Potent Inhibitor (potent + inhibitor)

Distribution by Scientific Domains
Distribution within Chemistry


Selected Abstracts


Synthesis of Novel Macrolactam and Macroketone Analogues of Migrastatin from D -Glucal and Comparison with Macrolactone and Acyclic Analogues: A Dorrigocin A Congener Is a Potent Inhibitor of Gastric Cancer Cell Migration

EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 11 2008
Guillaume Anquetin
Abstract Novel macrolactam and macroketone analogues of the migrastatin macrolide core have been synthesised from tri- O -acetyl- D -glucal in order to facilitate structure-activity studies. The Horner olefination, followed by ring-closing metathesis were key steps in the synthesis of the macroketone. The ability of the macroketone and macrolactam derivatives to inhibit the migration of gastric tumour cells as determined using a transwell migration assay were compared with macrolactone analogues and dorrigocin A analogues. One dorrigocin A congener was the most potent inhibitor of gastric cancer cell migration.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008) [source]


The Ether Lipid Inositol-C2-PAF is a Potent Inhibitor of Cell Proliferation in HaCaT Cells

CHEMBIOCHEM, Issue 3 2006
Annette Fischer
Abstract The search for specific anticancer drugs that do not interfere with DNA synthesis or influence the cytoskeleton has led to the development of modified phospholipids with antiproliferative properties. These compounds cause remodeling of the structure and function of plasma membranes. Recently, we described novel compounds, the glycosidated phospholipids, that surprisingly inhibit cell proliferation. These compounds contain ,- D -glucose in the sn -2 position of the glycerol backbone of phosphatidylcholine (PC) and platelet-activating factor (PAF), which gives rise to 2-glucophosphatidylcholine (Glc-PC) and 1- O -octadecyl-2- O -,- d- glucopyranosyl- sn -2-glycero-3-phosphatidylcholine (Glc-PAF), respectively. Glc-PC and Glc-PAF inhibit the growth of HaCaT cells at nontoxic concentrations. Here we report the introduction of myo -inositol, in place of ,- D -glucose, in the sn -2 position of the glycerol backbone; this leads to two diastereomeric 1- O -octadecyl-2- O -(2-(myo -inositolyl)-ethyl)- sn -glycero-3-(R/S)-phosphatidylcholines (Ino-C2-PAF). The inositol-containing PAF enhances the antiproliferative capacity (IC50=1.8 ,M) and reduces the cytotoxicity relative to Glc-PAF (LC50=15 ,M). Through biological assays, we showed that, in HaCaT cells, Ino-C2-PAF causes upregulation of the keratinocyte-specific differentiation marker involucrin, increases the activity of the differentiation marker transglutaminase, and induces apoptosis at nontoxic concentrations. Ino-C2-PAF therefore seems to be a promising candidate for development as an antiproliferative drug for the treatment of hyperproliferative diseases of the skin. [source]


Carboxy Derivatized Glucosamine Is a Potent Inhibitor of Matrix Metalloproteinase-9 in HT1080 Cells.

CHEMINFORM, Issue 38 2006
Eresha Mendis
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source]


A Short, Stereocontrolled, and Practical Synthesis of ,-Methylomuralide (I), a Potent Inhibitor of Proteasome Function.

CHEMINFORM, Issue 32 2003
P. Saravanan
No abstract is available for this article. [source]


New Peptolides from the Cyanobacterium Nostoc insulare as Selective and Potent Inhibitors of Human Leukocyte Elastase

CHEMBIOCHEM, Issue 16 2008
Christian Mehner
Abstract Eight new cyanopeptolins (insulapeptolides A,H) were obtained from the cyanobacterium Nostoc insulare. Their isolation was guided by their bioactivity toward the target enzyme human leukocyte elastase, molecular biological investigations, and MALDI-TOF analysis. These peptides are selective inhibitors of human leukocyte elastase with activities in the nanomolar range. Insulapeptolide D (4) was the most potent compound with an IC50 value of 85 nM (Ki value of 36 nM). [source]


ChemInform Abstract: Discovery of Pentacyclic Compounds as Potent Inhibitors of Hepatitis C Virus NS5B RNA Polymerase.

