Synthesis of novel benzofurocoumarin analogues and their anti-proliferative effect on human cancer cell lines

The synthesis of five new tetracyclic benzofurocoumarin (benzopsoralen) analogues is described. Their inhibitory effects on the growth of three human tumour cell lines (MDA MB 231 (breast adenocarcinoma), HeLa (cervix adenocarcinoma) and TCC-SUP (bladder transitional cell carcinoma)) were evaluated, and discussed in terms of structure–activity relationship.FCT and FEDER, for National NMR Network (Bruker Avance II 400), REEQ/630/QUI/2005 (LC/MS instrument) and the PhD grant (SFRH/BD/48636/2008)

Gravitational lens effect of a holonomy corrected Schwarzschild black hole

In this paper we study the gravitational lensing effect for the Schwarzschild solution with holonomy corrections. We use two types of approximation methods to calculate the deflection angle, namely the weak and strong field limits. For the first method, we calculate the deflection angle up to the fifth order of approximation and show the influence of the parameter $\lambda$ (in terms of loop quantum gravity) on it. In addition, we construct expressions for the magnification, the position of the lensed images and the time delay as functions of the coefficients from the deflection angle expansion. We find that $\lambda$ increases the deflection angle. In the strong field limit, we use a logarithmic approximation to compute the deflection angle. We then write four observables, in terms of the coefficients $b_1$, $b_2$ and $u_m$, namely: the asymptotic position approached by a set of images $\theta_{\infty}$, the distance between the first image and the others $s$, the ratio between the flux of the first image and the flux of all other images $r_m$, and the time delay between two photons $\Delta T_{2,1}$. We then use the experimental data of the black hole Sagittarius $A^{\star}$ and calculate the observables and the coefficients of the logarithmic expansion. We find that the parameter $\lambda$ increases the deflection angle, the separation between the lensed images and the delay time between them. In contrast, it decreases the brightness of the first image compared to the others.Comment: 26 pages, 17 figure

Synthesis of novel psoralen analogues and in vitro antitumor activity

Psoralens are natural products present in several plant families that are extremely toxic to a wide variety of prokaryotic and eukaryotic organisms. They are potentially active in diseases such as vitiligo, psoriasis, and several types of cancer. Following our interest on this type of compounds 1 four new psoralen analogues were prepared, 1a-1c and 1e. To synthesize 1a (R = H) the method of Harayama and Ishii was used where the cinnamate was obtained by the Wittig reaction followed by ring closure. Condensation of 1-formyl-2-hydroxycarbazole with diethyl malonate gave 1b which by basic hydrolysis yielded compound 1c. Compound 1d was prepared before.2 Condensation of the 2-hydroxycarbazole with ethyl acetoacetate gave 1e. The products were characterized by elemental analysis, 1H and 13C NMR. Moreover, the anti-proliferative effect of compounds 1a-1e on human cancer cell lines (MDA-MB 231, HeLa and TCCSUP) was evaluated. Results suggest that these psoralen analogues possess a potent cytotoxic effect against the cell lines studied. Computational and molecular docking studies are being carried out.Fundação para a Ciência e a Tecnologia (FCT)(PEst-C/QUI/UI0686/2011), FEDER-COMPET

Synthesis of novel psoralen analogues derived from 7-hydroxy-4-methylcoumarin

Fundação para a Ciência e a Tecnologia (FCT) FEDER (European Fund for Regional Development)-COMPETE-QREN-EU FCOMP-01-0124-FEDER-022716FEDER (European Fund for Regional Development)-COMPETE-QREN-EU FCOMP-01-0124-FEDER-02271

Synthesis of novel psoralen analogues and their in vitro antitumor activity

New tetracyclic benzofurocoumarin (benzopsoralen) analogues were synthesized and their inhibitory effect on the growth of tumor cell lines was evaluated. The human tumor cell lines used were MDA MB231 (breast adenocarcinoma), HeLa (cervix adenocarcinoma) and TCC-SUP (bladder transitional cell carcinoma). The in vitro antitumor activity of the new benzopsoralens was discussed in terms of structure–activity relationship. Molecular docking studies with human-CYP2A6 enzymes were also carried out with the synthesized compounds in order to evaluate the potential of these compounds to interact with the heme group of the enzymes. The results have demonstrated that the linear compounds have the most pronounced activity against tumor cell lines and this might be related to the better accessibility that these compounds have to the active site in relation to the angular ones that have shown in the majority of the cases multiple binding poses in the active site of CYP2A6.To the Foundation for the Science and Technology (FCT, Portugal) for financial support to the NMR portuguese network (PTNMR, Bruker Avance III 400-Univ. Minho). FCT and FEDER (European Fund for Regional Development)-COMPETE-QREN-EU for financial support to the Research Centre, CQ/UM [PEst-C/QUI/UI0686/2011 (FCOMP-01-0124-FEDER-022716)], (Pest-C/EQB/LA0006/2011) and the PhD grant to C.S.F. (SFRH/BD/48636/2008). The authors also acknowledge the Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP, Porto, Portugal) for kindly providing the breast cancer cell line used in this work

Quasivariational solutions for first order quasilinear equations with gradient constraint

We prove the existence of solutions for an evolution quasi-variational inequality with a first order quasilinear operator and a variable convex set, which is characterized by a constraint on the absolute value of the gradient that depends on the solution itself. The only required assumption on the nonlinearity of this constraint is its continuity and positivity. The method relies on an appropriate parabolic regularization and suitable {\em a priori} estimates. We obtain also the existence of stationary solutions, by studying the asymptotic behaviour in time. In the variational case, corresponding to a constraint independent of the solution, we also give uniqueness results

