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203 results on '"La Motta C"'

1. Nanostructured ultra-thin patches for ultrasound-modulated delivery of anti-restenotic drug

Author

Vannozzi L, Ricotti L, Filippeschi C, Sartini S, Coviello V, Piazza V, Pingue P, La Motta C, Dario P, and Menciassi A

Subjects
restenosis, micro/nano therapeutic systems, thin films, layer-by-layer polyelectrolytes, barium titanate nanoparticles, drug delivery, ultrasound., Medicine (General), R5-920
Abstract

Lorenzo Vannozzi,1 Leonardo Ricotti,1 Carlo Filippeschi,2 Stefania Sartini,3 Vito Coviello,3 Vincenzo Piazza,4 Pasqualantonio Pingue,5 Concettina La Motta,3 Paolo Dario,1 Arianna Menciassi1 1The BioRobotics Institute, Scuola Superiore Sant’Anna, 2Center for MicroBioRobotics at SSSA, Istituto Italiano di Tecnologia, Pontedera, 3Department of Pharmacy, University of Pisa, 4Center for Nanotechnology Innovation at NEST, Istituto Italiano di Tecnologia, 5NEST, Scuola Normale Superiore, Istituto Nanoscienze-CNR, Pisa, Italy Abstract: This work aims to demonstrate the possibility to fabricate ultra-thin polymeric films loaded with an anti-restenotic drug and capable of tunable drug release kinetics for the local treatment of restenosis. Vascular nanopatches are composed of a poly(lactic acid) supporting membrane (thickness: ~250 nm) on which 20 polyelectrolyte bilayers (overall thickness: ~70 nm) are alternatively deposited. The anti-restenotic drug is embedded in the middle of the polyelectrolyte structure, and released by diffusion mechanisms. Nanofilm fabrication procedure and detailed morphological characterization are reported here. Barium titanate nanoparticles (showing piezoelectric properties) are included in the polymeric support and their role is investigated in terms of influence on nanofilm morphology, drug release kinetics, and cell response. Results show an efficient drug release from the polyelectrolyte structure in phosphate-buffered saline, and a clear antiproliferative effect on human smooth muscle cells, which are responsible for restenosis. In addition, preliminary evidences of ultrasound-mediated modulation of drug release kinetics are reported, thus evaluating the influence of barium titanate nanoparticles on the release mechanism. Such data were integrated with quantitative piezoelectric and thermal measurements. These results open new avenues for a fine control of local therapies based on smart responsive materials. Keywords: restenosis, micro/nanotherapeutic systems, thin films, layer-by-layer polyelectrolytes, barium titanate nanoparticles, drug delivery, ultrasound

Published
2015

7. Identification of anxiolytic/non sedative agents among indol-3-ylglyoxylamides acting as functionally selective agonists at the GABAA alfa2 benzodiazepine receptor

Author

Taliani S., Da Settimo F., Marini A. M., La Motta C., Simorini F., Salerno S., Cosconati S., Salvetti F., L’Abbate G., Trasciatti S., Montali M., Costa B., Martini C., COSIMELLI, BARBARA, NOVELLINO, ETTORE, GRECO, GIOVANNI, MARINELLI, LUCIANA, Taliani, S., Cosimelli, Barbara, Da Settimo, F., Marini, A. M., La Motta, C., Simorini, F., Salerno, S., Novellino, Ettore, Greco, Giovanni, Cosconati, S., Marinelli, Luciana, Salvetti, F., L’Abbate, G., Trasciatti, S., Montali, M., Costa, B., and Martini, C.

Published
2009

10. 2-Phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1-one derivatives as a new class of adenosine receptor antagonists

Author

Primofiore G., Da Settimo F., Taliani S., Sergianni V., Simorini F., La Motta C., Marini A. M., Tuscano D., Martini C., GRECO, GIOVANNI, COSIMELLI, BARBARA, NOVELLINO, ETTORE, Ettmayer P., Eckert G., Primofiore, G., Da Settimo, F., Taliani, S., Sergianni, V., Simorini, F., La Motta, C., Marini, A. M., Tuscano, D., Martini, C., Greco, Giovanni, Cosimelli, Barbara, and Novellino, Ettore

Subjects
heterocycles, antagonist, adenosine receptor
Published
2005

15. Inhibition of Ocular Aldose Reductase by a New Benzofuroxane Derivative Ameliorates Rat Endotoxic Uveitis

Author

Di Filippo, C., primary, Zippo, M. V., additional, Maisto, R., additional, Trotta, M. C., additional, Siniscalco, D., additional, Ferraro, B., additional, Ferraraccio, F., additional, La Motta, C., additional, Sartini, S., additional, Cosconati, S., additional, Novellino, E., additional, Gesualdo, C., additional, Simonelli, F., additional, Rossi, S., additional, and D’Amico, M., additional

Published
2014
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16. Effects of the New Aldose Reductase Inhibitor Benzofuroxane Derivative BF-5m on High Glucose Induced Prolongation of Cardiac QT Interval and Increase of Coronary Perfusion Pressure.

Author

Di Filippo, C., Ferraro, B., Maisto, R., Trotta, M. C., Di Carluccio, N., Sartini, S., La Motta, C., Ferraraccio, F., Rossi, F., and D’Amico, M.

Subjects
ALDOSE reductase, BENZOFURAN, HETEROCYCLIC compound derivatives, HEART beat measurement, PERFUSION, CARDIOTONIC agents, SIRTUINS
Abstract

This study investigated the effects of the new aldose reductase inhibitor benzofuroxane derivative 5(6)-(benzo[d]thiazol-2-ylmethoxy)benzofuroxane (BF-5m) on the prolongation of cardiac QT interval and increase of coronary perfusion pressure (CPP) in isolated, high glucose (33.3 mM D-glucose) perfused rat hearts. BF-5m was dissolved in the Krebs solution at a final concentration of 0.01 μM, 0.05 μM, and 0.1 μM. 33.3 mM D-glucose caused a prolongation of the QT interval and increase of CPP up to values of 190 ± 12 ms and 110 ± 8 mmHg with respect to the values of hearts perfused with standard Krebs solution (11.1 mM D-glucose). The QT prolongation was reduced by 10%, 32%, and 41%, respectively, for the concentration of BF-5m 0.01 μM, 0.05 μM, and 0.1 μM. Similarly, the CPP was reduced by 20% for BF-5m 0.05 μM and by 32% for BF-5m 0.1 μM. BF-5m also increased the expression levels of sirtuin 1, MnSOD, eNOS, and FOXO-1, into the heart. The beneficial actions of BF-5m were partly abolished by the pretreatment of the rats with the inhibitor of the sirtuin 1 activity EX527 (10 mg/kg/day/7 days i.p.) prior to perfusion of the hearts with high glucose + BF-5m (0.1 μM). Therefore, BF-5m supplies cardioprotection from the high glucose induced QT prolongation and increase of CPP. [ABSTRACT FROM AUTHOR]

Published
2015
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17. Poster session 2

