Substituent and ring effects on enthalpies of formation: 2-methyl- and 2-ethylbenzimidazoles versus benzene-and imidazole-derivatives

The enthalpies of combustion, heat capacities, enthalpies of sublimation and enthalpies of formation of 2-methylbenzimidazole (2MeBIM) and 2-ethylbenzimidazole (2EtBIM) are reported and the results compared with those of benzimidazole itself (BIM). Theoretical estimates of the enthalpies of formation were obtained through the use of atom equivalent schemes. The necessary energies were obtained in single-point calculations at the B3LYP/6-311+G(d,p) on B3LYP/6-31G* optimized geometries. The comparison of experimental and calculated values of benzenes, imidazoles and benzimidazoles bearing H (unsubstituted), methyl and ethyl groups shows remarkable homogeneity. The energetic group contribution transferability is not followed, but either using it or adding an empirical interaction term, it is possible to generate an enormous collection of reasonably accurate data for different substituted heterocycles (pyrazole-derivatives, pyridine-derivatives, etc.) from the large amount of values available for substituted benzenes and those of the parent (pyrazole, pyridine) heterocycles.We acknowledge the financial support of the DGI/MCyT (project nos. BQU-2003-00976, 01251 and 05827). This work has been partially supported by the DGI project no. BQU-2003-00894. A generous allocation of computational time at the CCC of the Universidad Auto´noma de Madrid is also gratefully acknowledged. Thanks are also due to Instituto de Cooperac¸a˜o Cientı´fica e Tecnolo´gica Internacional (ICCTI), Lisbon, Portugal, and Consejo Superior de Investigaciones Cientı´ficas (CSIC), Madrid, Spain, for a joint research project ICCTI/CSIC. MLPFA thanks Fundac¸a˜o para a Cieˆncia e Tecnologia (FCT), Lisbon, Portugal, for the award of a postdoctoral fellowship (PRAXIS XXI/BPD/16319/98) and MT thanks MECD/SEEU (AP 2002-0603), Spain, for financial support

Experimental thermochemical study of two 2-alkylbenzimidazole isomers (alkyl = propyl and isopropyl)

This paper reports the values of the standard (p∘=0.1 MPa) molar enthalpy of formation in the condensed, at T=298.15 K, for 2-R-benzimidazoles (R=propyl, isopropyl), derived from, the respective enthalpies of combustion in oxygen, measured by static bomb combustion calorimetry and the standard molar enthalpies of sublimation, at T=298.15 K, obtained using Calvet microcalorimetry in the case of 2-isopropylbenzimidazole and, by the variation of vapour pressures, determined by the Knudsen effusion technique, with temperatures between (344 and 365) K for 2-propylbenzimidazole. Heat capacities, in the temperature ranges from T=268 K to near their respective melting temperatures, T=421 K for 2-propylbenzimidazole and T=464 K for 2-isopropylbenzimidazole, were measured with a differential scanning calorimeter. These values were used to derive the standard molar enthalpies of formation, of the two 2-benzimidazole derivatives, in gaseous phase.Thanks are due to Instituto de Cooperação Cientı́fica e Tecnológica Industrial (ICCTI), Lisbon, Portugal, and Consejo Superior de Investigaciones Cientı́ficas (CSIC), Madrid, Spain for a joint research project CSIC/ICCTI; M.L.P.F.A. thanks Fundação para a Ciência e Tecnologia (FCT), Lisbon, Portugal, for the award of a postdoctoral fellowship (SRFH/BPD/5595/2001). The Spanish DGI/MCyT is acknowledged under projects BQU2000-0252, 0906 and 1497; M.T. thanks MECD/SEEU, AP2002-0603, Spain for financial support

Substituent effects on enthalpies of formation of nitrogen heterocycles: 2-substituted benzimidazoles and related compounds

The enthalpies of combustion, heat capacities, enthalpies of sublimation and enthalpies of formation of 2-tert-butylbenzimidazole (2tBuBIM) and 2-phenylimidazole (2PhIM) are reported and the results compared with those of benzene derivatives and a series of azoles (imidazoles, pyrazoles, benzimidazoles and indazoles). Theoretical estimates of the enthalpies of formation were obtained through the use of atom equivalent schemes. The necessary energies were obtained in single-point calculations at the B3LYP/6-311++G(d,p) on B3LYP/6-31G* optimized geometries. The comparison of experimental and calculated values of all studied compounds bearing H (unsubstituted), methyl (Me) ethyl (Et), propyl (Pr), isopropyl (iPr), tert-butyl (tBu), benzyl (Bn) and phenyl (Ph) groups show remarkable homogeneity. The remarkable consistency of both the calculated and experimental results allows us to predict with reasonable certainty the missing experimental values. The crystal and molecular structure of the 2-benzylbenzimidazole (2BnBIM) has been determined by X-ray analysis. The observed molecular conformation permits the crystal being built up through N−H···N hydrogen bonds and van der Waals contacts between the molecules. An attempt has been made to relate the crystal structure to the enthalpies of sublimation.Thanks are due to Instituto de Cooperac¸a˜o Cientı´fica e Tecnolo´gica International (ICCTI), Lisbon, Portugal, and Consejo Superior de Investigaciones Cientı´ficas (CSIC), Madrid, Spain. L.M.P.F.A. thanks Fundac¸a˜o para a Cieˆncia e Tecnologia (FCT), Lisbon, Portugal, for the award of a postdoctoral fellowship (PRAXIS XXI/BPD/16319/98). This work has also been financed by DGICYT (BQU-2003- 00894, -00976 and -01251)

