Synthetic and immunological studies of N-acyl modified S-linked STn derivatives as anticancer vaccine candidates

Abstract

It is well known that tumor cells express some aberrant glycans, termed tumor-associated carbohydrate antigens (TACAs). TACAs are good targets for the development of carbohydrate-based anticancer vaccines. However, one of the major problems is that carbohydrate antigens possess a weak immunogenicity. To tackle this problem, a number of unnatural N-modified S-linked STn analogues were designed and prepared. Reaction of the modified STn disaccharides with bifunctional adipic acid p-nitrophenyl diester provided the corresponding activated esters, which was followed by the conjugation with keyhole limpet hemocyanin (KLH), affording the corresponding protein conjugates. The immunological properties of these glycoconjugates were evaluated in a mouse model. The results showed that the modified glycoconjugates stimulated the production of IgG antibodies that are capable of recognizing the naturally occurring STn antigen, helping the discovery of carbohydrate-based anticancer vaccine candidates.

Prognostic significance of ST6GalNAc-1 expression in patients with non-metastatic clear cell renal cell carcinoma

“…S Julien found an increased tumorigenicity after transplantation of ST6GalNAc-1 transfected sTn-positive human breast cell line in to mice [ 11 ]. In addition, sTn has also been used as a target for cancer immunotherapy in preclinical and clinical studies [ 24 , 25 ].…”

Carbohydrate‐based vaccines for oncotherapy

“…However, the evoked cross‐reactive antibodies did not increase when compared with the native ones . Our group also synthesized and evaluated some S ‐linked STn glycoconjugates, and the experimental results demonstrated that the modified glycoconjugates could stimulate the induction of cross‐reactive IgG antibodies …”

“…195 Our group also synthesized and evaluated some S-linked STn glycoconjugates, and the experimental results demonstrated that the modified glycoconjugates could stimulate the induction of cross-reactive IgG antibodies. 196,197 Hoffmann-Röder and co-workers modified the TF antigen by fluorine substituting the hydroxyl groups, and conjugated the antigen derivatives to TT. The constructed vaccines evoked immune responses.…”

Synthesis of an S‐Linked α(2→8) GD3 Antigen and Evaluation of the Immunogenicity of Its Glycoconjugate

“…[19,20] Despite the almost universal use of b-sialyl chloride [12,21] fort he synthesis of a-S-sialosides, use of this reagent is often complicated by the competing elimination reaction. [21,23] It should be noted that the synthesis of 2-mercapto-Neu5Acd erivatives suffers from unsatisfactory yields because of competing reactions such as elimination and disulfide bond formation under the experimental conditions, [22] whichf urther complicates the formation of the desired thioglycosides.R ecently,amore-reactive cyclic N-acetyl-N5,O4-oxazolidinone-pro-tected sialyl donor with ad ibutyl phosphate anomericl eaving group has been introduced for the synthesis of a-S-sialosides, which eliminates some of these limitations. [21,23] It should be noted that the synthesis of 2-mercapto-Neu5Acd erivatives suffers from unsatisfactory yields because of competing reactions such as elimination and disulfide bond formation under the experimental conditions, [22] whichf urther complicates the formation of the desired thioglycosides.R ecently,amore-reactive cyclic N-acetyl-N5,O4-oxazolidinone-pro-tected sialyl donor with ad ibutyl phosphate anomericl eaving group has been introduced for the synthesis of a-S-sialosides, which eliminates some of these limitations.…”

“…[22] Amongo therr eported approaches, anomeric S-alkylation has been investigated for the synthesis of a-S-sialosides via generation of af ree sulfhydryl group at the anomeric position in situ. [21,23] It should be noted that the synthesis of 2-mercapto-Neu5Acd erivatives suffers from unsatisfactory yields because of competing reactions such as elimination and disulfide bond formation under the experimental conditions, [22] whichf urther complicates the formation of the desired thioglycosides.R ecently,amore-reactive cyclic N-acetyl-N5,O4-oxazolidinone-pro-tected sialyl donor with ad ibutyl phosphate anomericl eaving group has been introduced for the synthesis of a-S-sialosides, which eliminates some of these limitations. [24] Previously,w er eported the use of sialyl disulfides as nucleophilic donors for the exclusive formation of S-linked a(2!9) disialyll inkages.…”