Ac homopolymers as camouflage to escape host immune response (13, 14).

OH

1

3

Figure 1. The a-anomeric forms of some sialic acids, Neu5Ac (I), KDN (2 and KDO (3). The linkage of neuraminic acid to glycoconjugates is among the most labile glycosidic linkages and can be cleaved in vitro under mildly acidic conditions

In Chemical Glycobiology; Chen, X., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.




Figure 2. O-glycosides vs C-glycosides stability.


ROH


H

OH

HO OH NRE

9 |

2

v

GlcNAc

^ ^OH OH

/

I NH

/ HN

Asn

RE

Η -ΝNHAc Ο il

OH

Synthesis and Evaluation of Anticancer Vaccine Candidates, C

Recommend Documents