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

Kuei-Yao Tseng; Zheng-Hao Tzeng; Ting-Jen Rachel Cheng; Pi-Hui Liang; Shang-Cheng Hung

doi:10.3389/fchem.2022.947475

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

Front Chem. 2022 Jul 13:10:947475. doi: 10.3389/fchem.2022.947475. eCollection 2022.

Authors

Kuei-Yao Tseng^{1

2}, Zheng-Hao Tzeng², Ting-Jen Rachel Cheng², Pi-Hui Liang^{1

2}, Shang-Cheng Hung^{2

3

4}

Affiliations

¹ School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
² Genomics Research Center, Academia Sinica, Taipei, Taiwan.
³ Department of Applied Science, National Taitung University, Taitung, Taiwan.
⁴ Department of Chemistry, National Cheng Kung University, Tainan, Taiwan.

Abstract

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-GlcNS6OSO₂NH₂-IdoA2OS-OMe and IdoA2OS-GlcNS6NS-IdoA2OS-OMe, were rationally designed and synthesized as the Sulf-1 inhibitors with IC₅₀ values at 0.27 and 4.6 μM, respectively.

Keywords: carbohydrate chemistry; endo-6-O-sulfatases; glycosaminoglycans; heparan sulfate; inhibitors.