Author

Perez-Pomares, J. M., primary, Ruiz-Villalba, A., additional, Ziogas, A., additional, Segovia, J. C., additional, Ehrbar, M., additional, Munoz-Chapuli, R., additional, De La Rosa, A., additional, Dominguez, J. N., additional, Hove-Madsen, L., additional, Sankova, B., additional, Sedmera, D., additional, Franco, D., additional, Aranega Jimenez, A., additional, Babaeva, G., additional, Chizh, N., additional, Galchenko, S., additional, Sandomirsky, B., additional, Schwarzl, M., additional, Seiler, S., additional, Steendijk, P., additional, Huber, S., additional, Maechler, H., additional, Truschnig-Wilders, M., additional, Pieske, B., additional, Post, H., additional, Simrick, S., additional, Kreutzer, R., additional, Rao, C., additional, Terracciano, C. M., additional, Kirchhof, P., additional, Fabritz, L., additional, Brand, T., additional, Theveniau-Ruissy, M., additional, Parisot, P., additional, Francou, A., additional, Saint-Michel, E., additional, Mesbah, K., additional, Kelly, R. G., additional, Wu, H.-T., additional, Sie, S.-S., additional, Chen, C.-Y., additional, Kuan, T.-C., additional, Lin, C. S., additional, Ismailoglu, Z., additional, Guven, M., additional, Yakici, A., additional, Ata, Y., additional, Ozcan, S., additional, Yildirim, E., additional, Ongen, Z., additional, Miroshnikova, V., additional, Demina, E., additional, Rodygina, T., additional, Kurjanov, P., additional, Denisenko, A., additional, Schwarzman, A., additional, Rubanenko, A., additional, Shchukin, Y., additional, Germanov, A., additional, Goldbergova, M., additional, Parenica, J., additional, Lipkova, J., additional, Pavek, N., additional, Kala, P., additional, Poloczek, M., additional, Vasku, A., additional, Parenicova, I., additional, Spinar, J., additional, Gambacciani, C., additional, Chiavacci, E., additional, Evangelista, M., additional, Vesentini, N., additional, Kusmic, C., additional, Pitto, L., additional, Chernova, A., additional, Nikulina, S. U. Y., additional, Arvanitis, D. A., additional, Mourouzis, I., additional, Pantos, C., additional, Kranias, E. G., additional, Cokkinos, D. V., additional, Sanoudou, D., additional, Vladimirskaya, T. E., additional, Shved, I. A., additional, Kryvorot, S. G., additional, Schirmer, I. M., additional, Appukuttan, A., additional, Pott, L., additional, Jaquet, K., additional, Ladilov, Y., additional, Archer, C. R., additional, Bootman, M. D., additional, Roderick, H. L., additional, Fusco, A., additional, Sorriento, D., additional, Santulli, G., additional, Trimarco, B., additional, Iaccarino, G., additional, Hagenmueller, M., additional, Riffel, J., additional, Bernhold, E., additional, Katus, H. A., additional, Hardt, S. E., additional, Maqsood, A., additional, Zi, M., additional, Prehar, S., additional, Neyses, L., additional, Ray, S., additional, Oceandy, D., additional, Khatami, N., additional, Wadowski, P., additional, Wagh, V., additional, Hescheler, J., additional, Sachinidis, A., additional, Mohl, W., additional, Chaudhry, B., additional, Burns, D., additional, Henderson, D. J., additional, Bax, N. A. M., additional, Van Marion, M. H., additional, Shah, B., additional, Goumans, M. J., additional, Bouten, C. V. C., additional, Van Der Schaft, D. W. J., additional, Van Oorschot, A. A. M., additional, Maas, S., additional, Braun, J., additional, Van Tuyn, J., additional, De Vries, A. A. F., additional, Gittenberger-De Groot, A. C., additional, Bageghni, S., additional, Drinkhill, M. J., additional, Batten, T. F. C., additional, Ainscough, J. F. X., additional, Onate, B., additional, Vilahur, G., additional, Ferrer-Lorente, R., additional, Ybarra, J., additional, Diez-Caballero, A., additional, Ballesta-Lopez, C., additional, Moscatiello, F., additional, Herrero, J., additional, Badimon, L., additional, Martin-Rendon, E., additional, Clifford, D. M., additional, Fisher, S. A., additional, Brusnkill, S. J., additional, Doree, C., additional, Mathur, A., additional, Clarke, M., additional, Watt, S. M., additional, Hernandez-Vera, R., additional, Kavanagh, D., additional, Yemm, A. I., additional, Frampton, J., additional, Kalia, N., additional, Terajima, Y., additional, Shimizu, T., additional, Tsuruyama, S., additional, Ishii, H., additional, Sekine, H., additional, Hagiwara, N., additional, Okano, T., additional, Vrijsen, K. R., additional, Chamuleau, S. A. J., additional, Sluijter, J. P. G., additional, Doevendans, P. F. M., additional, Madonna, R., additional, Delli Pizzi, S., additional, Di Donato, L., additional, Mariotti, A., additional, Di Carlo, L., additional, D'ugo, E., additional, Teberino, M. A., additional, Merla, A., additional, T, A., additional, De Caterina, R., additional, Kolker, L., additional, Ali, N. N., additional, Maclellan, K., additional, Moore, M., additional, Wheeler, J., additional, Harding, S. E., additional, Fleck, R. A., additional, Rowlinson, J. M., additional, Kraenkel, N., additional, Ascione, R., additional, Madeddu, P., additional, O'sullivan, J. F., additional, Leblond, A. L., additional, Kelly, G., additional, Kumar, A. H. S., additional, Metharom, P., additional, Buneker, C. K., additional, Alizadeh-Vikali, N., additional, Hynes, B. G., additional, O'connor, R., additional, Caplice, N. M., additional, Noseda, M., additional, De Smith, A. J., additional, Leja, T., additional, Rao, P. H., additional, Al-Beidh, F., additional, Abreu Pavia, M. S., additional, Blakemore, A. I., additional, Schneider, M. D., additional, Stathopoulou, K., additional, Cuello, F., additional, Ehler, E., additional, Haworth, R. S., additional, Avkiran, M., additional, Morawietz, H., additional, Eickholt, C., additional, Langbein, H., additional, Brux, M., additional, Goettsch, C., additional, Goettsch, W., additional, Arsov, A., additional, Brunssen, C., additional, Mazilu, L., additional, Parepa, I. R., additional, Suceveanu, A. I., additional, Suceveanu, A. P., additional, De Man, F. S., additional, Guignabert, C., additional, Tu, L., additional, Handoko, M. L., additional, Schalij, I., additional, Fadel, E., additional, Postmus, P. E., additional, Vonk-Noordegraaf, A., additional, Humbert, M., additional, Eddahibi, S., additional, Del Giudice, C., additional, Anastasio, A., additional, Fazal, L., additional, Azibani, F., additional, Bihry, N., additional, Merval, R., additional, Polidano, E., additional, Samuel, J.-L., additional, Delcayre, C., additional, Zhang, Y., additional, Mi, Y. M., additional, Ren, L. L., additional, Cheng, Y. P., additional, Guo, R., additional, Liu, Y., additional, Jiang, Y. N., additional, Kokkinos, A. D., additional, Tretjakovs, P., additional, Jurka, A., additional, Bormane, I., additional, Mikelsone, I., additional, Reihmane, D., additional, Elksne, K., additional, Krievina, G., additional, Verbovenko, J., additional, Bahs, G., additional, Lopez-Andres, N., additional, Rousseau, A., additional, Calvier, L., additional, Akhtar, R., additional, Labat, C., additional, Cruickshank, K., additional, Diez, J., additional, Zannad, F., additional, Lacolley, P., additional, Rossignol, P., additional, Hamesch, K., additional, Subramanian, P., additional, Li, X., additional, Thiemann, A., additional, Heyll, K., additional, Dembowsky, K., additional, Chevalier, E., additional, Weber, C., additional, Schober, A., additional, Yang, L., additional, Kim, G., additional, Gardner, B., additional, Earley, J., additional, Hofmann-Bowman, M., additional, Cheng, C.-F., additional, Lian, W.-S., additional, Lin, H., additional, Jinjolia, N. J., additional, Abuladze, G. A., additional, Tvalchrelidze, S. H. T., additional, Khamnagadaev, I., additional, Shkolnikova, M., additional, Kokov, L., additional, Miklashevich, I., additional, Drozdov, I., additional, Ilyich, I., additional, Bingen, B. O., additional, Askar, S. F. A., additional, Ypey, D. L., additional, Van Der Laarse, A., additional, Schalij, M. J., additional, Pijnappels, D. A., additional, Roney, C. H., additional, Ng, F. S., additional, Chowdhury, R. A., additional, Chang, E. T. Y., additional, Patel, P. M., additional, Lyon, A. R., additional, Siggers, J. H., additional, Peters, N. S., additional, Obergrussberger, A., additional, Stoelzle, S., additional, Bruggemann, A., additional, Haarmann, C., additional, George, M., additional, Fertig, N., additional, Moreira, D., additional, Souza, A., additional, Valente, P., additional, Kornej, J., additional, Reihardt, C., additional, Kosiuk, J., additional, Arya, A., additional, Hindricks, G., additional, Adams, V., additional, Husser, D., additional, Bollmann, A., additional, Camelliti, P., additional, Dudhia, J., additional, Dias, P., additional, Cartledge, J., additional, Connolly, D. J., additional, Nobles, M., additional, Sebastian, S., additional, Tinker, A., additional, Opel, A., additional, Daimi, H., additional, Haj Khelil, A., additional, Be Chibani, J., additional, Barana, A., additional, Amoros, I., additional, Gonzalez De La Fuente, M., additional, Caballero, R., additional, Aranega, A., additional, Kelly, A., additional, Bernus, O., additional, Kemi, O. J., additional, Myles, R. C., additional, Ghouri, I. A., additional, Burton, F. L., additional, Smith, G. L., additional, Del Lungo, M., additional, Sartiani, L., additional, Spinelli, V., additional, Baruscotti, M., additional, Difrancesco, D., additional, Mugelli, A., additional, Cerbai, E., additional, Thomas, A. M., additional, Aziz, Q., additional, Khambra, T., additional, Addlestone, J. M. A., additional, Cartwright, E. J., additional, Wilkinson, R., additional, Song, W., additional, Marston, S., additional, Jacquet, A., additional, Mougenot, N. M., additional, Lipskaia, A. J., additional, Paalberends, E. R., additional, Stam, K., additional, Van Dijk, S. J., additional, Van Slegtenhorst, M., additional, Dos Remedios, C., additional, Ten Cate, F. J., additional, Michels, M., additional, Niessen, H. W. M., additional, Stienen, G. J. M., additional, Van Der Velden, J., additional, Read, M. I., additional, Andreianova, A. A., additional, Harrison, J. C., additional, Goulton, C. S., additional, Kerr, D. S., additional, Sammut, I. A., additional, Wallner, M., additional, Von Lewinski, D., additional, Kindsvater, D., additional, Saes, M., additional, Morano, I., additional, Muegge, A., additional, Buyandelger, B., additional, Kostin, S., additional, Gunkel, S., additional, Vouffo, J., additional, Ng, K., additional, Chen, J., additional, Eilers, M., additional, Isaacson, R., additional, Milting, H., additional, Knoell, R., additional, Cattin, M.-E., additional, Crocini, C., additional, Schlossarek, S., additional, Maron, S., additional, Hansen, A., additional, Eschenhagen, T., additional, Carrier, L., additional, Bonne, G., additional, Coppini, R., additional, Ferrantini, C., additional, Olivotto, I., additional, Belardinelli, L., additional, Poggesi, C., additional, Leung, M. C., additional, Messer, A. E., additional, Copeland, O., additional, Marston, S. B., additional, Mills, A. M., additional, Collins, T., additional, O'gara, P., additional, Thum, T., additional, Regalla, K., additional, Macleod, K. T., additional, Prodromakis, T., additional, Chaudhry, U., additional, Darzi, A., additional, Yacoub, M. H., additional, Athanasiou, T., additional, Bogdanova, A., additional, Makhro, A., additional, Hoydal, M., additional, Stolen, T. O., additional, Johnssen, A. B., additional, Alves, M., additional, Catalucci, D., additional, Condorelli, G., additional, Koch, L. G., additional, Britton, S. L., additional, Wisloff, U., additional, Bito, V., additional, Claus, P., additional, Vermeulen, K., additional, Huysmans, C., additional, Ventura-Clapier, R., additional, Sipido, K. R., additional, Seliuk, M. N., additional, Burlaka, A. P., additional, Sidorik, E. P., additional, Khaitovych, N. V., additional, Kozachok, M. M., additional, Potaskalova, V. S., additional, Driesen, R. B., additional, Galan, D. T., additional, De Paulis, D., additional, Arnoux, T., additional, Schaller, S., additional, Pruss, R. M., additional, Poitz, D. M., additional, Augstein, A., additional, Braun-Dullaeus, R. C., additional, Schmeisser, A., additional, Strasser, R. H., additional, Micova, P., additional, Balkova, P., additional, Hlavackova, M., additional, Zurmanova, J., additional, Kasparova, D., additional, Kolar, F., additional, Neckar, J., additional, Novak, F., additional, Novakova, O., additional, Pollard, S., additional, Babba, M., additional, Hussain, A., additional, James, R., additional, Maddock, H., additional, Alshehri, A. S., additional, Baxter, G. F., additional, Dietel, B., additional, Altendorf, R., additional, Daniel, W. G., additional, Kollmar, R., additional, Garlichs, C. D., additional, Sirohi, R., additional, Roberts, N., additional, Lawrence, D., additional, Sheikh, A., additional, Kolvekar, S., additional, Yap, J., additional, Arend, M., additional, Walkinshaw, G., additional, Hausenloy, D. J., additional, Yellon, D. M., additional, Posa, A., additional, Szabo, R., additional, Szalai, Z., additional, Szablics, P., additional, Berko, M. A., additional, Orban, K., additional, Murlasits, Z. S., additional, Balogh, L., additional, Varga, C., additional, Ku, H. C., additional, Su, M. J., additional, Chreih, R.