1-Aryl-3-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas as potential inhibitors of VEGFR-2: synthesis and molecular modelling studies

Angiogenesis is a requirement for tumor growth and metastasis and occurs through several signalling pathways. One key pathway that initiates proliferation and migration of endothelial cells is signalling through the vascular endothelial growth factor receptor-2 (VEGFR-2).1 Therefore, small molecules that block this signalling pathway through inhibition of the VEGFR tyrosine kinase activity could potentially inhibit angiogenesis and tumour growth. Recently works describing thienopyrimidines2 and thienopyridine ureas3 as inhibitors of VEGFR-2 have appeared in the literature. Here we present the synthesis of new 1,3-diarylureas 2 starting by regioselective nucleophilic substitution of the 4-chlorothieno[3,2-d]pyrimidine with 4-aminophenol to obtain 4-(thieno[3,2-d]pyridin-4-yloxy)aniline 1 which reacts with different arylisocyanate

1-aryl-3-(4-(7-methylthieno[3,2-d]pyrimidin-4-yloxy)phenyl)ureas: synthesis and molecular modelling studies using VEGFR-2

The development of anticancer drugs inhibiting angiogenesis has been an area of extensive research in the past decade. Angiogenesis is a requirement for tumor growth and metastasis and occurs through several signalling pathways. One key pathway that initiates proliferation and migration of endothelial cells is signalling through the vascular endothelial growth factor receptor-2 (VEGFR-2).1 Therefore, small molecules that block this signalling pathway through inhibition of VEGFR-2 tyrosine kinase activity could potentially inhibit angiogenesis and tumor growth. Recently works describing thienopyrimidine2 and thienopyrimidine 1,3-diarylureas3 as VEGFR-2 inhibitors have emerged in the literature. Here we present the synthesis of new 1-aryl-3-(4-(7-methylthieno[3,2-d]pyrimidin-4-yloxy)phenyl)ureas 2 in high yields by reaction of 4-[(7-methylthieno[3,2-d]pyridin-4-yl)oxy]aniline 1 with arylisocyanates. The former was prepared by regioselective nucleophilic substitution of 4-chloro-7-methylthieno[3,2-d]pyrimidine with 4-aminopheno

NEW SEISMIC SOURCE ZONE MODEL FOR PORTUGAL AND AZORES

The development of seismogenic source models is one of the first steps in seismic hazard assessment. In seismic hazard terminology, seismic source zones (SSZ) are polygons (or volumes) that delineate areas with homogeneous characteristics of seismicity. The importance of using knowledge on geology, seismicity and tectonics in the definition of source zones has been recognized for a long time [1]. However, the definition of SSZ tends to be subjective and controversial. Using SSZ based on broad geology, by spreading the seismicity clusters throughout the areal extent of a zone, provides a way to account for possible long-term non-stationary seismicity behavior [2,3]. This approach effectively increases seismicity rates in regions with no significant historical or instrumental seismicity, while decreasing seismicity rates in regions that display higher rates of seismicity. In contrast, the use of SSZ based on concentrations of seismicity or spatial smoothing results in stationary behavior [4]. In the FP7 Project SHARE (Seismic Hazard Harmonization in Europe), seismic hazard will be assessed with a logic tree approach that allows for three types of branches for seismicity models: a) smoothed seismicity, b) SSZ, c) SSZ and faults. In this context, a large-scale zonation model for use in the smoothed seismicity branch, and a new consensus SSZ model for Portugal and Azores have been developed. The new models were achieved with the participation of regional experts by combining and adapting existing models and incorporating new regional knowledge of the earthquake potential. The main criteria used for delineating the SSZ include distribution of seismicity, broad geological architecture, crustal characteristics (oceanic versus continental, tectonically active versus stable, etc.), historical catalogue completeness, and the characteristics of active or potentially-active faults. This model will be integrated into an Iberian model of SSZ to be used in the Project SHARE seismic hazard assessment

COMPILATION OF ACTIVE FAULT DATA IN PORTUGAL FOR USE IN SEISMIC HAZARD ANALYSIS

To estimate where future earthquakes are likely to occur, it is essential to combine information about past earthquakes with knowledge about the location and seismogenic properties of active faults. For this reason, robust probabilistic seismic hazard analysis (PSHA) integrates seismicity and active fault data. Existing seismic hazard assessments for Portugal rely exclusively on seismicity data and do not incorporate data on active faults. Project SHARE (Seismic Hazard Harmonization in Europe) is an EC-funded initiative (FP7) that aims to evaluate European seismic hazards using an integrated, standardized approach. In the context of SHARE, we are developing a fully-parameterized active fault database for Portugal that incorporates existing compilations, updated according to the most recent publications. The seismogenic source model derived for SHARE will be the first model for Portugal to include fault data and follow an internationally standardized approach. This model can be used to improve both seismic hazard and risk analyses and will be combined with the Spanish database for use in Iberian- and European-scale assessments

Exposure to Leishmania braziliensis triggers neutrophil activation and apoptosis.

