Design and Synthesis of 1-O- and 6′-C-Modified Heparan Sulfate Trisaccharides as Human Endo-6-O-Sulfatase 1 Inhibitors

The extracellular human endo-6- O -sulfatases (Sulf-1 and Sulf-2) are responsible for the endolytic cleavage of the 6-sulfate groups from the internal D-glucosamine residues in the highly sulfated subdomains of heparan sulfate proteoglycans. A trisaccharide sulfate, IdoA2OS-GlcNS6S-IdoA2OS, was iden...

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Published inFrontiers in chemistry Vol. 10; p. 947475
Main Authors Tseng, Kuei-Yao, Tzeng, Zheng-Hao, Cheng, Ting-Jen Rachel, Liang, Pi-Hui, Hung, Shang-Cheng
Format Journal Article
LanguageEnglish
Published Frontiers Media S.A 13.07.2022
Subjects
carbohydrate chemistry
Chemistry
endo-6-O-sulfatases
glycosaminoglycans
heparan sulfate
inhibitors
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Summary:The extracellular human endo-6- O -sulfatases (Sulf-1 and Sulf-2) are responsible for the endolytic cleavage of the 6-sulfate groups from the internal D-glucosamine residues in the highly sulfated subdomains of heparan sulfate proteoglycans. A trisaccharide sulfate, IdoA2OS-GlcNS6S-IdoA2OS, was identified as the minimal size of substrate for Sulf-1. In order to study the complex structure with Sulf-1 for developing potential drugs, two trisaccharide analogs, IdoA2OS-GlcNS6OSO 2 NH 2 -IdoA2OS-OMe and IdoA2OS-GlcNS6NS-IdoA2OS-OMe, were rationally designed and synthesized as the Sulf-1 inhibitors with IC 50 values at 0.27 and 4.6 μM, respectively.
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Reviewed by: Raghavendra Kikkeri Venkatanarayan, Indian Institute of Science Education and Research, Pune, India
Edited by: M. Carmen Galan, University of Bristol, United Kingdom
This article was submitted to Organic Chemistry, a section of the journal Frontiers in Chemistry
Gavin Miller, Keele University, United Kingdom
ISSN:2296-2646
2296-2646
DOI:10.3389/fchem.2022.947475