Enthalpies of formation of N-substituted pyrazoles and imidazoles

Accurate experimental enthalpies of formation measured using static bomb combustion calorimetry, the “vacuum sublimation” drop calorimetry method, and the Knudsen-effusion method are reported for the first time for four azoles:  1-methylimidazole (1MeIMI), 1-methylpyrazole (1MePYR), 1-benzylimidazole (1BnIMI), and 1-benzylpyrazole (1BnPYR). These values and those corresponding to imidazole (1HIMI), pyrazole (1HPYR), 1-ethylimidazole (1EtIMI), 1-ethylpyrazole (1EtPYR), 1-phenylimidazole (1PhIMI), and 1-phenylpyrazole (1PhPYR) are compared with theoretical values using the G2(MP2) and the B3LYP/6-311*G(3df,2p)//6-31G(d) approaches. In general, there is a very good agreement between calculated and experimental values for the series of N-substituted imidazoles, while the agreement is less good for the series of the N-substituted pyrazoles. Experimentally, the gap between the enthalpies of formation of imidazoles and pyrazoles decreases significantly upon N-substitution, while the theoretical estimates indicate that this decrease is smaller.This work has been partially supported by the DGES Projects PB 96-0001-C03-03, PB96-0067, and PB96-0927-C02-01. A generous allocation of computational time at the Centro de Computacio´n Cientı´fica de la Facultad de Ciencias (CCCFC) de la UAM is also gratefully acknowledged. Thanks are due to Junta National de Investigac¸a˜o Cientı´fica e Tecnolo´gica (JNICT), Lisbon, Portugal and Consejo Superior de Investigaciones Cientı´ficas (CSIC), Madrid, Spain, for a joint research project CSIC/JNICT. Financial support from the Praxis XXI, Project 2/2.1/qui/54/94, is acknowledged. L.M.P.F.A. thanks Fundac¸aˆo para a Cieˆncia e Tecnologia, Lisbon, Portugal for the award of a postdoctoral fellowship (Praxis XXI/BDP/16319/98). J.F.L. acknowledges funding from “Dow Chemical Company” for partial support of his thermochemical studies

The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin

Producción CientíficaRecent preclinical evidence has suggested that Ewing Sarcoma (ES) bearing EWSR1-ETS fusions could be particularly sensitive to PARP inhibitors (PARPinh) in combination with DNA damage repair (DDR) agents. Trabectedin is an antitumoral agent that modulates EWSR1-FLI1 transcriptional functions, causing DNA damage. Interestingly, PARP1 is also a transcriptional regulator of EWSR1-FLI1, and PARPinh disrupts the DDR machinery. Thus, given the impact and apparent specificity of both agents with regard to the DNA damage/DDR system and EWSR1-FLI1 activity in ES, we decided to explore the activity of combining PARPinh and Trabectedin in in vitro and in vivo experiments. The combination of Olaparib and Trabectedin was found to be highly synergistic, inhibiting cell proliferation, inducing apoptosis, and the accumulation of G2/M. The drug combination also enhanced γH2AX intranuclear accumulation as a result of DNA damage induction, DNA fragmentation and global DDR deregulation, while EWSR1-FLI1 target expression remained unaffected. The effect of the drug combination was corroborated in a mouse xenograft model of ES and, more importantly, in two ES patient-derived xenograft (PDX) models in which the tumors showed complete regression. In conclusion, the combination of the two agents leads to a biologically significant deregulation of the DDR machinery that elicits relevant antitumor activity in preclinical models and might represent a promising therapeutic tool that should be further explored for translation to the clinical setting.Ministerio de Economía y Competitividad (PI081828)Ministerio de Economía y Competitividad (RD06/0020/0059 )Ministerio de Economía y Competitividad (RD12/0036/0017)Ministerio de Economía y Competitividad (PT13/0010/0056

Genetic and Non-genetic Predictors of LINE-1 Methylation in Leukocyte DNA.