BACKGROUND: Neutrophils are the first line of defense against invading pathogens and are rapidly recruited to the sites of Leishmania inoculation. During Leishmania braziliensis infection, depletion of inflammatory cells significantly increases the parasite load whereas co-inoculation of neutrophils plus L. braziliensis had an opposite effect. Moreover, the co-culture of infected macrophages and neutrophils also induced parasite killing leading us to ask how neutrophils alone respond to an L. braziliensis exposure. Herein we focused on understanding the interaction between neutrophils and L. braziliensis, exploring cell activation and apoptotic fate. METHODS AND FINDINGS: Inoculation of serum-opsonized L. braziliensis promastigotes in mice induced neutrophil accumulation in vivo, peaking at 24 h. In vitro, exposure of thyoglycollate-elicited inflammatory or bone marrow neutrophils to L. braziliensis modulated the expression of surface molecules such as CD18 and CD62L, and induced the oxidative burst. Using mCherry-expressing L. braziliensis, we determined that such effects were mainly observed in infected and not in bystander cells. Neutrophil activation following contact with L. braziliensis was also confirmed by the release of TNF-α and neutrophil elastase. Lastly, neutrophils infected with L. braziliensis but not with L. major displayed markers of early apoptosis. CONCLUSIONS: We show that L. braziliensis induces neutrophil recruitment in vivo and that neutrophils exposed to the parasite in vitro respond through activation and release of inflammatory mediators. This outcome may impact on parasite elimination, particularly at the early stages of infection

Modification of the ground state in Sm-Sr manganites by oxygen isotope substitution

The effect of $^{16}$O $\to$ $^{18}$O isotope substitution on electrical resistivity and magnetic susceptibility of Sm$_{1-x}$Sr$_x$MnO$_3$ manganites is analyzed. It is shown that the oxygen isotope substitution drastically affects the phase diagram at the crossover region between the ferromagnetic metal state and that of antiferromagnetic insulator (0.4 $< x <$ 0.6), and induces the metal-insulator transition at for $x$ = 0.475 and 0.5. The nature of antiferromagnetic insulator phase is discussed.Comment: 4 pages, 3 eps figures, RevTeX, submitted to Phys. Rev. Let

Bulk-sensitive photoemission spectroscopy of A_2FeMoO_6 double perovskites (A=Sr, Ba)

Electronic structures of Sr_2FeMoO_6 (SFMO) and Ba_2FeMoO_6 (BFMO) double perovskites have been investigated using the Fe 2p->3d resonant photoemission spectroscopy (PES) and the Cooper minimum in the Mo 4d photoionization cross section. The states close to the Fermi level are found to have strongly mixed Mo-Fe t_{2g} character, suggesting that the Fe valence is far from pure 3+. The Fe 2p_{3/2} XAS spectra indicate the mixed-valent Fe^{3+}-Fe^{2+} configurations, and the larger Fe^{2+} component for BFMO than for SFMO, suggesting a kind of double exchange interaction. The valence-band PES spectra reveal good agreement with the LSDA+U calculation.Comment: 4 pages, 3 figure

Incorporating Descriptive Metadata into Seismic Source Zone Models for Seismic Hazard Assessment: A case study of the Azores-West Iberian region

In probabilistic seismic-hazard analysis (PSHA), seismic source zone (SSZ) models are widely used to account for the contribution to the hazard from earth- quakes not directly correlated with geological structures. Notwithstanding the impact of SSZ models in PSHA, the theoretical framework underlying SSZ models and the criteria used to delineate the SSZs are seldom explicitly stated and suitably docu- mented. In this paper, we propose a methodological framework to develop and docu- ment SSZ models, which includes (1) an assessment of the appropriate scale and degree of stationarity, (2) an assessment of seismicity catalog completeness-related issues, and (3) an evaluation and credibility ranking of physical criteria used to delin- eate the boundaries of the SSZs. We also emphasize the need for SSZ models to be supported by a comprehensive set of metadata documenting both the unique character- istics of each SSZ and the criteria used to delineate its boundaries. This procedure ensures that the uncertainties in the model can be properly addressed in the PSHA and that the model can be easily updated whenever new data are available. The pro- posed methodology is illustrated using the SSZ model developed for the Azores–West Iberian region in the context of the Seismic Hazard Harmonization in Europe project (project SHARE) and some of the most relevant SSZs are discussed in detail