-M., additional, Ginghina, C., additional, Deleanu, D., additional, Ferreira, A. L. B. J., additional, Belal, A., additional, Ali, M. A., additional, Fan, X., additional, Holt, A., additional, Campbell, R., additional, Schulz, R., additional, Bonanad, C., additional, Bodi, V., additional, Sanchis, J., additional, Morales, J. M., additional, Marrachelli, V., additional, Nunez, J., additional, Forteza, M. J., additional, Chaustre, F., additional, Gomez, C., additional, Chorro, F. J., additional, Csont, T., additional, Fekete, V., additional, Murlasits, Z., additional, Aypar, E., additional, Bencsik, P., additional, Sarkozy, M., additional, Varga, Z. V., additional, Ferdinandy, P., additional, Duerr, G. D., additional, Zoerlein, M., additional, Dewald, D., additional, Mesenholl, B., additional, Schneider, P., additional, Ghanem, A., additional, Rittling, S., additional, Welz, A., additional, Dewald, O., additional, Becker, E., additional, Peigney, C., additional, Bouleti, C., additional, Galaup, A., additional, Monnot, C., additional, Ghaleh, B., additional, Germain, S., additional, Timmermans, A., additional, Ginion, A., additional, De Meester, C., additional, Sakamoto, K., additional, Vanoverschelde, J.-L., additional, Horman, S., additional, Beauloye, C., additional, Bertrand, L., additional, Maroz-Vadalazhskaya, N., additional, Drozd, E., additional, Kukharenko, L., additional, Russkich, I., additional, Krachak, D., additional, Seljun, Y., additional, Ostrovski, Y., additional, Martin, A.-C., additional, Le Bonniec, B., additional, Lecompte, T., additional, Dizier, B., additional, Emmerich, J., additional, Fischer, A.-M., additional, Samama, C.-M., additional, Godier, A., additional, Mogensen, S., additional, Furchtbauer, E. M., additional, Aalkjaer, C., additional, Choong, W. L., additional, Jovanovic, A., additional, Khan, F., additional, Daniel, J. M., additional, Dutzmann, J. M., additional, Widmer-Teske, R., additional, Guenduez, D., additional, Sedding, D., additional, Castro, M. M., additional, Cena, J. J. C., additional, Cho, W. J. C., additional, Goobie, G. G., additional, Walsh, M. P. W., additional, Schulz, R. S., additional, Dutzmann, J., additional, Preissner, K. T., additional, Sones, W., additional, Kotlikoff, M., additional, Serizawa, K., additional, Yogo, K., additional, Aizawa, K., additional, Hirata, M., additional, Tashiro, Y., additional, Ishizuka, N., additional, Varela, A., additional, Katsiboulas, M., additional, Tousoulis, D., additional, Papaioannou, T. G., additional, Vaina, S., additional, Davos, C. H., additional, Piperi, C., additional, Stefanadis, C., additional, Basdra, E. K., additional, Papavassiliou, A. G., additional, Hermenegildo, C., additional, Lazaro-Franco, M., additional, Sobrino, A., additional, Bueno-Beti, C., additional, Martinez-Gil, N., additional, Walther, T., additional, Peiro, C., additional, Sanchez-Ferrer, C. F., additional, Novella, S., additional, Ciccarelli, M., additional, Franco, A., additional, Dorn, G. W., additional, Cseplo, P., additional, Torok, O., additional, Springo, Z. S., additional, Vamos, Z., additional, Kosa, D., additional, Hamar, J., additional, Koller, A., additional, Bubb, K. J., additional, Ahluwalia, A., additional, Stepien, E. L., additional, Gruca, A., additional, Grzybowska, J., additional, Goralska, J., additional, Dembinska-Kiec, A., additional, Stolinski, J., additional, Partyka, L., additional, Zhang, H., additional, Sweeney, D., additional, Thomas, G. N., additional, Fish, P. V., additional, Taggart, D. P., additional, Cioffi, S., additional, Bilio, M., additional, Martucciello, S., additional, Illingworth, E., additional, Caporali, A., additional, Shantikumar, S., additional, Marchetti, M., additional, Martelli, F., additional, Emanueli, C., additional, Meloni, M., additional, Al Haj Zen, A., additional, Sala-Newby, G., additional, Del Turco, S., additional, Saponaro, C., additional, Dario, B., additional, Sartini, S., additional, Menciassi, A., additional, Dario, P., additional, La Motta, C., additional, Basta, G., additional, Santiemma, V., additional, Bertone, C., additional, Rossi, F., additional, Michelon, E., additional, Bianco, M. J., additional, Castelli, A., additional, Shin, D. I., additional, Seung, K. B., additional, Seo, S. M., additional, Park, H. J., additional, Kim, P. J., additional, Baek, S. H., additional, Choi, Y. S., additional, Her, S. H., additional, Kim, D. B., additional, Lee, J. M., additional, Park, C. S., additional, Rocchiccioli, S., additional, Cecchettini, A., additional, Pelosi, G., additional, Citti, L., additional, Parodi, O., additional, Trivella, M. G., additional, Michel-Monigadon, D., additional, Burger, F., additional, Dunoyer-Geindre, S., additional, Pelli, G., additional, Cravatt, B., additional, Steffens, S., additional, Didangelos, A., additional, Mayr, U., additional, Yin, X., additional, Stegemann, C., additional, Shalhoub, J., additional, Davies, A. H., additional, Monaco, C., additional, Mayr, M., additional, Lypovetska, S., additional, Grytsenko, S., additional, Njerve, I. U., additional, Pettersen, A. A., additional, Opstad, T. B., additional, Bratseth, V., additional, Arnesen, H., additional, Seljeflot, I., additional, Dumitriu, I. E., additional, Baruah, P., additional, Antunes, R. F., additional, Kaski, J. C., additional, Trapero, I., additional, Benet, I., additional, Alguero, C., additional, Chaustre, F. J., additional, Mangold, A., additional, Puthenkalam, S., additional, Distelmaier, K., additional, Adlbrecht, C., additional, Lang, I. M., additional, Koizumi, T., additional, Inoue, I., additional, Komiyama, N., additional, Nishimura, S., additional, Korneeva, O. N., additional, Drapkina, O. M., additional, Fornai, L., additional, Angelini, A., additional, Kiss, A., additional, Giskes, F., additional, Eijkel, G., additional, Fedrigo, M., additional, Valente, M. L., additional, Thiene, G., additional, Heeren, R. M. A., additional, Padro, T., additional, Casani, L., additional, Suades, R., additional, Bertoni, B., additional, Carminati, R., additional, Carlini, V., additional, Pettinari, L., additional, Martinelli, C., additional, Gagliano, N., additional, Noppe, G., additional, Buchlin, P., additional, Marquet, N., additional, Baeyens, N., additional, Morel, N., additional, Baysa, A., additional, Sagave, J., additional, Dahl, C. P., additional, Gullestad, L., additional, Carpi, A., additional, Di Lisa, F., additional, Giorgio, M., additional, Vaage, J., additional, Valen, G., additional, Vafiadaki, E., additional, Papalouka, V., additional, Terzis, G., additional, Spengos, K., additional, Manta, P., additional, Gales, C., additional, Genet, G., additional, Dague, E., additional, Cazorla, O., additional, Payre, B., additional, Mias, C., additional, Ouille, A., additional, Lacampagne, A., additional, Pathak, A., additional, Senard, J. M., additional, Abonnenc, M., additional, Da Costa Martins, P., additional, Srivastava, S., additional, Gautel, M., additional, De Windt, L., additional, Comelli, L., additional, Lande, C., additional, Ucciferri, N., additional, Ikonen, L., additional, Vuorenpaa, H., additional, Kujala, K., additional, Sarkanen, J.-R., additional, Heinonen, T., additional, Ylikomi, T., additional, Aalto-Setala, K., additional, Capros, H., additional, Sprincean, N., additional, Usurelu, N., additional, Egorov, V., additional, Stratu, N., additional, Matchkov, V., additional, Bouzinova, E., additional, Moeller-Nielsen, N., additional, Wiborg, O., additional, Gutierrez, P. S., additional, Aparecida-Silva, R., additional, Borges, L. F., additional, Moreira, L. F. P., additional, Dias, R. R., additional, Kalil, J., additional, Stolf, N. A. G., additional, Zhou, W., additional, Suntharalingam, K., additional, Brand, N., additional, Vilar Compte, R., additional, Ying, L., additional, Bicknell, K., additional, Dannoura, A., additional, Dash, P., additional, Brooks, G., additional, Tsimafeyeu, I., additional, Tishova, Y., additional, Wynn, N., additional, Oyeyipo, I. P., additional, Olatunji, L. A., additional, Maegdefessel, L., additional, Azuma, J., additional, Toh, R., additional, Raaz, U., additional, Merk, D. R., additional, Deng, A., additional, Spin, J. M., additional, Tsao, P. S., additional, Tedeschi, L., additional, Taranta, M., additional, Naldi, I., additional, Grimaldi, S., additional, Cinti, C., additional, Bousquenaud, M., additional, Maskali, F., additional, Poussier, S., additional, Marie, P. Y., additional, Boutley, H., additional, Karcher, G., additional, Wagner, D. R., additional, Devaux, Y., additional, Torre, I., additional, Psilodimitrakopoulos, S., additional, Iruretagoiena, I., additional, Gonzalez-Tendero, A., additional, Artigas, D., additional, Loza-Alvarez, P., additional, Gratacos, E., additional, Amat-Roldan, I., additional, Murray, L., additional, Carberry, D. M., additional, Dunton, P., additional, Miles, M. J., additional, Suleiman, M.-S., additional, Kanesalingam, K., additional, Taylor, R., additional, Mc Collum, C. N., additional, Parniczky, A., additional, Solymar, M., additional, Porpaczy, A., additional, Miseta, A., additional, Lenkey, Z. S., additional, Szabados, S., additional, Cziraki, A., additional, Garai, J., additional, Myloslavska, I., additional, Menazza, S. M., additional, Canton, M. C., additional, Di Lisa, F. D. L., additional, Oliveira, S. H. V., additional, Morais, C. A. S., additional, Miranda, M. R., additional, Oliveira, T. T., additional, Lamego, M. R. A., additional, Lima, L. M., additional, Goncharova, N. S., additional, Naymushin, A. V., additional, Kazimli, A. V., additional, Moiseeva, O. M., additional, Carvalho, M. G., additional, Sabino, A. P., additional, Mota, A. P. L., additional, Sousa, M. O., additional, Niessner, A., additional, Richter, B., additional, Hohensinner, P. J., additional, Rychli, K., additional, Zorn, G., additional, Berger, R., additional, Moertl, D., additional, Pacher, R., additional, Wojta, J., additional, Huelsmann, M., additional, Kukharchik, G., additional, Nesterova, N., additional, Pavlova, A., additional, Gaykovaya, L., additional, Krapivka, N., additional, Konstantinova, I., additional, Sichinava, L., additional, Prapa, S., additional, Mccarthy, K. P., additional, Kilner, P. J., additional, Xu, X. Y., additional, Johnson, M. R., additional, Ho, S. Y., additional, Gatzoulis, M. A., additional, Stoupel, E. G., additional, Garcia, R., additional, Merino, D., additional, Montalvo, C., additional, Hurle, M. A., additional, Nistal, J. F., additional, Villar, A. V., additional, Perez-Moreno, A., additional, Gilabert, R., additional, and Ros, E., additional