CHEMINFORM, Issue 26 2009
Joerg Habermann
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source]


2-Phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole Derivatives: New Potent Inhibitors of fMLP-Induced Neutrophil Chemotaxis.

CHEMINFORM, Issue 43 2007
Olga Bruno
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source]


Synthesis and Biological Activities of Aryl-Ether-, Biaryl-, and Fluorene-Aspartic Acid and Diaminopropionic Acid Analogues as Potent Inhibitors of the High-Affinity Glutamate Transporter EAAT-2.

CHEMINFORM, Issue 8 2006
Alexander Greenfield
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access the actual ChemInform Abstract, please click on HTML or PDF. [source]


Substituted 6-Phenyl-pyridin-2-ylamines: Selective and Potent Inhibitors of Neuronal Nitric Oxide Synthase.

CHEMINFORM, Issue 52 2004
Deane M. Nason
Abstract For Abstract see ChemInform Abstract in Full Text. [source]


,,,-Difluoro-,-ketophosphonates as Potent Inhibitors of Protein Tyrosine Phosphatase 1B.

CHEMINFORM, Issue 50 2004
Xianfeng Li
Abstract For Abstract see ChemInform Abstract in Full Text. [source]


Cinnamic Acid Esters as Potent Inhibitors of Fungal 17,-Hydroxysteroid Dehydrogenase , A Model Enzyme of the Short-Chain Dehydrogenase/Reductase Superfamily

CHEMINFORM, Issue 46 2004
Stanislav Gobec
Abstract For Abstract see ChemInform Abstract in Full Text. [source]


The Discovery of N-(1,3-Thiazol-2-yl)pyridin-2-amines as Potent Inhibitors of KDR Kinase.

CHEMINFORM, Issue 38 2004
Mark T. Bilodeau
Abstract For Abstract see ChemInform Abstract in Full Text. [source]


Imidazopyrimidines, Potent Inhibitors of p38 MAP Kinase.

CHEMINFORM, Issue 23 2003
Kenneth C. Rupert
Abstract For Abstract see ChemInform Abstract in Full Text. [source]


N-[2-(Indan-1-yl)-3-mercapto-propionyl] Amino Acids as Highly Potent Inhibitors of the Three Vasopeptidases (NEP, ACE, ECE): In vitro and in vivo Activities.

CHEMINFORM, Issue 48 2002
Bernard-Pierre Roques
Abstract For Abstract see ChemInform Abstract in Full Text. [source]


ChemInform Abstract: 6-Arylamino-5,8-quinazolinediones as Potent Inhibitors of Endothelium-Dependent Vasorelaxation.

CHEMINFORM, Issue 25 2002
Chung-Kyu Ryu
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source]


Rapid Diversity-Oriented Synthesis in Microtiter Plates for In Situ Screening of HIV Protease Inhibitors

CHEMBIOCHEM, Issue 11 2003
Ashraf Brik Dr.
Click and go: By using click chemistry based on a new triazole forming reaction condition (see scheme), over 100 triazole compounds generated in microtiter plates from a core structure were screened for HIV protease inhibition in situ without product isolation. Potent inhibitors, active at nanomolar concentrations, against the wild type and drug resistant mutants were identified. [source]


Hepatic dysfunction and insulin insensitivity in type 2 diabetes mellitus: a critical target for insulin-sensitizing agents

