Synthesis and evaluation of several oleanolic acid glycoconjugates as protein tyrosine phosphatase 1B inhibitors

Qingchao Liu; Tiantian Guo; Dong Li; Fahui Li; Wenhong Li

doi:10.1016/j.ejmech.2014.03.080

Synthesis and evaluation of several oleanolic acid glycoconjugates as protein tyrosine phosphatase 1B inhibitors

Eur J Med Chem. 2014 May 22:79:34-46. doi: 10.1016/j.ejmech.2014.03.080. Epub 2014 Mar 29.

Authors

Qingchao Liu¹, Tiantian Guo², Dong Li¹, Fahui Li³, Wenhong Li⁴

Affiliations

¹ Department of Pharmaceutical Engineering, Northwest University, Xi'an 710069, Shaanxi, PR China.
² Department of Chemical Medicine, Xi'an Institute for Food and Drug Control, Xi'an 710054, Shaanxi, PR China.
³ College of Chemistry and Chemical Engineering and Environmental Engineering, Weifang University, Weifang, Shandong 261061, PR China.
⁴ Department of Pharmaceutical Engineering, Northwest University, Xi'an 710069, Shaanxi, PR China. Electronic address: liuqc21@nwu.edu.cn.

PMID: 24721313
DOI: 10.1016/j.ejmech.2014.03.080

Abstract

Sixteen novel oleanolic acid triterpenoid saponins were synthesized in an efficient and practical strategy, and their inhibitory activities against protein tyrosine phosphatase 1B (PTP1B) and selectivity over T-cell protein tyrosine phosphatase (TCPTP) were evaluated in vitro. The preliminary structure-activity relationship studies demonstrated that sugar-substituted moiety attached to the C-3 and C-28 positions of OA scaffold greatly affected the inhibitory activity against PTP1B and the selectivity over TCPTP. All the compounds showed inhibitory potencies, and compounds 1h, 1i and 1j exhibited remarkably potent inhibitory activities against PTP1B with IC50 values of 1.03, 0.78 and 3.12 μM, respectively. More significantly, compound 1h showed greater than 4 folds selectivity over highly homologous TCPTP. In parallel, the lipophilicity evaluation of all synthesized compounds was tested as a prediction for pharmacological potency. According to the predicted log P values, the predicted Log P results showed that lipophilicity may correlate with the evaluated biological potency.

Keywords: Glycosylation; Log P; Oleanolic acid triterpenoid saponins; PTP1B inhibitors; Strucutre–activity relationships.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Glycoconjugates / chemical synthesis
Glycoconjugates / chemistry
Glycoconjugates / pharmacology*
Humans
Molecular Conformation
Oleanolic Acid / chemical synthesis
Oleanolic Acid / chemistry
Oleanolic Acid / pharmacology*
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Glycoconjugates
Oleanolic Acid
Protein Tyrosine Phosphatase, Non-Receptor Type 1