Bromophenols as inhibitors of protein tyrosine phosphatase 1B with antidiabetic properties.
ABSTRACT 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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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 01/2013; 11(2):350-62. · 3.98 Impact Factor
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ABSTRACT: Introduction: Thromboembolic incidences have increased nearly 33% in the past decade and directly affect nearly 0.5% of the population. Heparin, warfarin and current direct thrombin inhibitors (DTIs), the primary anticoagulants of choice, suffer from several drawbacks. Thus, the search for an antithrombotic devoid of adverse effect continues in earnest. Areas covered: Literature search covering PubMed, SciFinder(™) Scholar, Web of Knowledge, Espacenet, PatentScope and Google Patent Search was used to uncover > 35 patents describing new chemical entities and advances in DTI technologies. Our search uncovered considerable emphasis on the development of larger more complex molecules such as peptide-based inhibitors, prodrug derivatives, bivalent tryptophan zippers, triple action inhibitors and allosteric inhibitors. Advances in formulation technologies for clinically relevant DTIs have also been made. Expert opinion: Thrombin is a multifaceted, dynamic enzyme with both coagulant and anticoagulant functions. Newer DTIs are attempting to fine tune thrombin's activity by targeting allosteric sites or by site-specific targeting of clotting. The complexity of thrombin's functions is driving the design of complex anticoagulants. Advancements in formulations and production processes have attempted to make traditional DTIs more cost effective to produce. The literature reveals a trend to develop a thrombin 'modulator' rather than an 'inhibitor.'Expert Opinion on Therapeutic Patents 10/2013; · 3.53 Impact Factor
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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).European journal of medicinal chemistry 04/2013; 64C:129-136. · 3.27 Impact Factor