Background: Altered DNA methylation has been associated with various diseases. Objective: We evaluated the association between levels of methylation in leukocyte DNA at long interspersed nuclear element 1 (LINE-1) and genetic and non-genetic characteristics of 892 control participants from the Spanish Bladder Cancer/EPICURO study. Methods: We determined LINE-1 methylation levels by pyrosequencing. Individual data included demographics, smoking status, nutrient intake, toenail concentrations of 12 trace elements, xenobiotic metabolism gene variants, and 515 polymorphisms among 24 genes in the one-carbon metabolism pathway. To assess the association between LINE-1 methylation levels (percentage of methylated cytosines) and potential determinants, we estimated beta coefficients (βs) by robust linear regression. Results: Women had lower levels of LINE-1 methylation than men (β = –0.7, p = 0.02). Persons who smoked blond tobacco showed lower methylation than nonsmokers (β = –0.7, p = 0.03). Arsenic toenail concentration was inversely associated with LINE-1 methylation (β = –3.6, p = 0.003). By contrast, iron (β = 0.002, p = 0.009) and nickel (β = 0.02, p = 0.004) were positively associated with LINE-1 methylation. Single nucleotide polymorphisms (SNPs) in DNMT3A (rs7581217-per allele, β = 0.3, p = 0.002), TCN2 (rs9606756-GG, β = 1.9, p = 0.008; rs4820887-AA, β = 4.0, p = 4.8 × 10–7; rs9621049-TT, β = 4.2, p = 4.7 × 10–9), AS3MT (rs7085104-GG, β = 0.7, p = 0.001), SLC19A1 (rs914238, TC vs. TT: β = 0.5 and CC vs. TT: β = –0.3, global p = 0.0007) and MTHFS (rs1380642, CT vs. CC: β = 0.3 and TT vs. CC; β = –0.8, global p = 0.05) were associated with LINE-1 methylation. Conclusions: We identified several characteristics, environmental factors, and common genetic variants that predicted DNA methylation among study participants.This work was partially supported by the Association for International Cancer Research (AICR; grant 09-0780, and a doctoral scholarship awarded to S.M.T.); Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, MINECO, Spain (grants 00/0745, PI051436, PI061614, PI09-02102, and G03/174); Red Temática de Investigación Cooperativa en Cáncer (grant RD06/0020-RTICC); the U.S. National Institutes of Health (grant RO1-CA089715); a postdoctoral fellowship awarded to A.F.S.A. from the Fundación Científica de la AECC; Fundació Marató TV3; and The Johns Hopkins University Vredenburg Scholarship awarded to A.L.C

Imperios ibéricos en comarcas americanas. Estudios regionales de historia colonial brasilera y neogranadina

Una de las principales preocupaciones de la historiografía de America Latina ha sido entender las similitudes y diferencias existentes entre las sociedades hispanohablantes y las lusohablantes del continente. Habitualmente, junto a la afirmación de que ambas Américas son herederas de las mismas tradiciones fundamentales la africana, la ibérica y las precolombinas-, se insiste en sus diferencias estructurales y se subrayan los matices de sus similitudes. De esta manera, semejanzas y contrastes se contraponen permanentemente, produciendo un juego en el que los objetos investigados las America española y la portuguesa- se acercan y se distancian, generando entre ellos cordeles que se prolongan y se envuelven, para crear ese lienzo que es la historia de America Latina. Los artículos que componen este libro dibujan parte de este tapiz e ilustran cómo los espacios locales se integran en una órbita imperial clara y manifiesta, que ejerció presión sobre las personas que componían cada sociedad.No obstante, éstas construían realidades a partir de sus propios intereses y posibilidades, que respondían a un contexto regional específico

Climate change facilitated the early colonization of the Azores Archipelago during medieval times

Humans have made such dramatic and permanent changes to Earth's landscapes that much of it is now substantially and irreversibly altered from its preanthropogenic state. Remote islands, until recently isolated from humans, offer insights into how these landscapes evolved in response to human-induced perturbations. However, little is known about when and how remote systems were colonized because archaeological data and historical records are scarce and incomplete. Here, we use a multiproxy approach to reconstruct the initial colonization and subsequent environmental impacts on the Azores Archipelago. Our reconstructions provide unambiguous evidence for widespread human disturbance of this archipelago starting between 700 -60/+50 and 850 -60/+60 Common Era (CE), ca. 700 y earlier than historical records suggest the onset of Portuguese settlement of the islands. Settlement proceeded in three phases, during which human pressure on the terrestrial and aquatic ecosystems grew steadily (i.e., through livestock introductions, logging, and fire), resulting in irreversible changes. Our climate models suggest that the initial colonization at the end of the early Middle Ages (500 to 900 CE) occurred in conjunction with anomalous northeasterly winds and warmer Northern Hemisphere temperatures. These climate conditions likelyinhibited exploration from southern Europe and facilitated human settlers from the northeast Atlantic. These results are consistent with recent archaeological and genetic data suggesting that the Norse were most likely the earliest settlers on the islands

23 CHARGE consortium, Institutes of Health, Department of Health and Human Services

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