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 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)

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

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

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

Neudesin is involved in anxiety behavior: structural and neurochemical correlates

Neudesin (also known as neuron derived neurotrophic factor, Nenf) is a scarcely studied putative non-canonical neurotrophic factor. In order to understand its function in the brain, we performed an extensive behavioral characterization (motor, emotional, and cognitive dimensions) of neudesin-null mice. The absence of neudesin leads to an anxious-like behavior as assessed in the elevated plus maze (EPM), light/dark box (LDB) and novelty suppressed feeding (NSF) tests, but not in the acoustic startle (AS) test. This anxious phenotype is associated with reduced dopaminergic input and impoverished dendritic arborizations in the dentate gyrus granule neurons of the ventral hippocampus. Interestingly, shorter dendrites are also observed in the bed nucleus of the stria terminalis (BNST) of neudesin-null mice. These findings lead us to suggest that neudesin is a novel relevant player in the maintenance of the anxiety circuitry.This work is supported by a grant from FCT (PTDC/SAU-OSM/104475/2008) under POCTI-COMPETE funds. Ashley Novais, Ana Catarina Ferreira, Ana David-Pereira and Filipa L. Campos are recipients of doctoral fellowships and Fernanda Marques is a recipient of postdoctoral fellowship from Fundacao para a Ciencia e Tecnologia (FCT), Portugal. We acknowledge Merck Serono for providing the neudesin-null mouse strain. We are thankful to Despina Papasava and Vasileios Kafetzopoulos for the assistance given in the HPLC analysis of neurotransmitters

La experiencia de importacion de equipos para investigacion en el ELSA-Brasil

OBJETIVO: Políticas de fomento à pesquisa em saúde foram estabelecidas na última década, avançando a produção científica nacional. Tal movimento não foi acompanhado do aperfeiçoamento do arcabouço legal-institucional, dificultando o desenvolvimento dos projetos de pesquisa. Isso inclusive no que tange às atividades de importação de equipamentos. O objetivo deste artigo foi analisar o processo de importação de equipamentos para o Estudo Longitudinal de Saúde do Adulto (ELSA-Brasil). MÉTODOS: Trata-se de estudo de caso, com dados coletados em documentos internos do ELSA-Brasil em cinco Centros de Investigação e respectivas fundações de apoio. Foram analisados documentos de importação de: velocidade de onda de pulso, bioimagem e retinografia. Adicionalmente, foram realizadas entrevistas não estruturadas com pesquisadores e informantes chave nas fundações. Os dados foram tratados e organizados em três etapas: administrativa-operacional, cambial e fiscal. Foram calculados os intervalos de duração dessas etapas de modo comparativo entre os centros. RESULTADOS: A necessidade de padronização dos equipamentos em estudo multicêntrico exigiu atuação conjunta de instituições executoras e fundações. Dos equipamentos analisados, a primeira etapa, a administrativa-operacional, teve duração variada (mínimo 8 e máximo de 101, com média de 55 dias), sendo mais demorada quando incluía pareceres jurídicos. A segunda etapa, a cambial, mais longa que a primeira, não apresentou entraves ao processo (mínimo 11 e máximo 381, média de 196 dias). A terceira etapa, a fiscal, foi a mais longa (mínimo 43 e máximo 388 dias, média de 215,5 dias), devido à liberação dos equipamentos sem registro no País. Outros fatores que representaram entraves: inexperiência dos centros de investigação e das instituições em trabalhar em rede; inadequação da legislação nacional às especificidades da pesquisa científica; e falta de profissionais especializados em gestão de projeto científico. CONCLUSÕES: Os resultados mostram morosidade no processo de importação de equipamentos para pesquisa no Brasil, devido, especialmente, a entraves de ordem legal, burocrática e gerencial.OBJECTIVE: Policies that promote research in health were established in the last decade, developing the Brazilian scientific production. This development has not been accompanied by an improvement in the legal-institutional framework, thus hindering the development of research projects, including equipment importation activities. The present study aimed to analyze the equipment importation process for the Brazilian Longitudinal Study for Adult Health (ELSA-Brasil). METHODS: A case study was performed with data collected from internal ELSA-Brasil documents in five Investigation Centers and their respective supporting foundations. The following importation documents were analyzed: pulse wave velocity, bioimaging and retinography. Additionally, non-structured interviews with researchers and key informers were conducted in the foundations. Data were treated and organized into three stages: administrative-operational, exchange rate, and fiscal. Lengths of duration of these stages were calculated comparatively among centers. RESULTS: The need to standardize equipment in a multicenter study required a joint action of implementing institutions and foundations. Of all pieces of equipment analyzed, the first stage was administrative-operational, with a varying duration (minimum of eight, maximum of 101, and mean of 55 days) which was longer when legal opinions were included. The second stage was the exchange rate, which was longer than the former and did not pose any obstacles to the process (minimum of 11, maximum of 381, and mean of 196 days). The third stage was fiscal, which was the longest one (minimum of 43, maximum of 388, and mean of 215.5 days), due to the release of equipment without registration into the country. There were other factors that posed obstacles: inexperience of investigation centers and institutions in networking; inadequacy of the national legislation on scientific research particularities; and the lack of specialized professionals in scientific project management. CONCLUSIONS: The results show the slowness of the equipment importation process in Brazil, especially due to legal, bureaucratic and managerial obstacles