Issue 11, 2022

Automated solid phase assisted synthesis of a heparan sulfate disaccharide library

Abstract

Heparan sulfate (HS) regulates a wide range of biological events, including blood coagulation, cancer development, cell differentiation, and viral infections. It is generally recognized that structures of HS can critically impact its biological functions. However, with complex structures of naturally existing HS, systematic investigations into the structure–activity relationship (SAR) of HS and efforts to unlock its “sulfation code” have been largely limited due to the challenges in preparing diverse HS oligosaccharide sequences. Herein, we report an automated machine-aided solid-phase strategy that significantly expedited the assembly of HS disaccharides. The key strategically protected advanced disaccharide intermediates were immobilized onto Synphase lanterns. Divergent deprotections and sulfations of the disaccharides were achieved on the lanterns in high yields. In addition, the full synthetic process was automated, enabling the reproducible production of HS disaccharides. A library of 16 HS disaccharides with diverse sulfation patterns was prepared via this method. Compared to the traditional HS synthesis, this new strategy led to a reduction of 50% of the number of synthetic steps and over 80% of the number of column purification steps needed from the disaccharide intermediates, significantly improving the overall synthetic efficiency. The potential utility of the method was highlighted in a microarray study using the synthetic HS disaccharide library with fibroblast growth factor-2 (FGF-2), which yielded insights into the SAR of HS/FGF-2 interactions.

Graphical abstract: Automated solid phase assisted synthesis of a heparan sulfate disaccharide library

Supplementary files

Article information

Article type
Research Article
Submitted
18 mars 2022
Accepted
18 avr. 2022
First published
19 avr. 2022

Org. Chem. Front., 2022,9, 2910-2920

Automated solid phase assisted synthesis of a heparan sulfate disaccharide library

S. Ramadan, G. Su, K. Baryal, L. C. Hsieh-Wilson, J. Liu and X. Huang, Org. Chem. Front., 2022, 9, 2910 DOI: 10.1039/D2QO00439A

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