DIABETES OBESITY & METABOLISM, Issue 9 2008
P. D. Home
The liver plays an essential role in maintaining glucose homeostasis, which includes insulin-mediated processes such as hepatic glucose output (HGO) and uptake, as well as in clearance of insulin itself. In type 2 diabetes, the onset of hyperglycaemia [itself a potent inhibitor of hepatic glucose output (HGO)], alongside hyperinsulinaemia, indicates the presence of hepatic insulin insensitivity. Increased HGO is central to the onset of hyperglycaemia and highlights the need to target hepatic insulin insensitivity as a central component of glucose-lowering therapy. The mechanisms underlying the development of hepatic insulin insensitivity are not well understood, but may be influenced by factors such as fatty acid oversupply and altered adipocytokine release from dysfunctional adipose tissue and increased liver fat content. Furthermore, although the impact of insulin insensitivity as a marker of cardiovascular disease is well known, the specific role of hepatic insulin insensitivity is less clear. The pharmacological tools available to improve insulin sensitivity include the biguanides (metformin) and thiazolidinediones (rosiglitazone and pioglitazone). Data from a number of sources indicate that thiazolidinediones, in particular, can improve multiple aspects of hepatic dysfunction, including reducing HGO, insulin insensitivity and liver fat content, as well as improving other markers of liver function and the levels of mediators with potential involvement in hepatic function, including fatty acids and adipocytokines. The current review addresses this topic from the perspective of the role of the liver in maintaining glucose homeostasis, its key involvement in the pathogenesis of type 2 diabetes and the tools currently available to reduce hepatic insulin insensitivity. [source]


The pharmacology of cilostazol

DIABETES OBESITY & METABOLISM, Issue 2002
Karsten Schrör
Cilostazol (6-[4-(1-cyclohexyl- 1H -tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone; OPC-13013) is a 2-oxo-quinoline derivative with antithrombotic, vasodilator, antimitogenic and cardiotonic properties. The compound is a potent inhibitor of phosphodiesterase (PDE) 3A, the isoform of PDE 3 in the cardiovascular system (IC50: 0.2 µm). In addition, there is inhibition of adenosine uptake, eventually resulting in changes in cAMP levels, dependent on the type of adenosine receptors (A1 or A2). Cilostazol inhibits platelet aggregation and has considerable antithrombotic effects in vivo. The compound relaxes vascular smooth muscle and inhibits mitogenesis and migration of vascular smooth muscle cells. In the heart, cilostazol causes positive inotropic and chronotropic effects. Most, if not all, of these actions are cAMP-mediated, including the modification of cAMP-controlled gene expression. Cilostazol decreases levels of serum triglycerides and causes some increase in HDL-cholesterol levels. The compound has a number of additional effects which might contribute to its overall clinical efficacy. Cilostazol undergoes intensive and finally complete hepatic metabolism via the cytochrome P450 systems. This might result in some drug interaction, i.e. with erythromycin and omeprazole. The half-life is approximately 10 h, resulting in about 2-fold accumulation of the drug during repeated administration. [source]


Protective role of pigment epithelium-derived factor (PEDF) in early phase of experimental diabetic retinopathy

DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 7 2009
Yumiko Yoshida
Abstract Background Pigment epithelium-derived factor (PEDF) is the most potent inhibitor of angiogenesis in the mammalian eye, thus suggesting that PEDF may protect against proliferative diabetic retinopathy. However, a role for PEDF in early diabetic retinopathy remains to be elucidated. We investigated here whether and how PEDF could prevent the development of diabetic retinopathy. Methods Streptozotocin-induced diabetic rats were treated with or without intravenous injection of PEDF for 4 weeks. Early neuronal derangements were evaluated by electroretinogram (ERG) and immunofluorescent staining of glial fibrillary acidic protein (GFAP). Expression of PEDF and 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative stress, was localized by immunofluorescence. Vascular endothelial growth factor (VEGF) and p22phox expression were evaluated with western blots. Breakdown of blood retinal barrier (BRB) was quantified with fluorescein isothiocynate (FITC)-conjugated dextran. NADPH oxidase activity was measured with lucigenin luminescence. Results Retinal PEDF levels were reduced, and amplitudes of a- and b-wave in the ERG were decreased in diabetic rats, which were in parallel with GFAP overexpression in the Müller cells. Further, retinal 8-OHdG, p22phox and VEGF levels and NADPH oxidase activity were increased, and BRB was broken in diabetic rats. Administration of PEDF ameliorated all of the characteristic changes in early diabetic retinopathy. Conclusions Results suggest that PEDF could prevent neuronal derangements and vascular hyperpermeability in early diabetic retinopathy via inhibition of NADPH oxidase-driven oxidative stress generation. Substitution of PEDF may offer a promising strategy for halting the development of diabetic retinopathy. Copyright © 2009 John Wiley & Sons, Ltd. [source]