Expressão e distribuição da conexina 32 em fígados de ratos com fibrose induzida experimentalmente

The connexin 32 (Cx32) is a protein that forms the channels that promote the gap junction intercellular communication (GJIC) in the liver, allowing the diffusion of small molecules through cytosol from cell-to-cell. Hepatic fibrosis is characterized by a disruption of normal tissue architeture by cellular lesions, and may alter the GJIC. This work aimed to study the expression and distribution of Cx32 in liver fibrosis induced by the oral administration of dimethylnitrosamine in female Wistar rats. The necropsy of the rats was carried out after five weeks of drug administration. They presented a hepatic fibrosis state. Sections from livers with fibrosis and from control livers were submitted to immunohistochemical, Real Time-PCR and Western-Blot analysis to Cx32. In fibrotic livers the Cxs were diffusely scattered in the cytoplasm, contrasting with the control livers, where the Cx32 formed junction plaques at the cell membrane. Also it was found a decrease in the gene expression of Cx32 without reduction in the protein quantity when compared with controls. These results suggest that there the mechanism of intercellular communication between hepatocytes was reduced by the fibrotic process, which may predispose to the occurrence of a neoplastic process, taken in account that connexins are considered tumor suppressing genes.A conexina 32 (Cx32) é uma proteína que constitui os canais que promovem as comunicações intercelulares via junções comunicantes (CIJC) no fígado, permitindo difusão de pequenas moléculas citoplasmáticas de uma célula à outra. A fibrose hepática caracteriza-se pela alteração da arquitetura normal do fígado e podem alterar as CIJCs. O objetivo deste trabalho foi estudar a expressão e distribuição de Cx32 na fibrose hepática. O objetivo do presente trabalho foi estudar a expressão e distribuição da Cx32 em fígados com fibrose induzida pela administração oral de dimetilnitrosamina em fêmeas de ratos Wistar. A necropsia foi realizada após cinco semanas da última administração da droga e observou-se um quadro de fibrose hepática. Amostras dos fígados com fibrose e de animais controle foram submetidas à análise imunoistoquímica, por Real Time-PCR e por Western-Blot verificando-se a presença de Cx32 difusa e dispersa no citoplasma dos fígados com fibrose. No grupo controle a Cx32 localizou-se na membrana citoplasmática com a formação de placas juncionais. O fígado com fibrose também revelou diminuição da expressão gênica de Cx32, embora sem a redução da quantidade do produto protéico, quando comparado ao grupo controle. Estes resultados sugerem que o mecanismo de comunicação intercelular entre os hepatócitos reduziu-se durante o processo fibrótico, o que pode predispor a ocorrência de processos neoplásicos, uma vez que as conexinas são consideradas genes supressores de tumores.FAPESPCNP

Novel benzopsoralen analogues : synthesis, biological activity and molecular docking studies

New benzopsoralen analogues were synthesized and their inhibitory effect on the growth of tumourtumour cell lines (MDA MB231 and TCC-SUP) was evaluated. The in vitro antitumour activity of the new benzopsoralen analogues was discussed in terms of structure–activity relationship. Molecular docking studies with human-CYP2A6 enzymes were also carried out with the synthesized compounds to evaluate the potential of these molecules to interact with the haem group of the enzymes. The results demonstrated that the compounds that are able to interact with the iron ion of the haem cofactor and at the same time with active site Asn297 are those that have better anti-proliferative activity.To the Foundation for the Science and Technology (FCT, Portugal) for financial support to the NMR Portuguese network (PTNMR, Bruker Avance III 400-Univ. Minho). FCT and FEDER (European Fund for Regional Development)-COMPETE-QREN-EU for financial support to the Chemistry Research Centre, CQ/UM [PEst-C/QUI/UI0686/2011 (FCOMP-01-0124-FEDER-022716)], to REQUIMTE (PEst-C/EQB/LA0006/2011), to the Centre of Biological Engineering (PEst-OE/EQB/LA0023/2013) and the PhD grant to C.S.F. (SFRH/BD/48636/2008). The authors also acknowledge the Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP, Porto, Portugal) for kindly providing the breast cancer cell lines used in this work

Combined effects from γ radiation and fluoranthene exposure on carbon transfer from phytoplankton to zooplankton

Risk assessment does not usually take into account mixtures of contaminants, thus potentially under- or overestimating environmental effects. We investigated how the transfer of carbon between a primary producer, Pseudokirchneriella subcapitata, and a consumer, Daphnia magna, is affected by acute exposure of γ radiation (GR) in combination with the polycyclic aromatic hydrocarbon fluoranthene (FA). We exposed D. magna to five concentrations of FA and five acute doses of GR as single contaminants and in nine binary combinations. We compared the observed data for three end points (incorporation of carbon by D. magna, D. magna ingestion rates, and growth) to the predicted joint effects of the mixed stressors based on the independent action (IA) concept. There were deviations from the IA predictions, especially for ingestion rates and carbon incorporation by D. magna, where antagonistic effects were observed at the lower doses, while synergism was seen at the highest doses. Our results highlight the importance of investigating the effects of exposure to GR in a multistressor context. In mixtures of GR and FA, the IA-predicted effects seem to be conservative as antagonism between the two stressors was the dominant pattern, possibly due to stimulation of cellular antioxidative stress mechanisms