Bromophenols as inhibitors of protein tyrosine phosphatase 1B with antidiabetic properties

Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 03/2012; 22(8):2827-32. DOI: 10.1016/j.bmcl.2012.02.074
Source: PubMed


A series of bromophenol derivatives were synthesized and evaluated as protein tyrosine phosphatase 1B (PTP1B) inhibitors in vitro and in vivo based on bromophenol 4e (IC(50)=2.42 μmol/L), which was isolated from red algae Rhodomela confervoides. The results showed that all of the synthesized compounds displayed weak to good PTP1B inhibition at tested concentration. Among them, highly brominated compound 4g exhibited promising inhibitory activity against PTP1B with IC(50) 0.68 μmol/L, which was approximately fourfold more potent than lead compound 4e. Further, compound 4g demonstrated high selectivity against other PTPs (TCPTP, LAR, SHP-1 and SHP-2). More importantly, in vivo antidiabetic activities investigations of compound 4g also demonstrated inspiring results.

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    • "Further modification of the initial compound led to identification of a more potent bromo-retrochalone derivative 53 (Fig. 7), which inhibited PTP1B with an IC 50 of 2 M [143]. Shi and colleagues showed that addition of two extra Br atoms to bromphenol derivative isolated from marine algae Rhodomela confervoides, decreased IC 50 from 2.42 M to 0.68 M [144]. Resulting compound 4 (Fig. 7) showed high selectivity over TCPTP (> 70 times) and was able to decrease plasma glucose, total cholesterol and HbA1c in db/db mice after 6 weeks of administration. "
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    ABSTRACT: Obesity and metabolic syndrome represent public health problems, and is one of the biggest preventable causes of death worldwide. Obesity is the leading risk factor for type 2 diabetes mellitus, cardiovascular diseases and non-alcoholic fatty liver disease. Obesity-associated insulin resistance, which is characterized by reduced glucose uptake and utilization in muscle, adipose and liver tissues, is a key predictor of metabolic syndrome and type 2 diabetes mellitus. With increasing prevalence of obesity in adults and children, the need to identify and characterize potential targets for treating metabolic syndrome is imminent. Emerging evidence from animal models, clinical studies and cell lines studies suggest that protein tyrosine phosphatase 1B (PTP1B), an enzyme that negatively regulates insulin signaling, is likely to be involved in the pathways leading to insulin resistance. PTP1B is tethered to the cytosolic surface of endoplasmic reticulum (ER), an organelle that is responsible for folding, modification, and trafficking of proteins. Recent evidence links the disruption of ER homeostasis, referred to as ER stress, to the pathogenesis of obesity and T2DM. PTP1B has been recognized as an important player linking ER stress and insulin resistance in obese subjects. The present review highlights recent advances in the research related to the role of PTP1B in signal transduction processes implicated in pathophysiology of obesity and type 2 diabetes, and focuses on the potential therapeutic exploitation of PTP1B inhibitors for the management of these conditions.
    Current Medicinal Chemistry 04/2013; 20(21). DOI:10.2174/0929867311320210001 · 3.85 Impact Factor
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    • "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. Fortunately, two of the bromophenol derivatives exhibited enhanced PTP1B inhibitory activity and are promising development prospects [26,27]. In the present study, we selected BPN (3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(ethoxymethyl)benzyl)benzene-1,2-diol) as the lead compound due to its potent PTP1B inhibition (IC50 = 0.84 μmol/L). "
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    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 (IC(50) = 0.84 μmol/L). The in vitro assay showed that HPN exhibited enhanced inhibitory activity against PTP1B with IC(50) 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.
    Marine Drugs 02/2013; 11(2):350-62. DOI:10.3390/md11020350 · 2.85 Impact Factor
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    ABSTRACT: Marine algae contain various bromophenols with a variety of biological activities, including antimicrobial, anticancer, and anti-diabetic effects. Here, we briefly review the recent progress in researches on the biomaterials from marine algae, emphasizing the relationship between the structure and the potential anti-diabetic applications. Bromophenols from marine algae display their hyperglycemic effects by inhibiting the activities of protein tyrosine phosphatase 1B, α-glucosidase, as well as other mechanisms.
    Journal of Ocean University of China 12/2012; 11(4). DOI:10.1007/s11802-012-2109-1 · 0.56 Impact Factor
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