Published
2012
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29. Synthesis and local anaesthetic activity of some 7-amino-2-dialkylaminoalkylpyrrolo[3,4-c]pyridine derivatives

Author

Da Settimo F, Am, Marini, La Motta C, Simorini F, Luchetti E, and Simone Bertini

Subjects
Male, Solubility, Pyridines, Animals, Rabbits, Anesthetics, Local
Abstract

A number of 7-amino-2-dialkylaminoalkylpyrrolo[3,4-c] pyridin-1,3(2H)-dione derivatives were synthesized and their local anaesthetic activity was evaluated in vivo by corneal anaesthesia in rabbits. Only compounds 3,9 and 14 showed any activity, albeit lower than that of the reference drug lidocaine.

30. Acid derivatives of benzisothiazole-1,1-dioxide as inhibitors of rat lens aldose reductase

Author

Da Settimo, A., Primofiore, G., La Motta, C., Da Settimo, F., Francesca SIMORINI, Boldrini, E., and Bianchini, P.

Subjects
Rats, Sprague-Dawley, Structure-Activity Relationship, Thiazoles, Aldehyde Reductase, Animals, Aldose reductase inhibitors, Enzyme Inhibitors, Rats
Abstract

A number of 6-substituted 1, 2-benzisothiazole-1, 1-dioxide alkanoic acids were synthesized and evaluated for crude rat lens aldose reductase inhibitory activity. The inhibitory potency of the acetic (6a, 10a), propionic (6b, 10b, 11b), and isopropionic (6c, 10c, 11c) derivatives was very similar and generally lower than that of the reference compound, Sorbinil. The presence of an acyl moiety on the amino group in position 6, as in the acetic and propionic derivatives 14a-f and 15a, b, respectively, resulted in a significant increase in activity. A good potency was shown by compounds 14g and 15g, in which a second carboxylic function is present on the 6-acylamino group. Also the open products 16, which contain the phenylsulfonyl fragment found in several known inhibitors of aldose reductase, were obtained and tested in the rat lens assay.

31. Benzisothiazole-1,1-dioxide alkanoic acid derivatives as inhibitors of rat lens aldose reductase

Author

Primofiore, G., Da Settimo, F., La Motta, C., Francesca SIMORINI, Minutolo, A., and Boldrini, E.

Subjects
Galactosemias, Rats, Sprague-Dawley, Thiazoles, Chemical Phenomena, Aldehyde Reductase, Chemistry, Physical, Lens, Crystalline, Animals, Enzyme Inhibitors, In Vitro Techniques, Glutathione, Rats
Abstract

Derivatives of 4-substituted 1,2-benzisothiazole-1,1-dioxide alkanoic acids were prepared and their in vitro aldose reductase inhibitory activity was tested in rat lens enzyme. The acetic derivatives 10, 12, and 16a-d proved to be much more potent inhibitors than the propionic derivatives 11, 13, and 17a-d. The presence of an acyl moiety on the amino group in position 4 of the acetic derivatives 16a-d led to a significant increase in activity with respect to the parent compound 14. One of the most active compounds in vitro, 10, was also evaluated in vivo as an inhibitor of glutathione lens depletion in galactosemic rats, but it did not show any activity in maintaining the rat lens glutathione level, probably due to problems of ocular bioavailability or metabolism.

37. Identification of novel molecular scaffolds for the design of MMP-13 inhibitors: A first round of lead optimization

Author

Valeria La Pietra, Sabrina Taliani, Hideaki Nagase, Elisa Nuti, Robert Visse, Federico Da Settimo, Francesco Saverio Di Leva, Ettore Novellino, Luciana Marinelli, Concettina La Motta, Salvatore Santamaria, Sandro Cosconati, Matteo Morelli, Armando Rossello, F Casalini, Isabella Pugliesi, La Pietra, V, Marinelli, L, Cosconati, Sandro, Di Leva, F, Nuti, E, Santamaria, S, Pugliesi, I, Morelli, M, Casalini, F, Rossello, A, La Motta, C, Taliani, S, Visse, R, Nagase, H, da Settimo, F, Novellino, E., LA PIETRA, Valeria, Marinelli, Luciana, Cosconati, S., Di Leva, Francesco Saverio, Nuti, E., Santamaria, S., Pugliesi, I., Morelli, M., Casalini, F., Rossello, A., La Motta, C., Taliani, S., Visse, R., Nagase, H., da Settimo, F., and Novellino, Ettore

Subjects
Virtual screening, High selectivity, Drug Evaluation, Preclinical, Nanotechnology, Articular cartilage, Osteoarthritis, Matrix Metalloproteinase Inhibitors, Matrix metalloproteinase, Crystallography, X-Ray, Inhibitory Concentration 50, User-Computer Interface, Catalytic Domain, Matrix Metalloproteinase 13, Drug Discovery, medicine, Humans, Protease Inhibitors, IC50, Cancer, Pharmacology, MMP, Chemistry, Cartilage, Organic Chemistry, General Medicine, medicine.disease, medicine.anatomical_structure, Docking (molecular), Drug Design, Molecular docking, Cancer research, Osteoarthriti
Abstract

Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. Thus, MMP-13-selective inhibitors are promising candidates in osteoarthritis therapy. Recently, we designed an N-isopropoxy-arylsulfonamide-based hydroxamate inhibitor, which showed low nanomolar activity and high selectivity for MMP-13. In parallel to further studies aiming to assess the in vivo activity of our compound, we screened the Life Chemicals database through computational docking to seek for novel scaffolds as zinc-chelating non-hydroxamate inhibitors. Experimental evaluation of 20 selected candidate compounds verified five novel leads with IC 50 in the low μM range. These newly discovered inhibitors are structurally unrelated to the ones known so far and provide useful scaffolds to develop compounds with more desirable properties. Finally, a first round of structure-based optimization on lead 1 was accomplished and led to an increase in potency of more than 5 fold. © 2011 Elsevier Masson SAS. All rights reserved.

