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ABSTRACT: To obtain higher potency and specificity, a series of 7-alkoxy analogues of illudalic acid was synthesized on the base of structure-activity relationship (SAR). All of these compounds exhibited submicromolar inhibition of the enzyme when tested against human leukocyte common antigen-related phosphatase (LAR) (for example, for 15e, IC50 = 180 nmol x L(-1)). They represent the most potent small-molecule inhibitors of LAR so far. These analogues also display excellent selectivity for LAR over other protein tyrosine phosphatases (PTPs) except for the highly homologous PTPsigma. The compound 15f is of 120-fold selectivity for LAR versus PTP-1B inhibition. The development of potent enzyme-specific inhibitors is so important that they may serve both as tools to study the role of LAR and as therapeutic agents for treatment of type II diabetes.
Yao xue xue bao = Acta pharmaceutica Sinica 11/2010; 45(11):1385-97.
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ABSTRACT: The in vitro oxidative hemolysis of human red blood cells (RBCs) was used as a model to study the free radical-induced damage of biological membranes and the protective effect of resveratrol (3,5,4′-trihydroxy-trans-stilbene, 1) and its analogues, i. e., 4-hydroxy-trans-stilbene (2), 3, 5-dihydroxytrans-stilbene (3), 3,4-dihydroxy-trans-stilbene (4), 4,4′-dihydroxy-trans-stilbene (5) and 2, 4, 4′-trihydroxy-trans-stilbene (6). The hemolysis of RBCs was induced by a water-soluble free radical initiator 2, 2′-azobis (2-amidinopropane hydrochloride) (AAPH). It was found that addition of AAPH at 37 °C to the suspension of RBCs caused fast hemolysis after a short period of inhibition period, and addition of 1–6 significantly suppressed the hemolysis. Compound 4 which bears an ortho-dihydroxyl functionality showed much more effective anti-hemolysis activity than that of resveratrol and the other analogues.
Chinese Journal of Chemistry 08/2010; 20(11):1313 - 1318. · 0.75 Impact Factor
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Zhang Liu,
Qian Chai,
Yuan-yuan Li,
Qiang Shen, Lan-ping Ma,
Li-na Zhang,
Xin Wang,
Li Sheng,
Jing-ya Li,
Jia Li,
Jing-kang Shen
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ABSTRACT: To discover and optimize a series of novel PTP1B inhibitors containing a thiazolidinone-substituted biphenyl scaffold and to further evaluate the inhibitory effects of these compounds in vitro and in vivo.
A total of 36 thiazolidinone substituted biphenyl scaffold derivatives were prepared. An in vitro biological evaluation was done by Enzyme-based assay. The in vivo efficacy of 7Fb as an antihyperglycemic agent was evaluated in a BKS db/db diabetic mouse model with a dose of 50 mg.kg(-1).d(-1) for 4 weeks.
The in vitro biological evaluation showed that compounds 7Fb and 7Fc could increase the insulin-induced tyrosine phosphorylation of IRbeta in CHO/hIR cells. In in vivo experiments, compound 7Fb significantly lowered the postprandial blood glucose, from 29.4+/-1.2 mmol/L with the vehicle to 24.7+/-0.6 mmol/L (P<0.01), and the fasting blood glucose from 27.3+/-1.5 mmol/L with the vehicle to 23.6+/-1.2 mmol/L (P<0.05).
A novel series of compounds were discovered to be PTP1B inhibitors. Among them, compound 7Fb significantly lowered the postprandial and fasting glucose levels, and the blood glucose level declined more rapidly than in metformin-treated mice. Thus, 7Fb may be a potential lead compound for developing new agents for the treatment of type II diabetes.
Acta Pharmacologica Sinica 08/2010; 31(8):1005-12. · 1.95 Impact Factor
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ABSTRACT: The aim of this study was to design and synthesize a series of high activity compounds against aspartyl protease beta-secretase (BACE-1) bearing hydroxyethylene (HE) framework.
First, we designed the small library based on our previous work and rational analysis. Subsequently, thirteen compounds were selected and synthesized using skilled solid phase synthetic methods to explore the relationship between structure and activity. We then used molecular modeling to explain the possible binding mode.
Thirteen new compounds (6-18) have been designed, synthesized and bioassayed. Their structures were determined by nuclear magnetic resonance (NMR) spectra, low- and high-resolution mass spectra and optical rotation. Most compounds have shown moderate to excellent activities, and compound 10, which contains fewer amino acids and amide bonds than GRL-7234, was about 5-fold more potent than the control compound 4 discovered by Merck. The molecular modeling results have indicated the possible binding mode and explained the difference between compounds 10 and 16, providing direction for further study.
