Discovery of dihydroquinoxalinone acetamides containing bicyclic amines as potent Bradykinin B1 receptor antagonists

Replacement of the core beta-amino acid in our previously reported piperidine acetic acid and beta-phenylalanine-based Bradykinin B1 antagonists by dihydroquinoxalinone acetic acid increases the in vitro potency and metabolic stability. The most potent compounds from this series have IC(50)s<0.2 nM in a human B1 receptor functional assay. A molecular modeling study of the binding modes of key compounds, based on a B1 homology model, explains the structure-activity relationship (SAR) for these analogs.     

Matrix GLA protein, an inhibitory morphogen in pulmonary vascular development

Deficiency of matrix GLA protein (MGP), an inhibitor of bone morphogenetic protein (BMP)-2/4, is known to cause arterial calcification and peripheral pulmonary artery stenosis. Yet the vascular role of MGP remains poorly understood. To further investigate MGP, we created a new MGP transgenic mouse model with high expression of the transgene in the lungs. The excess MGP led to a disruption of the pulmonary pattern of BMP-4, and resulted in significant morphological defects in the pulmonary artery tree. Specifically, the vascular branching pattern lacked characteristic side branching, whereas control lungs had extensive side branching accounting for as much as 40% of the vascular endothelium. The vascular changes could be explained by a dramatic reduction of phosphorylated SMAD1/5/8 in the alveolar epithelium, and in epithelial expression of the activin-like kinase receptor 1 and vascular endothelial growth factor, both critical in vascular formation. Abnormalities were also found in the terminal airways and in lung cell differentiation; high levels of surfactant protein-B were distributed in an abnormal pattern suggesting lost coordination between vasculature and airways. Ex vivo, lung cells from MGP transgenic mice showed higher proliferation, in particular surfactant protein B-expressing cells, and conditioned medium from these cells poorly supported in vitro angiogenesis compared with normal lung cells. The vascular branching defect can be mechanistically explained by a computational model based on activator/inhibitor reaction-diffusion dynamics, where BMP-4 and MGP are considered as an activating and inhibitory morphogen, respectively, suggesting that morphogen interactions are important for vascular branching.     

Inhibition of fungal and bacterial plant pathogens in vitro and in planta with ultrashort cationic lipopeptides

Plant diseases constitute an emerging threat to global food security. Many of the currently available antimicrobial agents for agriculture are highly toxic and nonbiodegradable and cause extended environmental pollution. Moreover, an increasing number of phytopathogens develop resistance to them. Recently, we have reported on a new family of ultrashort antimicrobial lipopeptides which are composed of only four amino acids linked to fatty acids (A. Makovitzki, D. Avrahami, and Y. Shai, Proc. Natl. Acad. Sci. USA 103:15997-16002, 2006). Here, we investigated the activities in vitro and in planta and the modes of action of these short lipopeptides against plant-pathogenic bacteria and fungi. They act rapidly, at low micromolar concentrations, on the membranes of the microorganisms via a lytic mechanism. In vitro microscopic analysis revealed wide-scale damage to the microorganism's membrane, in addition to inhibition of pathogen growth. In planta potent antifungal activity was demonstrated on cucumber fruits and leaves infected with the pathogen Botrytis cinerea as well as on corn leaves infected with Cochliobolus heterostrophus. Similarly, treatment with the lipopeptides of Arabidopsis leaves infected with the bacterial leaf pathogen Pseudomonas syringae efficiently and rapidly reduced the number of bacteria. Importantly, in contrast to what occurred with many native lipopeptides, no toxicity was observed on the plant tissues. These data suggest that the ultrashort lipopeptides could serve as native-like antimicrobial agents economically feasible for use in plant protection.     