Published
2012

38. 3-Aryl-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one: a novel template for the design of highly selective A2B adenosine receptor antagonists

Author

Barbara Cosimelli, Federico Da Settimo, Ettore Novellino, Salvatore Di Maro, Sabrina Taliani, Giovanni Greco, Simona Daniele, Claudia Martini, Anna Maria Marini, Silvia Salerno, Francesca Simorini, Maria Letizia Trincavelli, Elisabetta Barresi, Isabella Pugliesi, Luciana Marinelli, Concettina La Motta, Sandro Cosconati, Taliani, S., Pugliesi, I., Barresi, E., Simorini, F., Salerno, S., La Motta, C., Marini, A. M., Cosimelli, Barbara, Cosconati, S., DI MARO, Salvatore, Marinelli, Luciana, Daniele, S., Trincavelli, M. L., Greco, Giovanni, Novellino, Ettore, Martini, C., Da Settimo, F., Taliani, S, Pugliesi, I, Barresi, E, Simorini, F, Salerno, S, La Motta, C, Marini, Am, Cosimelli, B, Cosconati, Sandro, Marinelli, L, Daniele, S, Trincavelli, Ml, Greco, G, Novellino, E, and Martini, C

Subjects
Stereochemistry, Aryl, Chlorine atom, antagonist, Highly selective, Ring (chemistry), Adenosine receptor, chemistry.chemical_compound, pharmacology, Benzimidazoles, chemistry, Drug Discovery, Molecular Medicine, adenosine receptor, Selectivity, IC50
Abstract

In an effort to identify novel ligands possessing high affinity and selectivity for the A2B AR subtype, we further investigated the class of 3-aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones V, previously disclosed by us as selective A1 AR antagonists. Preliminary assays on a number of triazinobenzimidazoles derived from our "in-house" collection revealed that all the derivatives selected showed significant affinity at A 2B AR, no affinity at A3 AR, and various degrees of selectivity toward A1 and A2A ARs. Investigation of a new series featuring modified substituents at the 10-position (4′-chlorophenyl or phenylethyl groups), and a chlorine atom at the 7-position (X) of the triazinobenzimidazole nucleus, yielded highly potent and selective A 2B AR antagonists. The presence of a pendant 3-phenyl ring appears to hamper the interaction with A2A AR, conferring high A 2B/A2A AR selectivity. Derivative 13 (X = Cl, R = C 6H5) is the most potent and selective compound, with an IC50 of 3.10 nM at A2B AR and no affinity at A 1, A2A, and A3 ARs. © 2012 American Chemical Society.

Published
2012

39. Novel N(2)-Substituted Pyrazolo[3,4-d]pyrimidine Adenosine A(3) Receptor Antagonists: Inhibition of A(3)-Mediated Human Glioblastoma Cell Proliferation (dagger)

Author

Luciana Marinelli, Concettina La Motta, Claudia Martini, Giovanni Greco, Sandro Cosconati, Federico Da Settimo, L. Mugnaini, Simona Daniele, Barbara Cosimelli, Anna Maria Marini, Silvia Salerno, Osele Ciampi, Francesca Simorini, Maria Letizia Trincavelli, Sabrina Taliani, Vittorio Limongelli, Ettore Novellino, Taliani, S., La Motta, C., Mugnaini, L., Simorini, F., Salerno, S., Marini, A. M., Da Settimo, F., Cosconati, S., Cosimelli, Barbara, Greco, Giovanni, Limongelli, Vittorio, Marinelli, Luciana, Novellino, Ettore, Ciampi, O., Daniele, S., Trincavelli, M. L., Martini, C., Taliani, S, La Motta, C, Mugnaini, L, Simorini, F, Salerno, S, Marini, Am, Da Settimo, F, Cosconati, Sandro, Cosimelli, B, Greco, G, Limongelli, V, Marinelli, L, Novellino, E, Ciampi, O, Daniele, S, and Trincavelli, Ml

Subjects
Agonist, MAPK/ERK pathway, Models, Molecular, Pyrimidine, medicine.drug_class, Adenosine A3 Receptor Antagonists, Antineoplastic Agents, CHO Cells, Binding, Competitive, chemistry.chemical_compound, Radioligand Assay, Structure-Activity Relationship, Cricetulus, Adenosine A3 Receptor Agonists, Cell Line, Tumor, Cricetinae, Drug Discovery, medicine, Cyclic AMP, Animals, Humans, Phosphorylation, Cell Proliferation, Mitogen-Activated Protein Kinase 1, Glioblastoma cell, Mitogen-Activated Protein Kinase 3, Kinase, Chemistry, Molecular biology, Adenosine, Enzyme Activation, Pyrimidines, Biochemistry, Chemotherapy, Adjuvant, Molecular Medicine, Pyrazoles, Glioblastoma, Intracellular, medicine.drug
Abstract

Adenosine induces glioma cell proliferation by means of an antiapoptotic effect, which is blocked by cotreatment with selective A(3) AR antagonists. In this study, a novel series of N(2)-substituted pyrazolo[3,4-d]pyrimidines 2a-u was developed as highly potent and selective A(3) AR antagonists. The most performing compounds were derivatives 2a (R(1) = CH(3) and R(2) = COC(6)H(5); K(i) 334, 728, and 0.60 nM at the human A(1), A(2A), and A(3) ARs, respectively) and 2b (R(1) = CH(3) and R(2) = COC(6)H(4)-4-OCH(3); K(i) 1037, 3179, and 0.18 nM at the human A(1), A(2A), and A(3) ARs, respectively), which counteracted the effect of the A(3) AR agonists Cl-IB-MECA and IB-MECA on human glioma U87MG cell proliferation. This effect was concentration-dependent, with IC(50) values comparable to A(3) AR binding affinity values of 2a and 2b, thereby suggesting that their effects were receptor-mediated. Furthermore, the antiproliferative activity of the new compounds was demonstrated to be mediated by the block of A(3) AR agonist activation of intracellular kinases ERK 1/2.

Published
2010

40. Lenvatinib: an investigational agent for the treatment of differentiated thyroid cancer

Author

Mario Miccoli, Giovanni Guglielmi, Gilda Varricchi, Rudy Foddis, Poupak Fallahi, Francesca Ragusa, Alessandro Antonelli, Sabrina Rosaria Paparo, Silvia Martina Ferrari, Maria Rosaria Galdiero, Concettina La Motta, Valeria Mazzi, Giusy Elia, Salvatore Benvenga, Claudio Spinelli, Ferrari, S. M., Elia, G., Ragusa, F., Paparo, S. R., Mazzi, V., Miccoli, M., Galdiero, M. R., Varricchi, G., Foddis, R., Guglielmi, G., Spinelli, C., La Motta, C., Benvenga, S., Antonelli, A., and Fallahi, P.

Subjects
Oncology, Phenylurea Compound, medicine.medical_specialty, medicine.drug_class, medicine.medical_treatment, Quinoline, Protein Kinase Inhibitor, Antineoplastic Agents, lenvatinib, Tyrosine-kinase inhibitor, Antineoplastic Agent, chemistry.chemical_compound, tyrosine kinase inhibitor, Aggressive radioiodine-refractory differentiated thyroid cancer, thyroid cancer, tyrosine kinase inhibitors, Thyroid Hormone Treatment, Internal medicine, Follicular phase, medicine, Humans, Pharmacology (medical), Thyroid Neoplasms, Protein Kinase Inhibitors, Thyroid cancer, Thyroid Neoplasm, Pharmacology, Chemotherapy, business.industry, Phenylurea Compounds, Thyroidectomy, General Medicine, Drugs, Investigational, medicine.disease, Combined Modality Therapy, chemistry, Quinolines, Disease Progression, Lenvatinib, business, Hormone, Human
Abstract

Introduction Differentiated thyroid cancer (DTC; >90% of all TCs) derives from follicular cells. Surgery is the main therapeutic strategy, and radioiodine (RAI) is administered after thyroidectomy. When DTC progresses, it does not respond to RAI and thyroid-stimulating hormone (TSH)-suppressive thyroid hormone treatment, and other therapies (i.e. surgery, external beam radiation therapy and chemotherapy) do not lead to a better survival. Thanks to the understanding of the molecular pathways involved in TC progression, important advances have been done. Lenvatinib is a multitargeted tyrosine kinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRα, RET, and KIT signaling networks implicated in tumor angiogenesis, approved in locally recurrent or metastatic, progressive, RAI-refractory DTC. Unmet needs regarding the patient clinical therapy responsiveness in aggressive RAI-refractory DTC still remain. Areas covered We provide an overview from the literature of in vitro, in vivo and real-life studies regarding lenvatinib as an investigational agent for the treatment of aggressive TC. Expert opinion According to the SELECT trial, the treatment should be initiated with a dosage of 24 mg/day, subsequently decreasing it in relation to the side effects. The decision making process in patients with aggressive RAI-refractory DTC should be personalized and the potential toxicity should be properly managed.