This study yielded several high activity compounds bearing fewer amino acids and amide bonds than previous compounds, providing insight into the further development of potent BACE-1 inhibitors for the treatment of Alzheimer's disease.
Acta Pharmacologica Sinica 02/2009; 30(2):259-69. · 1.95 Impact Factor
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ABSTRACT: Peroxidation of linoleic acid was initiated by azobis(isobutyronitrile) in tert-butyl alcohol and inhibited by -tocopherol, β-carotene and retinal, either alone or in combination. Significant antioxidant synergism and a novel mutual protection of -tocopherol and β-carotene were found and the possible involvement of retinal in the process is discussed.
Journal of Physical Organic Chemistry 09/2004; 8(12):774 - 780. · 1.96 Impact Factor
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ABSTRACT: The antioxidative and free radical scavenging effects of four ecdysteroids, 20-hydroxyecdysone (E1), 25-deoxy-11,20-dihydroxyecdysone (E2), 24-(2-hydroxyethyl)-20-hydroxyecdysone (E3), and 20-hydroxyecdysone-20,22-monoacetonide (E4), isolated from the Chinese herb Serratula strangulata have been investigated in vitro. These ecdysteroids could protect human erythrocytes against oxidative hemolysis induced by a water-soluble azo initiator 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH). They could also inhibit the peroxidation of rat liver microsomes induced by hydroxyl radicals, as monitored by the formation of thiobarbituric acid reactive substances (TBARS), and prevent radical-induced decrease of membrane fluidity as determined by fluorescence polarization. They reacted with galvinoxyl radicals in homogeneous solution, and the pseudo-first-order rate constants were determined spectrophotometrically by following the disappearance of galvinoxyl radicals. Compounds E1 and (or) E3 were the most active in both antioxidative and radical-scavenging reactions.
Canadian Journal of Physiology and Pharmacology 01/2003; 80(12):1187-94. · 1.95 Impact Factor
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ABSTRACT: Resveratrol (3,5,4'-trans-trihydroxystilbene) is a natural phytoalexin present in grapes and red wine, which possesses a variety of biological activities including antioxidative activity. To find more efficient antioxidants by structural modification, resveratrol analogues, that is, 3,4-dihydroxy-trans-stilbene (3,4-DHS), 4,4'-dihydroxy-trans-stilbene (4,4'-DHS), 4-hydroxy-trans-stilbene (4-HS) and 3,5-dihydroxy-trans-stilbene (3,5-DHS), were synthesized and their antioxidant activity studied for the free radical-induced peroxidation of rat liver microsomes in vitro. The peroxidation was initiated by either a water-soluble azo compound 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH) or Fe(2+)/ascorbate, and monitored by oxygen uptake and formation of thiobarbituric acid reactive substances (TBARS). It was found that all of these trans-stilbene derivatives are effective antioxidants against both AAPH- and iron-induced peroxidation of rat liver microsomes with an activity sequence of 3,4-DHS>4,4'-DHS>resveratrol>4-HS>3,5-DHS. The remarkably higher antioxidant activity of 3,4-DHS is discussed.
Biochimica et Biophysica Acta 01/2003; 1637(1):31-8. · 4.66 Impact Factor
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ABSTRACT: Antioxidative effects of the principal polyphenolic components extracted from green tea leaves, i.e. (-)-epicatechin (EC), (-)-epicatechin gallate (ECG), (-)-epigallocatechin gallate (EGCG), (-)-epigallocatechin (EGC), and gallic acid (GA), against free radical initiated peroxidation of rat liver microsomes were studied. The peroxidation was initiated by a water-soluble azo compound 2,2'-azobis(2-amidinopropane hydrochloride (AAPH). The reaction kinetics was monitored by oxygen uptake and formation of malondialdehyde (MDA). Kinetic analysis of the antioxidation process demonstrates that these green tea polyphenols (GOHs), especially EC and ECG which bear ortho-dihydroxyl functionality, are good antioxidants for microsomal peroxidation. The antioxidant synergism of these GOHs with the endogenous alpha-tocopherol (TOH) (vitamin E) is also discussed.
Chemistry and Physics of Lipids 01/2003; 120(1-2):109-17. · 2.57 Impact Factor
