Structural And Chemical Basis For Anticancer Activity Of A Series Of β-tubulin Ligands: Molecular Modeling And 3d Qsar Studies

An important approach to cancer therapy is the design of small molecule modulators that interfere with microtubule dynamics through their specific binding to the β-subunit of tubulin. In the present work, comparative molecular field analysis (CoMFA) studies were conducted on a series of discodermolide analogs with antimitotic properties. Significant correlation coefficients were obtained (CoMFA(i), q2 = 0.68, r2 = 0.94; CoMFA(ii), q2 = 0.63, r2 = 0.91), indicating the good internal and external consistency of the models generated using two independent structural alignment strategies. The models were externally validated employing a test set, and the predicted values were in good agreement with the experimental results. The final QSAR models and the 3D contour maps provided important insights into the chemical and structural basis involved in the molecular recognition process of this family of discodermolide analogs, and should be useful for the design of new specific β-tubulin modulators with potent anticancer activity. ©2009 Sociedade Brasileira de Química.204693703Wittmann, T., Hyman, A., Desai, A., (2001) Nat. Cell. Biol., 3, pp. E28Jordan, M.A., Wilson, L., (2004) Nat. Ver. Cancer, 4, p. 253Hadfield, J.A., Ducki, S., Hirst, N., McGown, A.T., (2003) Prog. Cell Cycle Res., 5, p. 309Pellegrini, F., Budman, D.R., (2005) Cancer Invest, 23, p. 264Islam, M.N., Iskander, M.N., (2004) Mini Rev. Med. Chem., 4, p. 1077Snyder, J.P., (2007) Nat. Chem. Biol., 3, p. 81Schiff, P.B., Fant, J., Horwitz, S.B., (1979) Nature, 277, p. 665Rowinsky, E.K., (1997) Annu. Rev. Med., 48, p. 353Jordan, M.A., Toso, R.J., Thrower, D., Wilson, L., (1993) Proc. Natl. Acad. Sci. U. S. A., 90, p. 9552Orr, G.A., Verdier-Pinard, P., McDaid, H., Horwitz, S.B., (2003) Oncogene, 22, p. 7280He, L., Orr, G.A., Horwitz, S.B., (2001) Drug Discov. Today, 6, p. 1153Bollag, D.M., McQueney, P.A., Zhu, J., Hensens, O., Koupal, L., Liesch, J., Goetz, M., Woods, C.M., (1995) Cancer Res, 55, p. 2325Hung, D.T., Chen, J., Schreiber, S.L., (1996) Chem. Biol., 3, p. 287ter Haar, E., Kowalski, R.J., Hamel, E., Lin, C.M., Longley, R.E., Gunasekera, S.P., Rosenkranz, H.S., Day, B.W., (1996) Biochemistry, 35, p. 243Madiraju, C., Edler, M.C., Hamel, E., Raccor, B.S., Balachandran, R., Zhu, G., Giuliano, K.A., Day, B.W., (2005) Biochemistry, 44, p. 15053Dias, L.C., Lima, D.J.P., Gonçalves, C.C.S., Andricopulo, A.D., (2009) Eur. J. Org. Chem., p. 1491Mínguez, J.M., Kim, S.Y., Giuliano, K.A., Balachandran, R., Madiraju, C., Day, B.W., Curran, D.P., (2003) Bioorg. Med. Chem., 11, p. 3335Guido, R.V.C., Oliva, G., Andricopulo, A.D., (2008) Curr. Med. Chem., 15, p. 37Andricopulo, A.D., Montanari, C.A., (2005) Mini-Rev. Med. Chem., 5, p. 585Salum, L.B., Polikarpov, I., Andricopulo, A.D., (2007) J. Mol. Graphics Modell., 26, p. 43Castilho, M.S., Postigo, M.P., de Paula, C.B., Montanari, C.A., Oliva, G., Andricopulo, A.D., (2006) Bioorg. Med. Chem., 14, p. 516Andrade, C.H., Salum, L.B., Pasqualoto, K.F.M., Ferreira, E.I., Andricopulo, A.D., (2008) Lett. Drug Des. Discov., 5, p. 377Guido, R.V.C., Oliva, G., Montanari, C.A., Andricopulo, A.D., (2008) J. Chem. Inf. Model., 48, p. 918Salum, L.B., Polikarpov, I., Andricopulo, A.D., (2009) J. Chem. Inf. Model., 48, p. 2243Honório, K.M., Garratt, R.C., Polikarpov, I., Andricopulo, A.D., (2007) J. Mol. Graph. Modell., 25, p. 921Salum, L.B., Dias, L.C., Andricopulo, A.D., (2009) QSAR Comb. Sci., 28, p. 325Castilho, M.S., Guido, R.V.C., Andricopulo, A.D., (2007) Lett. Drug Des. Discov., 4, p. 106Manetti, F., Maccari, L., Corelli, F., Botta, M., (2005) J. Mol. Model., 11, p. 48Hansch, C., Verma, R.P., (2008) Mol. Pharm., 5, p. 151Manetti, F., Maccari, L., Corelli, F., Botta, M., (2004) Curr. Top. Med. Chem., 4, p. 203Cunningham, S.L., Cunningham, A.R., Day, B.W., (2005) J. Mol. Model., 11, p. 48Cramer, R.D., Patterson, D.E., Bunce, J.D., (1988) J. Am. Chem. Soc., 110, p. 5959Burlingame, M.A., Shaw, S.J., Sundermann, K.F., Zhang, D., Petryka, J., Mendoza, E., Liu, F., Smith A.B. III, (2004) Bioorg. Med. Chem. Lett., 14, p. 2335Shaw, S.J., Sundermann, K.F., Burlingame, M.A., Myles, D.C., Freeze, B.S., Xian, M., Brouard, I., Smith A.B. III, (2005) J. Am. Chem. Soc., 127, p. 6532Smith A.B. III, Freeze, B.S., Lamarche, M.J., Hirose, T., Brouard, I., Rucker, P.V., Xian, M., Myles, D.C., (2005) Org. Lett., 7, p. 311Smith A.B. III, Freeze, B.S., Lamarche, M.J., Hirose, T., Brouard, I., Xian, M., Sundermann, K.F., Myles, D.C., (2005) Org. Lett., 7, p. 315Smith A.B. III, Xian, M., (2005) Org. Lett., 7, p. 5229Martello, L.A., LaMarche, M.J., He, L., Beauchamp, T.J., Smith, A.B., Horwitz, S.B., (2001) Chem. Biol., 8, p. 843Gasteiger, J., Marsili, M., (1980) Tetrahedron, 36, p. 3219Clark, M., Cramer, R.D., Van Opdenbosch, N., (1989) J. Comput. Chem., 10, p. 982Verdonk, M.L., Cole, J.C., Hartshorn, M.J., Murray, C.W., Taylor, R.D., (2003) Proteins, 52, p. 609Snyder, J.P., Nettles, J.H., Cornett, B., Downing, K.H., Nogales, E., (2001) Proc. Natl. Acad. Sci. U. S. A., 98, p. 5312Nettles, J.H., Li, H., Cornett, B., Krahn, J.M., Snyder, J.P., Downing, K.H., (2004) Science, 305, p. 866Golbraikh, A., Shen, M., Xiao, Z., Xiao, Y.D., Lee, K.H., Tropsha, A., (2003) J. Comput.-Aided Mol. Des., 17, p. 241Golbraikh, A., Tropsha, A., (2002) J. Mol. Graphics Modell., 20, p. 269Cramer, R.D., Patterson, D.E., Bunce, J.D., (1989) Prog. Clin. Biol. Res., 291, p. 161Xia, S., Kenesky, C.S., Rucker, P.V., Smith A.B. III, Orr, G.A., Horwitz, S.B., (2006) Biochemistry, 45, p. 11762Smith A.B. III, LaMarche, M.J., Falcone-Hindley, M., (2001) Org. Lett., 3, p. 695Shin, Y., Fournier, J.H., Balachandran, R., Madiraju, C., Raccor, B.S., Zhu, G., Edler, M.C., Curran, D.P., (2005) Org. Lett., 7, p. 287

