Divergent Synthesis of Chondroitin Sulfate Disaccharides and Identification of Sulfate Motifs that Inhibit Triple Negative Breast Cancer.

Zhong Wei Poh,George W Yip,Yulin Lam,Eric J Lee,Suxian Guo,Chin Heng Gan

doi:10.1038/srep14355

Zhong Wei Poh, George W Yip + Show 4 more

Open Access

https://doi.org/10.1038/srep14355

Copy DOI

Abstract

Glycosaminoglycans (GAGs) regulate many important physiological processes. A pertinent issue to address is whether GAGs encode important functional information via introduction of position specific sulfate groups in the GAG structure. However, procurement of pure, homogenous GAG motifs to probe the “sulfation code” is a challenging task due to isolation difficulty and structural complexity. To this end, we devised a versatile synthetic strategy to obtain all the 16 theoretically possible sulfation patterns in the chondroitin sulfate (CS) repeating unit; these include rare but potentially important sulfated motifs which have not been isolated earlier. Biological evaluation indicated that CS sulfation patterns had differing effects for different breast cancer cell types, and the greatest inhibitory effect was observed for the most aggressive, triple negative breast cancer cell line MDA-MB-231.

Highlights

Glycosaminoglycans (GAGs) are heterogeneous polysaccharides comprising of repeating uronic acid and amino sugar disaccharide units
For D1 and D2, ester protected hydroxyl groups were denoted as sulfation sites; an orthogonal benzyl ether protecting group was required on C-4, achieved by the use of CoCl2 and BH3.THF to direct complete regio-reductive ring opening of the benzylidene acetal protecting group[43,44]
Mark benzyl ether protected hydroxyl groups as sulfation sites and require the orthogonal ester protection at C-4; chloroacetyl ester was chosen as this group could be selectively cleaved to allow for the synthesis of longer chondroitin sulfate (CS) fragments when required[45,46]

Summary

Introduction

Glycosaminoglycans (GAGs) are heterogeneous polysaccharides comprising of repeating uronic acid and amino sugar disaccharide units. Compositional analysis of GAG side chains isolated from malignant breast tissues indicate an elevation in CS expression[13,14,15], with an increase in CS-A and CS-E sulfation sequences and a decrease in CS-C and CS-D16–18 These indicate that the sulfate groups present on CS might play an important role in the cellular processes involved in the progression of breast cancer[7,8,19,20]. Since C-2 may contain a sulfate group, ester protected hydroxyl groups are required as both sulfation and non-sulfation sites depending on the target compound With this in mind, we modified some of the currently available CS precursors[24,31,35,38,40,41] to obtain glycosyl donors D1–D4 and acceptors A1–A4; these building blocks enable the synthesis of all 16 sulfation patterns theoretically possible in the CS repeating unit

Methods

Results

Conclusion