3H-[1,2,4]-Triazolo[5,1-i]purin-5-amine derivatives as adenosine A2A antagonists

A novel series of 3-substituted-8-aryl-[1,2,4]-triazolo[5,1-i]purin-5-amine analogs related to Sch 58261 was synthesized in order to identify potent adenosine A(2A) receptor antagonists with improved selectivity over the A(1) receptor, physiochemical properties, and pharmacokinetic profiles as compared to those of Sch 58261. As a result of structural modifications, numerous analogs with excellent in vitro binding affinities and selectivities were identified. Moreover, compound 27 displayed both superior in vitro and highly promising in vivo profiles.     

Potent, selective, and orally active adenosine A2A receptor antagonists: arylpiperazine derivatives of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines

Antagonism of the adenosine A2A receptor offers great promise in the treatment of Parkinson's disease. Employing the known pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A2A antagonist SCH 58261 as a starting point, we identified the potent and selective (vs. A1) antagonist 11h, orally active in the rat haloperidol-induced catalepsy model. We further optimized this lead to the methoxyethoxyethyl ether 12a (SCH 420814), which shows broad selectivity, good pharmacokinetic properties, and excellent in vivo activity.     

Polarization Insensitive and Broadband Terahertz Absorber Using Graphene Disks

Plasmonics - We demonstrate design and characterization of a polarization-independent ultra-broadband absorber of light consisting of periodic array of graphene disks on top of a lossless...     

The earliest steps in hepatitis B virus infection

The early steps in hepatitis B virus (HBV) infection, a human hepadnavirus, initiates from cell attachment followed by entry and delivery of the genetic information to the nucleus. Despite the fact that these steps determine the virus-related pathogenesis, their molecular basis is poorly understood. Cumulative data suggest that this process can be divided to cell attachment, endocytosis, membrane fusion and post-fusion consecutive steps. These steps are likely to be regulated by the viral envelope proteins and by the cellular membrane, receptors and extracellular matrix. In the absence of animal model for HBV, the duck hepadnavirus DHBV turned out to be a fruitful animal model. Therefore data concerning the early, post-attachment steps in hepadnaviral entry are largely based on studies performed with DHBV in primary duck liver hepatocytes. These studies are now starting to illuminate the mechanisms of hepadnavirus route of cell entry and to provide some new insights on the molecular basis of the strict species specificity of hepadnavirus infection.     

Chromenones as potent bradykinin B1 antagonists

A series of fused 6,6-bicyclic chromenones was investigated for activity against the bradykinin B1 receptor. SAR studies based on a pharmacophore model revealed compounds with high affinity for both human and rabbit B1. These compounds demonstrated favorable pharmacokinetic properties and 5-chlorochromenone 15 was efficacious in a carrageenan-induced mechanical hyperalgesia model for chronic pain.     

Proximate and Elemental Composition of <Emphasis Type="Italic">Chamelea gallina</Emphasis> from the Southern Coast of the Marmara Sea (Turkey)

The venerid clam Chamelea gallina is a popular and economic foodstuff around the Mediterranean countries especially in Italy, Spain, and France. The aim of this study is to evaluate the nutritional quality of striped venus of Southern Marmara. Samples were harvested seasonally at five stations and analyzed to determine meat yield, proximate, and elemental composition. According to the results, meat yield ranged from 20.24% to 29.94%. Means of water, protein, lipid, and ash content were 67%, 10.12%, 2.57%, and 1.66%, respectively. The mean concentrations (mg/kg wet weight) of elements in tissues are as follows: B: 2.37–4.24; Cr: 0–0.76; Co: 0–0.43; Cu: 0.71–5.30; Mn: 0.30–5.94; Zn: 13.08–77.76; Ni: 0–1.22; Fe: 2.46–114.22; Al: 1.23–75.49; Pb: 0.18–3.24; Ba: 0.66–15.97; Cd: 0.04–0.69. Among the reported metal levels, only Pb and Zn in two stations exceeded the maximum critical concentrations enforced by Turkish legislation and European Commission. Therefore, we report that striped venus from Southern Marmara Sea, in general, are safe for human consumption; nonetheless, Pb and Zn levels should be closely monitored in the future.