Gambling as a teaching aid in the introductory physics laboratory

Dice throwing is used to illustrate relevant concepts of the statistical theory of uncertainties, in particular the meaning of a limiting distribution, the standard deviation, and the standard deviation of the mean. It is an important part in a sequence of especially programmed laboratory activities, developed for freshmen, at the Institute of Physics of the University of S˜ao Paulo. It is shown how this activity is employed within a constructive teaching approach, which aims at a growing understanding of the measuring processes and of the fundamentals of correct statistical handling of experimental data

Explaining the Higgs Decays at the LHC with an Extended Electroweak Model

We show that the recent discovery of a new boson at the LHC, which we assume to be a Higgs boson, and the observed enhancement in its diphoton decays compared to the SM prediction, can be explained by a new doublet of charged vector bosons from an extended electroweak gauge sector model with SU(3)_C\otimesSU(3)_L\otimesU(1)_X symmetry. Our results show a good agreement between our theoretical expected sensitivity to a 126--125 GeV Higgs boson and the experimental significance observed in the diphoton channel at the 8 TeV LHC. Effects of an invisible decay channel for the Higgs boson are also taken into account, in order to anticipate a possible confirmation of deficits in the branching ratios into $ZZ^*$, $WW^*$, bottom quarks, and tau leptons.Comment: 16 pages, 5 figure

Fenologia e produção de cultivares de amoreira-preta em sistema agroecológico.

A amoreira-preta é uma espécie de exploração recente no Brasil. Nos últimos ano, s tem sido dada especial atenção ao cultivo orgânico ou agroecológico dessa espécie. O objetivo deste trabalho foi verificar o comportamento fenológico e produtivo das cultivares de amora-preta ‘Tupy’, ‘Guarani’, ‘Caingangue’, ‘Cherokee’ e ‘Brazos’, e das seleções denominadas ‘seleção 97’ e ‘seleção 787’ na região de Pelotas, Rio Grande do Sul(RS), em sistema agroecológico. O trabalho foi realizado na Estação Experimental de Cascata (EEC), Embrapa Clima Temperado. As plantas foram dispostas no pomar, em blocos varietais aleatórios, com 10 plantas por genótipo, perfazendo quatro linhas com duas cultivares por linha. Foram observadas as datas de início da floração e fim da floração, início e final de colheita, massa (gramas) e número de frutos por planta, teor de sólidos solúveis totais (ºBrix), produção média por planta (g pl-1) e produtividade estimada por hectare (kg ha-1). Para análise das características dos frutos, a média de cada ano de avaliação (três) foi considerada como uma repetição. Na região de Pelotas-RS, é viável o cultivo agroecológico de amoreira-preta. Não há diferenças de produção, produtividade, número de frutos e teores de sólidos solúveis totais entre os genótipos estudados

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results