Published
2021

41. New insights in the structure-activity relationships of 2-phenylamino-substituted benzothiopyrano[4,3-d]pyrimidines as kinase inhibitors

Author

Francesca Simorini, Lisa Dalla Via, Stefano Tomassi, Giorgio Amendola, Sabrina Taliani, Concettina La Motta, Anna Maria Marini, Elisabetta Barresi, Federico Da Settimo, Silvia Salerno, Ettore Novellino, Sandro Cosconati, Aída Nelly García-Argáez, Salerno, Silvia, García-Argáez, Aída Nelly, Barresi, Elisabetta, Taliani, Sabrina, Simorini, Francesca, La Motta, Concettina, Amendola, Giorgio, Tomassi, Stefano, Cosconati, Sandro, Novellino, Ettore, Da Settimo, Federico, Marini, Anna Maria, Via, Lisa Dalla, Salerno, S, García-Argáez, An, Barresi, E, Taliani, S, Simorini, F, La Motta, C, Amendola, G, Tomassi, S, Cosconati, S, Novellino, E, Da Settimo, F, Marini, Am, and Via, Ld.

Subjects
Models, Molecular, 0301 basic medicine, Pyrimidine, medicine.drug_class, Angiogenesis, Antineoplastic Agents, Antiproliferative activity, Monoclonal antibody, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cell Line, Tumor, Drug Discovery, Human Umbilical Vein Endothelial Cells, medicine, Humans, Protein Kinase Inhibitors, Cell Proliferation, Pyrans, Pharmacology, Kinase inhibitor, Aniline Compounds, Dose-Response Relationship, Drug, Molecular Structure, Kinase, Drug Discovery3003 Pharmaceutical Science, Organic Chemistry, Kinase insert domain receptor, General Medicine, Vascular Endothelial Growth Factor Receptor-2, Small molecule, Benzothiopyranopyrimidine, Pyrimidines, 030104 developmental biology, chemistry, Biochemistry, Kinase inhibitors, Cell culture, KDR kinase, 030220 oncology & carcinogenesis, Drug Screening Assays, Antitumor, Benzothiopyranopyrimidines, Signal transduction
Abstract

Inhibition of angiogenesis via blocking vascular endothelial growth factor receptor (VEGFR) signaling pathway emerged as an established approach in anticancer therapy. So far, many monoclonal antibodies and ATP-competitive small molecule inhibitors have been clinically validated and approved. In this study, structure-activity relationships (SAR) within the 2-phenylamino-substituted benzothiopyrano[4,3-d]pyrimidine class of kinase inhibitors were further refined by the synthesis and biological evaluation of new compounds 1–21 featuring different substitution patterns on the pendant phenyl moiety, combined with H, OCH3, or Cl at 8-position. Most compounds showed a promising human kinase insert domain receptor (KDR) inhibition profile, with IC50 values in the submicromolar/low micromolar range, and promising antiproliferative activity on human umbilical vein endothelial cells (HUVECs) as well as on a panel of three human tumor cell lines. The angio-kinase selectivity profile was assessed for the most promising compound 16 against a set of six human kinases. Finally, computational studies allowed clarifying at molecular level the interaction pattern established by the compounds with KDR, highlighting key stable cation-π interactions, and thus providing the basis for further designing novel inhibitors.

Published
2018

42. Synthesis, biological evaluation and molecular modeling of novel selective COX-2 inhibitors: sulfide, sulfoxide, and sulfone derivatives of 1,5-diarylpyrrol-3-substituted scaffold

Author

Maurizio Anzini, Giulia Chemi, Alessia Chelini, Germano Giuliani, Angela Di Capua, Lorenzo Di Cesare Mannelli, Gianluca Giorgi, Concettina La Motta, Annalisa Reale, Massimo Valoti, Antonietta Rossi, Lidia Sautebin, Simona Pace, Marco Paolino, Elena Lucarini, Andrea Cappelli, Simone Brogi, Alessandro Grillo, Carla Ghelardini, Reale, A., Brogi, S., Chelini, A., Paolino, M., Di Capua, A., Giuliani, G., Cappelli, A., Giorgi, G., Chemi, G., Grillo, A., Valoti, M., Sautebin, L., Rossi, A., Pace, S., La Motta, C., Di Cesare Mannelli, L., Lucarini, E., Ghelardini, C., and Anzini, M.

Subjects
Male, Molecular model, Clinical Biochemistry, Anti-Inflammatory Agents, Pharmaceutical Science, Carrageenan, Biochemistry, Sulfone, Rats, Sprague-Dawley, chemistry.chemical_compound, Mice, 1,5-Diarylpyrrole derivative, Drug Discovery, 1,5-Diarylpyrrole derivatives, Anti-inflammatory agents, Antinociceptive agents, COX-2 inhibitors, Molecular modeling, Sulfones, chemistry.chemical_classification, Analgesics, Molecular Structure, Sulfoxide, Biological activity, 5-Diarylpyrrole derivatives, Molecular Docking Simulation, Anti-inflammatory agent, Sulfoxides, Molecular Medicine, Protein Binding, Sulfides, Cell Line, Structure-Activity Relationship, In vivo, Antinociceptive Agents, Animals, Humans, Pyrroles, Rats, Wistar, COX-2 inhibitor, Molecular Biology, Inflammation, Cyclooxygenase 2 Inhibitors, Organic Chemistry, Antinociceptive agent, Combinatorial chemistry, In vitro, Enzyme, chemistry, Cyclooxygenase 2, Drug Design, 1,5-Diarylpyrrole derivatives, Anti-inflammatory agents, Antinociceptive agents, COX-2 inhibitors, Molecular modeling
Abstract

A novel series of 1,5-diarylpyrrol-3-sulfur derivatives (10–12) was synthesized and characterized by NMR and mass spectroscopy and x-ray diffraction. The biological activity of these compounds was evaluated in in vitro and in vivo tests to assess their COX-2 inhibitory activity along with anti-inflammatory and antinociceptive effect. Results showed that the bioisosteric transformation of previously reported alkoxyethyl ethers (9a-c) into the corresponding alkyl thioethers (10a-c) still leads to selective and active compounds being the COX-2 inhibitory activity for most of them in the low nanomolar range. The oxidation products of 10a,b were also investigated and both couple of sulfoxides (11a,b) and sulfones (12a,b) showed an appreciable COX-2 inhibitory activity. Molecular modeling studies were performed to investigate the binding mode of the representative compounds 10b, 11b, and 12b into COX-2 enzyme and to explore the potential site of metabolism of 10a and 10b due to the different in vivo efficacy. Among the developed compounds, compound 10b showed a significant in vivo anti-inflammatory and antinociceptive activity paving the way to develop novel anti-inflammatory drugs.

Published
2019

43. Effects of the New Aldose Reductase Inhibitor Benzofuroxane Derivative BF-5m on High Glucose Induced Prolongation of Cardiac QT Interval and Increase of Coronary Perfusion Pressure

Author

Maria Consiglia Trotta, Bartolo Ferraro, Stefania Sartini, C. La Motta, Francesca Ferraraccio, N. Di Carluccio, Rosa Maisto, Francesca Rossi, C Di Filippo, Michele D'Amico, DI FILIPPO, Clara, Ferraro, B., Maisto, R., Trotta, M. C., Di Carluccio, N., Sartini, S., La Motta, C., Ferraraccio, Franca, Rossi, Francesco, and D'Amico, Michele

Subjects
Male, 0301 basic medicine, Endocrinology, Diabetes and Metabolism, Endocrinology, Diabetic Cardiomyopathies, Blood Pressure, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Rats, Sprague-Dawley, Sirtuin 1, Heart Rate, Enos, Enzyme Inhibitors, Cardioprotection, biology, Forkhead Transcription Factors, Heart, Aldose reductase inhibitor, Diabetes and Metabolism, Perfusion, Research Article, medicine.drug, medicine.medical_specialty, Article Subject, Nerve Tissue Proteins, QT interval, 03 medical and health sciences, Aldehyde Reductase, Coronary Circulation, Internal medicine, medicine, Animals, Benzofurans, Cardiotoxicity, lcsh:RC648-665, Superoxide Dismutase, business.industry, Myocardium, Isolated Heart Preparation, biology.organism_classification, Surgery, Histone Deacetylase Inhibitors, Glucose, 030104 developmental biology, biology.protein, Coronary perfusion pressure, business
Abstract

This study investigated the effects of the new aldose reductase inhibitor benzofuroxane derivative 5(6)-(benzo[d]thiazol-2-ylmethoxy)benzofuroxane (BF-5m) on the prolongation of cardiac QT interval and increase of coronary perfusion pressure (CPP) in isolated, high glucose (33.3 mM D-glucose) perfused rat hearts. BF-5m was dissolved in the Krebs solution at a final concentration of 0.01 μM, 0.05 μM, and 0.1 μM. 33.3 mM D-glucose caused a prolongation of the QT interval and increase of CPP up to values of 190 ± 12 ms and 110 ± 8 mmHg with respect to the values of hearts perfused with standard Krebs solution (11.1 mM D-glucose). The QT prolongation was reduced by 10%, 32%, and 41%, respectively, for the concentration of BF-5m 0.01 μM, 0.05 μM, and 0.1 μM. Similarly, the CPP was reduced by 20% for BF-5m 0.05 μM and by 32% for BF-5m 0.1 μM. BF-5m also increased the expression levels of sirtuin 1, MnSOD, eNOS, and FOXO-1, into the heart. The beneficial actions of BF-5m were partly abolished by the pretreatment of the rats with the inhibitor of the sirtuin 1 activity EX527 (10 mg/kg/day/7 days i.p.) prior to perfusion of the hearts with high glucose + BF-5m (0.1 μM). Therefore, BF-5m supplies cardioprotection from the high glucose induced QT prolongation and increase of CPP.

