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Structure-activity relationship study of WSS25 derivatives with anti-angiogenesis effects

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Abstract

WGEW, an α(1-4) linked glucan with an α(1-4) linked branch attached to C-6, was isolated from the rhizoma of Gastrodia elata Bl. WSS25, a sulfated derivative of WGEW, was reported to inhibit angiogenesis by disrupting BMP2/Smad/Id1 signaling pathway. However, the structure-activity relationship (SAR) for WSS25 is not known. To study the SAR, seven sulfated saccharides derived from WGEW degradation products, six sulfated polysaccharides with varying degrees of substitution, and four aminopropylated, carboxymethylated, phosphorylated, and acetylated derivatives of WGEW were prepared. A sulfated, unbranched product of polysaccharide was also obtained. The structural features of these derivatives were characterized by infrared spectroscopy and nuclear magnetic resonance spectroscopy. An HMEC-1 cell tube formation assay was employed to measure the antiangiogenic effect of the derivatives. The results indicated that only sulfated polysaccharides with molecular weights of more than 41,000 Da could inhibit HMEC-1 cell tube formation. The inhibition effect was dependent on the presence of a sulfate group, since the tube formation was not blocked by aminopropylated, carboxymethylated, phosphorylated, or acetylated WGEW. A higher degree of sulfate substitution on the polysaccharide led to a stronger inhibitory effect, and the degree of sulfate substitution between 0.173 and 0.194 was found to be optimal. Interestingly, the WGEW side chain was not required for anti-tube formation activity. All these preliminary results may provide a clue for further modification of the core structure of WSS25 to discover polysaccharide derivatives as novel anti-angiogenic inhibitors.

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Abbreviations

bFGF:

Basic fibroblast growth factor

BMP2:

Bone morphogenic protein 2

DMSO:

Dimethyl sulfoxide

DS:

Degree of substitution

FBS:

Fetal bovine serum

FGF2:

Fibroblast growth factor 2

GC-MS:

Gas chromatography–mass spectrometry

HMEC-1:

Human microvascular endothelial cells

HPGPC:

High performance gel permeation chromatography

HS:

Heparan sulfate

Id1:

Inhibitor of DNA binding 1

IR:

Infrared

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

MW :

Molecular weight

NMR:

Nuclear magnetic resonance

QCM:

Quartz crystal microbalance

SAR:

Structure-activity relationship

TFA:

Trifluoroacetic acid

VEGF:

Vascular endothelial growth factor

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Acknowledgments

This work was supported by New Drug Creation and Manufacturing Program (2012ZX09301001-003), National Science Fund for Distinguished Young Scholars (81125025), and the funds for Industry-University-Research Institution Alliance in Guangdong Province, China (2010A090200041).

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Authors and Affiliations

  1. Glycochemistry & Glycobiology Lab, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chongzhi Road, Pudong, Shanghai, 201203, China

    Xia Chen, Fei Xiao, Ying Wang, Jianping Fang & Kan Ding

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  1. Xia Chen
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  2. Fei Xiao
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  3. Ying Wang
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  4. Jianping Fang
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  5. Kan Ding
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Correspondence to Jianping Fang or Kan Ding.

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Xia Chen and Fei Xiao contributed equally to this work.

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Chen, X., Xiao, F., Wang, Y. et al. Structure-activity relationship study of WSS25 derivatives with anti-angiogenesis effects. Glycoconj J 29, 389–398 (2012). https://doi.org/10.1007/s10719-012-9424-z

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  • DOI: https://doi.org/10.1007/s10719-012-9424-z

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