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Automated solid phase assisted synthesis of a heparan sulfate disaccharide library

Ramadan, Sherif and Su, Guowei and Baryal, Kedar and Hsieh-Wilson, Linda C. and Liu, Jian and Huang, Xuefei (2022) Automated solid phase assisted synthesis of a heparan sulfate disaccharide library. Organic Chemistry Frontiers, 9 (11). pp. 2910-2920. ISSN 2052-4129. doi:10.1039/d2qo00439a. https://resolver.caltech.edu/CaltechAUTHORS:20220520-231815000

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1039/D2QO00439ADOIArticle
https://www.rsc.org/suppdata/d2/qo/d2qo00439a/d2qo00439a1.pdfPublisherSupporting Information
ORCID:
AuthorORCID
Ramadan, Sherif0000-0002-8639-4105
Su, Guowei0000-0003-2668-9275
Baryal, Kedar0000-0003-1840-7485
Hsieh-Wilson, Linda C.0000-0001-5661-1714
Liu, Jian0000-0001-8552-1400
Huang, Xuefei0000-0002-6468-5526
Additional Information:© the Partner Organisations 2022. Received 18th March 2022, Accepted 18th April 2022. We are grateful for financial supports from the National Institute of General Medical Sciences, NIH (R01GM072667, U01GM116262, and R44GM134738) and Michigan State University for financial support of our work. Conflicts of interest. JL is a founder for Glycan Therapeutics. GS is an employee of Glycan Therapeutics. The authors declare no other conflicts of interests.
Funders:
Funding AgencyGrant Number
NIHR01GM072667
NIHU01GM116262
NIHR44GM134738
Michigan State UniversityUNSPECIFIED
Issue or Number:11
DOI:10.1039/d2qo00439a
Record Number:CaltechAUTHORS:20220520-231815000
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220520-231815000
Official Citation:Automated solid phase assisted synthesis of a heparan sulfate disaccharide library. Org. Chem. Front., 2022, 9, 2910-2920; DOI: 10.1039/d2qo00439a
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:114864
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:24 May 2022 14:24
Last Modified:14 Jun 2022 17:17

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