Published
2016
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44. Sampling protein motion and solvent effect during ligand binding

Author

Luciana Marinelli, Concettina La Motta, L. Mugnaini, Michele Parrinello, Vittorio Limongelli, Stefania Sartini, Ettore Novellino, Federico Da Settimo, Sandro Cosconati, Limongelli, V, Marinelli, L, Cosconati, Sandro, La Motta, C, Sartini, S, Mugnaini, L, Da Settimo, F, Novellino, E, Parrinello, M., Limongelli, Vittorio, Marinelli, Luciana, Cosconati, S., Motta, C. L., Sartini, S., Mugnaini, L., Settimo, F. D., and Novellino, E.

Subjects
Models, Molecular, ADA ∣ well-tempered metadynamics ∣ ligand/protein docking ∣ path collective variables ∣ reweighting algorithm, Well-tempered metadynamic, Molecular dynamics, Ligands, 010402 general chemistry, 01 natural sciences, Molecular recognition, Computational chemistry, 0103 physical sciences, Multidisciplinary, Ligand/protein docking, 010304 chemical physics, Chemistry, Solvation, Metadynamics, Proteins, Reweighting algorithm, Biological Sciences, Ligand (biochemistry), 0104 chemical sciences, ADA, Docking (molecular), Biological target, Solvents, Solvent effects, Adenosine deaminase inhibitors, Algorithms, Protein Binding, Path collective variable
Abstract

An exhaustive description of the molecular recognition mechanism between a ligand and its biological target is of great value because it provides the opportunity for an exogenous control of the related process. Very often this aim can be pursued using high resolution structures of the complex in combination with inexpensive computational protocols such as docking algorithms. Unfortunately, in many other cases a number of factors, like protein flexibility or solvent effects, increase the degree of complexity of ligand/protein interaction and these standard techniques are no longer sufficient to describe the binding event. We have experienced and tested these limits in the present study in which we have developed and revealed the mechanism of binding of a new series of potent inhibitors of Adenosine Deaminase. We have first performed a large number of docking calculations, which unfortunately failed to yield reliable results due to the dynamical character of the enzyme and the complex role of the solvent. Thus, we have stepped up the computational strategy using a protocol based on metadynamics. Our approach has allowed dealing with protein motion and solvation during ligand binding and finally identifying the lowest energy binding modes of the most potent compound of the series, 4-decyl-pyrazolo[1,5- a ]pyrimidin-7-one.

Published
2012

45. Antiproliferative and proapoptotic activity of CLM3, a novel multiple tyrosine kinase inhibitor, alone and in combination with SN-38 on endothelial and cancer cells

Author

Teresa Di Desidero, Paola Orlandi, Anna Fioravanti, Bastianina Canu, Concettina La Motta, L. Mugnaini, Guido Bocci, Rita Frati, Paolo Miccoli, Sandro Cosconati, Piero Berti, Stefania Sartini, Romano Danesi, Federico Da Settimo, Alessandro Antonelli, Bocci, G, Fioravanti, A, La Motta, C, Orlandi, P, Canu, B, Di Desidero, T, Mugnaini, L, Sartini, S, Cosconati, Sandro, Frati, R, Antonelli, A, Berti, P, Miccoli, P, Da Settimo, F, and Danesi, R.

Subjects
medicine.drug_class, Angiogenesis, Tyrosine kinase inhibitor, CLM3, Antineoplastic Agents, Enzyme-Linked Immunosorbent Assay, Biology, Irinotecan, Biochemistry, Tyrosine-kinase inhibitor, Cyclin D1, Cell Line, Tumor, medicine, Humans, Phosphorylation, Protein Kinase Inhibitors, Pharmacology, tyrosine kinase inhibitor, Synergism, Endothelial stem cell, Angiogenesi, Pyrimidines, Gene Expression Regulation, Cancer cell, Cancer research, Pyrazoles, Camptothecin, Drug Therapy, Combination, Endothelium, Vascular, Signal transduction, Tyrosine kinase
Abstract

Aims: To demonstrate the antiproliferative and pro-apoptotic activity of the novel pyrazolopyrimidine derivative multiple tyrosine kinase inhibitor CLM3, alone and in combination with SN-38 (the active metabolite of irinotecan), on endothelial and tumor cells and to show its mechanism of action. Methods: Proliferation and apoptotic assays were performed on microvascular endothelial (HMVEC-d) and lung (A549) and thyroid cancer (8305C, TT) cell lines exposed to CLM3 and to the simultaneous combination with SN38 for 72 h. Cell-based phospho-VEGFR-2, phospho-EGFR and phospho-RET inhibition assays were performed and ERK1/2 and Akt phosphorylation were quantified by ELISA kits. Cyclin D1 gene expression was performed with real-time PCR and cyclin D1 intracellular concentrations were measured by ELISA. Results: A strong effect on antiproliferative and pro-apoptotic activity was found with the CLM3 on endothelial and cancer cells, synergistically enhanced by SN38. Phospho-VEGFR-2, phospho-EGFR and phospho-RET levels significantly decreased after CLM3 treatments in activated endothelial and cancer cells; ERK1/2 and Akt phosphorylation were significantly inhibited by lower concentrations of the pyrazolopyrimidine drug in endothelial cells if compared to cancer cells. Moreover, CLM3 treatment greatly inhibited the expression of the cyclin D1 gene in endothelial and cancer cells, decreasing the cyclin D1 protein intracellular concentration. Conclusions: The pyrazolopyrimidine derivative CLM3 demonstrated a highly significant and promising antiproliferative and proapoptotic activity, alone and in combination with SN-38, for activated endothelial and cancer cells. These effects are mainly due to its inhibition of phosphorylation of VEGFR-2, EGFR and RET tyrosine kinases and their related signaling pathways. © 2011 Elsevier Inc. All rights reserved.

Published
2011

46. Non-Nucleoside Inhibitors of Human Adenosine Kinase: Synthesis, Molecular Modeling, and Biological Studies

Author

Sandra Gemma, Giovanni Maga, Stefania Butini, Ettore Novellino, Federico Da Settimo, Giuseppe Borrelli, Valeria La Pietra, Andrea Lossani, Daniela M. Zisterer, F. Focher, Andrea Torti, Stefania Sartini, Isabella Fiorini, Seema-Maria Nathwani, Giuseppe Campiani, Stefania Lamponi, Luciana Marinelli, Concettina La Motta, Anna Maria Ponte, Margherita Brindisi, Butini, S., Gemma, S., Brindisi, M., Borrelli, G., Lossani, A., Ponte, A. M., Torti, A., Maga, G., Marinelli, Luciana, LA PIETRA, Valeria, Fiorini, I., Lamponi, S., Campiani, G., Zisterer, D. M., Nathwani, S. M., Sartini, S., La Motta, C., Da Settimo, F., Novellino, Ettore, and Focher, F.

Subjects
Models, Molecular, Adenosine Kinase Inhibitors, Molecular model, Stereochemistry, Antineoplastic Agents, Apoptosis, Adenosine kinase, Mice, Structure-Activity Relationship, Allosteric Regulation, Cell Line, Tumor, Drug Discovery, medicine, Animals, Humans, Pyrroles, Adenosine Kinase, Cell Proliferation, chemistry.chemical_classification, Biological studies, biology, Chemistry, Stereoisomerism, DNA, Adenosine, Recombinant Proteins, Oxazepines, Enzyme, Biochemistry, biology.protein, RNA, Molecular Medicine, Phosphorylation, Drug Screening Assays, Antitumor, Nucleoside, Allosteric Site, medicine.drug
Abstract

Adenosine kinase (AK) catalyzes the phosphorylation of adenosine (Ado) to AMP by means of a kinetic mechanism in which the two substrates Ado and ATP bind the enzyme in a binary and/or ternary complex, with distinct protein conformations. Most of the described inhibitors have Ado-like structural motifs and are nonselective, and some of them (e.g., the tubercidine-like ligands) are characterized by a toxic profile. We have cloned and expressed human AK (hAK) and searched for novel non-substrate-like inhibitors. Our efforts to widen the structural diversity of AK inhibitors led to the identification of novel non-nucleoside, noncompetitive allosteric modulators characterized by a unique molecular scaffold. Among the pyrrolobenzoxa(thia)zepinones (4a-qq) developed, 4a was identified as a non-nucleoside prototype hAK inhibitor. 4a has proapoptotic efficacy, slight inhibition of short-term RNA synthesis, and cytostatic activity on tumor cell lines while showing low cytotoxicity and no significant adverse effects on short-term DNA synthesis in cells.

Published
2011

47. Exploiting the Pyrazolo[3,4-d]pyrimidin-4-one Ring System as a Useful Template To Obtain Potent Adenosine Deaminase Inhibitors

Author

Concettina La Motta, Mario Del Tacca, Matteo Fornai, Francesca Simorini, Silvia Salerno, Antonio Lavecchia, Ettore Novellino, Sabrina Taliani, Federico Da Settimo, Anna Maria Marini, Corrado Blandizzi, Luca Antonioli, L. Mugnaini, Stefania Sartini, LA MOTTA, C., Sartini, S., Mugnaini, L., Salerno, S., Simorini, F., Taliani, S., Marini, A. M., DA SETTIMO, F., Lavecchia, Antonio, Novellino, Ettore, Antonioli, L., Fornai, M., Blandizzi, C., and DEL TACCA, M.