Long-term follow-up of achalasic patients treated with botulinum toxin

DISEASES OF THE ESOPHAGUS, Issue 2 2000
D'Onofrio
Botulinum toxin A (BoTx), a potent inhibitor of acetylcholine release from nerve endings both within the myenteric plexus and at the nerve,muscle junction, has been shown to decrease the lower esophageal sphincter (LES) pressure in patients with achalasia. Because of this property, the esophageal injection of BoTx has been suggested as an alternative treatment in achalasia. The objective of this study was to determine the long-term efficacy and safety of intrasphincteric injection of BoTx in a group of achalasic patients. Nineteen patients (mean age 56.1 ± 19.2 years) were enrolled in the study. All of them were injected endoscopically with 100 U of BoTx by sclerotherapy needle at different sites of the LES. Symptom score (dysphagia, regurgitation and chest pain, each on a 0,3 scale), esophageal manometer and esophageal radionuclide emptying were assessed before the treatment and at 4 weeks, 3 months and 1 year after BoTx injection. In case of failure or relapse (symptom score >2), the treatment was repeated. All but five patients (74%) were in clinical remission at 1 month. Mean symptom score after 1 month of BoTx decreased from 7.1 ± 0.9 to 2.2 ± 2.5 (p < 0.05). LES pressure decreased from 38.4 ± 13.7 to 27.4 ± 13.5 mmHg (p < 0.05) and 10-min radionuclide retention decreased from 70.9 ± 20.7% to 33.8 ± 27.0% (p < 0.05). Side-effects (transient chest pain) were mild and infrequent. At 12 months, the clinical score was 0.9 ± 0.5 (p < 0.05 vs. basal); mean LES pressure was 22.0 ± 7.1 (p < 0.05 vs. basal) and 10-min radionuclide retention was 15.8 ± 6.0% (p < 0.05 vs. basal). The efficacy of the first injection of BoTx lasted for a mean period of 9 months (range 2,14 months). At the time of writing (follow-up period mean 17.6 months, range 2,31), 14 patients (10 with one injection) were still in remission (74%). Our results showed that one or two intrasphincteric injections of BoTx resulted in clinical and objective improvement in about 74% of achalasic patients and are not associated with serious adverse effects; the efficacy of BoTx treatment was long lasting; this procedure could be considered an attractive treatment, especially in elderly patients who are poor candidates for more invasive procedures. [source]


Proteomic analysis of liver cancer cells treated with 5-Aza-2,-deoxycytidine (AZA),

DRUG DEVELOPMENT RESEARCH, Issue 1 2009
Shujun Bai
Abstract 5-Aza-2,-deoxycytidine (AZA) is a potent inhibitor of DNA methylation that exhibits anti-tumor activity in a variety of tumor cells via reactivation of tumor suppressor genes. However, few studies have been done on the biological and clinical significance of AZA in human hepatocellular carcinoma. To identify potential genes that may be aberrantly methylated and confer growth advantage to neoplastic cells and to better understand the molecular mechanism(s) underlying AZA anti-tumor activity, a proteomics approach was used to annotate global gene expression changes of HepG2 cell line pre- and post-treatment with AZA. A total of 56 differentially expressed proteins were identified by 2D gel analysis, 48 of which were up-regulated while the remaining 8 were down regulated. Among the identified proteins, eight of these showed marked changed proteins, including seven up-regulated proteins: glutathione S-transferase P, protein DJ-1, peroxiredoxin-2, UMP-CMP kinase, cytochrome c-type heme lyase, enhancer of rudimentary homolog, profilin-1, and one down-regulated protein, heat-shock protein ,,1. The possible implication of these proteins in hepatocarcinogenesis is discussed. We tested two up-regulated proteins, glutathione S-transferase P and peroxiredoxin-2, using RT-PCR and their expression was consistent with the results obtained in the protein level. Both of these genes were methylated when methylation-specific PCR was used against their promoter regions. Following treatment with AZA, the gene promoter regions were found to be unmethylated, concomitant with overexpression of the proteins compared to HepG2 cells without treatment. These data provide useful information in evaluating the therapeutic potential of AZA for the treatment of HCC. Drug Dev Res 69, 2009. © 2009 Wiley-Liss, Inc. [source]


