Discovery of novel bromophenol 3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isobutoxymethyl)benzyl)benzene-1,2-diol as protein tyrosine phosphatase 1B inhibitor and its anti-diabetic properties in C57BL/KsJ-db/db mice

Bo Jiang; Shuju Guo; Dayong Shi; Chao Guo; Tao Wang

doi:10.1016/j.ejmech.2013.03.037

Discovery of novel bromophenol 3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isobutoxymethyl)benzyl)benzene-1,2-diol as protein tyrosine phosphatase 1B inhibitor and its anti-diabetic properties in C57BL/KsJ-db/db mice

Eur J Med Chem. 2013 Jun:64:129-36. doi: 10.1016/j.ejmech.2013.03.037. Epub 2013 Apr 1.

Authors

Bo Jiang¹, Shuju Guo, Dayong Shi, Chao Guo, Tao Wang

Affiliation

¹ Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China.

PMID: 23644196
DOI: 10.1016/j.ejmech.2013.03.037

Abstract

In an effort to develop novel small molecule PTP1B inhibitors, a series of bromophenol derivatives were designed, synthesized and evaluated in vitro and in vivo. All of the synthesized compounds displayed weak to potent PTP1B inhibitory activities (5.62-96.25%) at 20 μg/mL. Among these compounds, 3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isobutoxymethyl)benzyl)benzene-1,2-diol (9) exhibited enhanced PTP1B inhibitory activity (IC50 = 1.50 μM) than the lead compound BDDPM (IC50 = 2.42 μM) and high selectivity against other PTPs (TCPTP, LAR, SHP-1 and SHP-2). Results of anti-diabetic assay using C57BL/KsJ-db/db mouse model demonstrated that compound 9 was effective at lowering blood glucose, total cholesterol and HbA1c (P < 0.01).

Publication types

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

MeSH terms

Animals
Benzhydryl Compounds / chemical synthesis
Benzhydryl Compounds / chemistry
Benzhydryl Compounds / pharmacology*
Catechols / chemical synthesis
Catechols / chemistry
Catechols / pharmacology*
Diabetes Mellitus, Experimental / drug therapy*
Diabetes Mellitus, Experimental / enzymology
Diabetes Mellitus, Experimental / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Hypoglycemic Agents / chemical synthesis
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology*
Mice
Mice, Inbred C57BL
Mice, Obese
Molecular Structure
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
Recombinant Proteins / antagonists & inhibitors
Recombinant Proteins / metabolism
Structure-Activity Relationship

Substances

3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isobutoxymethyl)benzyl)benzene-1,2-diol
Benzhydryl Compounds
Catechols
Enzyme Inhibitors
Hypoglycemic Agents
Recombinant Proteins
PTPN1 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 1