Subjects
Pyridines, Stereochemistry, Chemical synthesis, Structure-Activity Relationship, chemistry.chemical_compound, Adenosine deaminase, In vivo, Catalytic Domain, Drug Discovery, Adenosine Deaminase Inhibitors, Animals, Structure–activity relationship, Enzyme Inhibitors, chemistry.chemical_classification, Trifluoromethyl, Dose-Response Relationship, Drug, biology, Colitis, Rats, Enzyme, chemistry, Docking (molecular), biology.protein, Pyrazoles, Molecular Medicine, Adenosine Deaminase Inhibitor
Abstract

A number of pyrazolo[3,4-d]pyrimidin-4-ones bearing either alkyl or arylalkyl substituents in position 2 of the nucleus were synthesized and tested for their ability to inhibit adenosine deaminase (ADA) from bovine spleen. The 2-arylalkyl derivatives exhibited excellent inhibitory activity, showing Ki values in the nanomolar/subnanomolar range. The most active compound, 1-(4-((4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-2-yl)methyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea, 14d, was tested in rats with colitis induced by 2,4-dinitrobenzenesulfonic acid to assess its efficacy to attenuate bowel inflammation. The treatment with 14d induced a significant amelioration of both systemic and intestinal inflammatory alterations in animals with experimental colitis. Docking simulations of the synthesized compounds into the ADA catalytic site were also performed to rationalize the structure−activity relationships observed and to highlight the key pharmacophoric elements of these products, thus prospectively guiding the design of novel ADA inhibitors.

Published
2009

48. 5-Amino-2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1-one: A Versatile Scaffold To Obtain Potent and Selective A3 Adenosine Receptor Antagonists

Author

Concettina La Motta, Giampaolo Primofiore, Francesca Simorini, Adriano Martinelli, Ettore Novellino, V. Sergianni, Sabrina Taliani, Giovanni Greco, Maria Letizia Trincavelli, Claudia Martini, Tiziano Tuccinardi, B Cosimelli, Osele Ciampi, Anna Maria Marini, Silvia Salerno, Federico Da Settimo, Da Settimo, F., Primofiore, G., Taliani, S., Marini, A. M., La Motta, C., Simorini, F., Salerno, S., Sergianni, V., Tuccinardi, T., Martinelli, A., Cosimelli, Barbara, Greco, Giovanni, Novellino, Ettore, Trincavelli, M. L., and Martini, C.

Subjects
Models, Molecular, Molecular model, Stereochemistry, Adenosine A3 Receptor Antagonists, CHO Cells, Binding, Competitive, Chemical synthesis, Amidine, Radioligand Assay, Structure-Activity Relationship, chemistry.chemical_compound, Cricetulus, Cricetinae, Amide, Drug Discovery, Cyclic AMP, Animals, Humans, Moiety, Receptor, Triazines, Chemistry, Triazoles, Adenosine receptor, Docking (molecular), Molecular Medicine
Abstract

Binding assays on human A1, A2A, and A3 adenosine receptors (ARs) and functional studies on A2B ARs revealed that various 2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1,5(6H)-diones VIII, previously reported as ligands at the central benzodiazepine receptor (BzR), possess nanomolar affinity at the A3 AR. Replacement of the amide of VIII with an amidine moiety gave the 5-amino-2-phenyl[1,2,3]triazolo[1, 2-a][1,2,4]benzotriazin-1-ones IX, which maintain a nanomolar potency at the A3 AR with selectivity over the BzR. Insertion of a p-methoxybenzoyl at the 5-amino moiety enhanced A3 AR affinity and selectivity over the A1, A2A, and A2B ARs. The best result of our lead optimization efforts is 9-chloro-5-(4-methoxybenzoyl)amino-2-phenyl[1, 2,3]triazolo[1,2-a][1,2,4]benzotriazin-1-one (23), which displayed a K i of 1.6 nM at the A3 AR and no significant affinity at the other ARs or the BzR. Docking simulations on selected ligands into a model of the A3 AR allowed us to rationalize the structure-activity relationships of phenyltriazolobenzotriazindiones VIII and aminophenyltriazolobenzotriazinones IX at the molecular level. © 2007 American Chemical Society.

Published
2007

49. Deepening the Topology of the Translocator Protein Binding Site by Novel N,N-Dialkyl-2-arylindol-3-ylglyoxylamides

Author

Barbara Cosimelli, Simona Daniele, Anna Maria Marini, Eleonora Da Pozzo, Francesca Simorini, Luciana Marinelli, Concettina La Motta, Elisabetta Barresi, Sabrina Taliani, Chiara Giacomelli, Claudia Martini, Federico Da Settimo, Sandro Cosconati, Silvia Salerno, Giovanni Greco, Agostino Bruno, Ettore Novellino, Barresi, Elisabetta, Bruno, Agostino, Taliani, Sabrina, Cosconati, Sandro, Da Pozzo, Eleonora, Salerno, Silvia, Simorini, Francesca, Daniele, Simona, Giacomelli, Chiara, Marini, Anna Maria, La Motta, Concettina, Marinelli, Luciana, Cosimelli, Barbara, Novellino, Ettore, Greco, Giovanni, Da Settimo, Federico, Martini, Claudia, Barresi, E, Bruno, A, Taliani, S, Da Pozzo, E, Salerno, S, Simorini, F, Daniele, S, Giacomelli, C, Marini, Am, La Motta, C, Marinelli, L, Cosimelli, B, Novellino, E, Greco, G, Da Settimo, F, and Martini, C.

Subjects
Binding Sites, Indoles, biology, Ligand, Stereochemistry, Chemistry, Drug Discovery3003 Pharmaceutical Science, Rats, Structure-Activity Relationship, GABA metabolism, Receptors, GABA, Docking (molecular), Molecular Medicine, Drug Discovery, Mitochondrial Membranes, Translocator protein, biology.protein, Structure–activity relationship, Animals, Binding site, Group performance
Abstract

As a continuation of our studies on 2-phenylindol-3-ylglyoxylamides as potent and selective translocator protein (TSPO) ligands, two subsets of novel derivatives, featuring hydrophilic group (OH, NH2, COOH) at the para-position of the pendent 2-phenyl ring (8-16) or different 2-aryl moieties, namely, 3-thienyl, p-biphenyl, 2-naphthyl (23-35), were synthesized and biologically evaluated, some of them showing K-i values in the subnanomolar range and the 2-naphthyl group performance being the best. The resulting SARs confirmed the key role played by interactions taking place between ligands and the lipophilic Li pocket of the TSPO binding site. Docking simulations were performed on the most potent compound of the present series (29) exploiting the recently available 3D structures of TSPO bound to its standard ligand (PK11195). Our theoretical model was fully consistent with SARs of the newly investigated as well of the previously reported 2-phenylindol-3-ylglyoxylamide derivatives.

Published
2015

50. Investigation of new 2-aryl substituted Benzothiopyrano[4,3-d[pyrimidines as kinase inhibitors targeting vascular endothelial growth factor receptor 2

Author

Guido Bocci, Silvia Salerno, Ettore Novellino, Sabrina Taliani, Sandro Cosconati, Stefania Sartini, Concettina La Motta, Lisa Dalla Via, Paola Orlandi, Federico Da Settimo, Anna Fioravanti, Anna Maria Marini, Pilar D'Ocon, Ornella Gia, Francesca Simorini, Aída Nelly García-Argáez, G. Fornaciari, Salerno, S, Marini, Am, Fornaciari, G, Simorini, F, La Motta, C, Taliani, S, Sartini, S, Da Settimo, F, García Argáez, An, Gia, O, Cosconati, Sandro, Novellino, E, D'Ocon, P, Fioravanti, A, Orlandi, P, Bocci, G, and Dalla Via, L.

Subjects
Models, Molecular, Angiogenesis, Receptor tyrosine kinase, Cell, Antineoplastic Agents, Benzothiopyranopirimidines, Kinase inhibitors, Receptor tyrosine kinases, Tumor angiogenesis, VEGFR, Structure-Activity Relationship, chemistry.chemical_compound, Benzothiopyranopirimidine, Cell Line, Tumor, Drug Discovery, Human Umbilical Vein Endothelial Cells, medicine, Humans, Protein Kinase Inhibitors, Cell Proliferation, Pyrans, Tumor angiogenesi, Pharmacology, Kinase inhibitor, Dose-Response Relationship, Drug, Molecular Structure, biology, Kinase, Cell growth, Organic Chemistry, Kinase insert domain receptor, General Medicine, Vascular Endothelial Growth Factor Receptor-2, Molecular biology, Vascular endothelial growth factor, Pyrimidines, medicine.anatomical_structure, chemistry, Cancer research, biology.protein, Drug Screening Assays, Antitumor, Ex vivo
Abstract

Vascular Endothelial Growth Factor (VEGF) pathway has emerged as one of the most important positive modulators of Angiogenesis, a central process implicated in tumour growth and metastatic dissemination. This led to the design and development of anti-VEGF monoclonal antibodies and small-molecule ATP-competitive VEGFR-inhibitors. In this study, we describe the synthesis and the biological evaluation of novel 2-aryl substituted benzothiopyrano-fused pyrimidines 1a-i, 2a-i and 3a-i. The ability of the compounds to target the VEGF pathway was determined in vitro exploiting the compounds' antiproliferative efficacy against HUVEC cells. The VEGFR-2 inhibition was confirmed by enzymatic assays on recombinant human kinase insert domain receptor (KDR), by cell-based phospho-VEGFR-2 inhibition assays, and by ex vivo rat aortic ring tests. The selectivity profile of the best performing derivatives belonging to series 2 was further explored combining modeling studies and additional assays in a panel of human cell lines and other kinases.

Published
2015

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