Targeted replacement of rodent CCR2 with the human orthologue CCR2B: A mouse model for in vivo analysis of human target-selective small molecule MCP-1 receptor antagonists

DRUG DEVELOPMENT RESEARCH, Issue 4 2002
Haydn M. Prosser
Abstract Rodent models for testing the efficacy of lead compounds are often invalidated by species selectivity of the compounds. The advent of mouse embryonic stem cell technology has allowed the development of genetically engineered mouse strains that incorporate a specific human gene in place of the orthologous mouse gene, a so-called knock-in mouse. This study describes the generation and validation of a mutant mouse line that expresses human CCR2B as a functional substitute for murine CCR2. The human CCR2B knock-in mice are viable and appear normal. In vitro assays indicate that the CCR2B knock-in is functionally expressed, giving a macrophage chemotactic profile in response to JE or MCP-1 that is similar to human peripheral blood monocytes rather than that of a murine macrophage cell line. In addition, the human selective CCR2B antagonist, SB-399721, was a more potent inhibitor of CCR2B knock-in macrophages in response to hMCP-1 than JE. The ability of the human CCR2B gene to functionally substitute for the mouse orthologue in vivo is demonstrated by a normal inflammatory response to intraperitoneal thioglycollate injection. Drug Dev. Res. 55:197,209, 2002. © 2002 Wiley-Liss, Inc. [source]


Pharmacologic profile of zoledronic acid: A highly potent inhibitor of bone resorption

DRUG DEVELOPMENT RESEARCH, Issue 4 2002
Jonathan R. Green
Abstract Bisphosphonates are effective in treating benign and malignant skeletal diseases characterized by enhanced osteoclastic bone resorption (i.e., osteoporosis, Paget's disease, tumor-induced osteolysis). The nitrogen-containing bisphosphonate pamidronate is currently the standard treatment for hypercalcemia of malignancy (HCM) and skeletal complications of bone metastases. Zoledronic acid, a novel nitrogen-containing bisphosphonate with an imidazole substituent, has demonstrated more potent inhibition of osteoclast-mediated bone resorption than all other bisphosphonates, including pamidronate, in both in vitro and in vivo preclinical models. Zoledronic acid inhibited ovariectomy-induced bone loss in adult monkeys and rats, and long-term treatment prevented skeletal turnover and subsequent bone loss, reduced cortical porosity, and increased mechanical strength. Zoledronic acid also significantly inhibited bone loss associated with arthritis, bone metastases, and prosthesis loosening. The increased potency of zoledronic acid vs. pamidronate has been demonstrated clinically: zoledronic acid (4 or 8 mg iv) was superior to pamidronate (90 mg iv) in normalizing corrected serum calcium in patients with HCM. In patients with bone metastases, low doses of zoledronic acid (, 2 mg) suppressed bone resorption markers , 50% below baseline, whereas pamidronate 90 mg yielded only 20 to 30% suppression. Importantly, the increased potency of zoledronic acid is not associated with an increased incidence of local (bone) or systemic adverse events. Zoledronic acid does not impair bone mineralization and, compared with pamidronate, has a greater renal and intestinal tolerability therapeutic index. Thus, based on preclinical assays and clinical data, zoledronic acid is the most potent bisphosphonate tested to date. Given its potency and excellent safety profile, zoledronic acid is now poised to become the new standard of treatment for HCM and metastatic bone disease. Drug Dev. Res. 55:210,224, 2002. © 2002 Wiley-Liss, Inc. [source]


