Abstract
3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isopropoxymethyl)benzyl)benzene-1,2-diol (HPN) is a synthetic analogue of 3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(ethoxymethyl)benzyl)benzene-1,2-diol (BPN), which is isolated from marine red alga Rhodomela confervoides with potent protein tyrosine phosphatase 1B (PTP1B) inhibition (IC50 = 0.84 μmol/L). The in vitro assay showed that HPN exhibited enhanced inhibitory activity against PTP1B with IC50 0.63 μmol/L and high selectivity against other PTPs (T cell protein tyrosine phosphatase (TCPTP), leucocyte antigen-related tyrosine phosphatase (LAR), Src homology 2-containing protein tyrosine phosphatase-1 (SHP-1) and SHP-2). The results of antihyperglycemic activity using db/db mouse model demonstrated that HPN significantly decreased plasma glucose (P < 0.01) after eight weeks treatment period. HPN lowered serum triglycerides and total cholesterol concentration in a dose-dependent manner. Besides, both of the high and medium dose groups of HPN remarkably decreased HbA1c levels (P < 0.05). HPN in the high dose group markedly lowered the insulin level compared to the model group (P < 0.05), whereas the effects were less potent than the positive drug rosiglitazone. Western blotting results showed that HPN decreased PTP1B levels in pancreatic tissue. Last but not least, the results of an intraperitoneal glucose tolerance test in Sprague–Dawley rats indicate that HPN have a similar antihyperglycemic activity as rosiglitazone. HPN therefore have potential for development as treatments for Type 2 diabetes.
Highlights
Type 2 diabetes mellitus (T2DM) is a complex endocrine and metabolic disorder
Molecular biology investigations have already proven that Protein tyrosine phosphatase 1B (PTP1B) knock-out mice exhibit the phenotypes of increased insulin sensitivity, improved glucose tolerance, and resistance to diet-induced obesity [3,4]
Based on the above research results, the inhibition of PTP1B has emerged as a novel therapeutic strategy for the treatments of Type 2 diabetes mellitus
Summary
Type 2 diabetes mellitus (T2DM) is a complex endocrine and metabolic disorder. On the World. Current treatment agents for T2DM mainly include insulin, biguanides, sulfonylureas, α-glucosidase inhibitors and thiazolidinediones (TZDs). Adverse effects such as hypoglycemia, weight gain and edema limit their clinical use [1]. Accumulated studies have reported that bromophenols exhibit a wide spectrum of biological and pharmacological activities including antioxidant activity [20,21], α-glucosidase inhibition [22], and antitumor effects [23]. In order to obtain new types of PTP1B inhibitors, a series of bromophenol derivatives were synthesized by using bis-(2,3-dibromo-4,5-dihydroxy-phenyl)-methane (BDDPM) and 3-bromo-4, 5-bis(2,3-dibromo-4,5-dihydroxybenzyl)-1,2-benzenediol (BDB) as lead compounds.
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