Anoxia,ischemia: A mechanism of seizure termination in ictal asystole

EPILEPSIA, Issue 1 2010
Stephan U. Schuele
Summary Cerebral anoxia,ischemia (CAI) is a potent inhibitor of cerebral hyperactivity and a potential mechanism of seizure self-termination. Prolonged ictal asystole (IA) invariably leads to CAI and has been implicated as a potential cause of sudden unexplained death in epilepsy (SUDEP). IA was seen in eight consecutive patients (0.12% of all patients monitored). Ten of their seizures with IA had evidence of CAI on electroencephalography (EEG), manifested by bilateral hypersynchronous slowing (BHS), and were compared to 18 seizures without signs of CAI. The ictal EEG pattern resolved in all 10 CAI events with onset of the BHS. The period from IA onset to seizure end was reduced in events with BHS compared to events without BHS (10.5 s vs. 28.3 s, respectively; p = 0.005), and the total seizure duration tended to be shorter. Anoxia,ischemia as a result of IA may represent an effective endogenous mechanism for seizure termination and may explain why the hearts of patients with ictal asystole reported to date in the literature resumed beating spontaneously. [source]


Polypropylene glycol is a selective binding inhibitor for LTA and other structurally related TLR2 agonists

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2008
Christian Draing
Abstract Polypropylene glycol (PPG) is commonly added to bacterial cultures to avoid foaming. However, lipoteichoic acid (LTA) from bacteria grown with PPG lacked cytokine-inducing potency in human blood. We tested the blocking efficacy of several glycols on the cytokine response to staphylococcal LTA in human blood. PPG 1200 was the most potent inhibitor tested, shown for TNF, IL-1,, IL-6, IL-8, IL-10 and TGF-, induction, and displayed no cytotoxic effects. TNF induction by Staphylococcus aureus or by Toll-like receptor (TLR)2 agonists (di- and triacylated lipopeptides and LTA) was also inhibited by PPG 1200, but not that induced by Escherichia,coli or TLR4 agonists. In flow cytometric studies, PPG-carrying nanobeads bound more rhodamine-labeled LTA than those with glycerol. Additionally, the methyl group peak in the 1H-NMR of LTA shifted after incubation with increasing PPG 1200 concentrations. Sequential incubation of polystyrene plates with LTA, then PPG 1200 and then blood, with washing steps in between, showed that LTA-induced TNF release was inhibited. But when PPG 1200 was pre-incubated with blood that was washed before LTA was added, TNF induction was not repressed, demonstrating that PPG binds LTA and not cellular structures. In summary, PPG 1200 is a novel inhibitor of cytokine induction by TLR2 agonists, which interferes directly with the ligands. [source]


Evidence for RPE65-independent vision in the cone-dominated zebrafish retina

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2007
Helia B. Schonthaler
Abstract An enzyme-based cyclic pathway for trans to cis isomerization of the chromophore of visual pigments (11- cis -retinal) is intrinsic to vertebrate cone and rod vision. This process, called the visual cycle, is mostly characterized in rod-dominated retinas and essentially depends on RPE65, an all- trans to 11- cis -retinoid isomerase. Here we analysed the role of RPE65 in zebrafish, a species with a cone-dominated retina. We cloned zebrafish RPE65 and showed that its expression coincided with photoreceptor development. Targeted gene knockdown of RPE65 resulted in morphologically altered rod outer segments and overall reduced 11- cis -retinal levels. Cone vision of RPE65-deficient larvae remained functional as demonstrated by behavioural tests and by metabolite profiling for retinoids. Furthermore, all- trans retinylamine, a potent inhibitor of the rod visual cycle, reduced 11- cis -retinal levels of control larvae to a similar extent but showed no additive effects in RPE65-deficient larvae. Thus, our study of zebrafish provides in vivo evidence for the existence of an RPE65-independent pathway for the regeneration of 11- cis -retinal for cone vision. [source]


Synthesis of Novel Macrolactam and Macroketone Analogues of Migrastatin from D -Glucal and Comparison with Macrolactone and Acyclic Analogues: A Dorrigocin A Congener Is a Potent Inhibitor of Gastric Cancer Cell Migration

EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 11 2008
Guillaume Anquetin
Abstract Novel macrolactam and macroketone analogues of the migrastatin macrolide core have been synthesised from tri- O -acetyl- D -glucal in order to facilitate structure-activity studies. The Horner olefination, followed by ring-closing metathesis were key steps in the synthesis of the macroketone. The ability of the macroketone and macrolactam derivatives to inhibit the migration of gastric tumour cells as determined using a transwell migration assay were compared with macrolactone analogues and dorrigocin A analogues. One dorrigocin A congener was the most potent inhibitor of gastric cancer cell migration.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008) [source]


An Efficient Method for the Large-Scale Preparation of 3- O -Acetyl-11-oxo-,-boswellic Acid and Other Boswellic Acids

EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 24 2003
Johann Jauch
Abstract 3- O -Acetyl-11-oxo-,-boswellic acid (AKBA), found in incense, is a potent inhibitor of 5-lipoxygenase, p38 and p42 MAP kinase and topoisomerases. Starting from crude extracts from incense, procedures are presented for the efficient large-scale synthesis of AKBA and other boswellic acids (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003) [source]


A novel, promoter-based, target-specific assay identifies 2-deoxy- d -glucose as an inhibitor of globotriaosylceramide biosynthesis

FEBS JOURNAL, Issue 18 2009
Tetsuya Okuda
Abnormal biosynthesis of globotriaosylceramide (Gb3) is known to be associated with Gb3-related diseases, such as Fabry disease. The Gb3 synthase gene (Gb3S) codes for ,1,4-galactosyltransferase, which is a key enzyme involved in Gb3 biosynthesis in vivo. Transcriptional repression of Gb3S is a way to control Gb3 biosynthesis and may be a suitable target for the treatment of Gb3-related diseases. To find a transcriptional inhibitor for Gb3S, we developed a convenient cell-based chemical screening assay system by constructing a fusion gene construct of the human Gb3S promoter and a secreted luciferase as reporter. Using this assay, we identified 2-deoxy- d -glucose as a potent inhibitor for the Gb3S promoter. In cultured cells, 2-deoxy- d -glucose markedly reduced endogenous Gb3S mRNA levels, resulting in a reduction in cellular Gb3 content and a corresponding accumulation of the precursor lactosylceramide. Moreover, cytokine-induced expression of Gb3 on the cell surface of endothelial cells, which is closely related to the onset of hemolytic uremic syndrome in O157-infected patients, was also suppressed by 2-deoxy- d -glucose treatment. These results indicate that 2-deoxy- d -glucose can control Gb3 biosynthesis through the inhibition of Gb3S transcription. Furthermore, we demonstrated the general utility of our novel screening assay for the identification of new inhibitors of glycosphingolipid biosynthesis. [source]


Insulin is a kinetic but not a thermodynamic inhibitor of amylin aggregation

FEBS JOURNAL, Issue 12 2009
Wei Cui
One of the most important pathological features of type 2 diabetes is the formation of islet amyloid, of which the major component is amylin peptide. However, the presence of a natural inhibitor such as insulin may keep amylin stable and physiologically functional in healthy individuals. Some previous studies demonstrated that insulin was a potent inhibitor of amylin fibril formation in vitro, but others obtained contradictory results. Hence, it is necessary to elucidate the effects of insulin on amylin aggregation. Here we report that insulin is a kinetic inhibitor of amylin aggregation, only keeping its inhibitory effect for a limited time period. Actually, insulin promotes amylin aggregation after long-term incubation. Furthermore, we found that this promotional effect could be attributed to the copolymerization of insulin and amylin. We also found that insulin copolymerized with amylin monomer or oligomer rather than preformed amylin fibrils. These results suggest that the interaction between insulin and amylin may contribute not only to the inhibition of amylin aggregation but also to the coaggregation of both peptides in type 2 diabetes. [source]