Research | Projects

DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF SMALL MOLECULE MODULATORS OF PROTEIN LYSINE METHYLTRANSFERASES (PKMTS)

- The first objective of this project will be the design and the synthesis of a small library of putative modulators of G9a. At first we will use 6,7-dimethoxyquinazoline analogues (potent and selective substrate competitive inhibitors of G9a) as lead compounds. These inhibitors, in fact, are generally excellent tools in vitro but are inadequate for animal studies due to their poor in vivo pharmacokinetic properties. - The second objective will be the design and the synthesis of a small library of putative modulators of Pr-Set7. To this aim, we will consider the optimization of dye-like scaffolds previously identified by our group.- The third part of the project will be aimed at evaluating the biological activity of novel compounds. All the derivatives will be preliminarily screened using AlphaScreen® technology. The most interesting derivatives will be further investigated to validate their capability to inhibit target enzymes in cellular assays. - The fourth part of the project will be the hit-to-lead optimization of most interesting active compounds. Basing on the preliminary structure-activity relationships obtained, the optimization will be driven by classical medicinal chemistry approaches, such as bioisosterism, frozen analog approach, insertion of privileged structures, appendage diversity etc., approaches already successfully used by our research group in the development of modulators of epigenetic enzymes.Elenco 2n+1 lavori da considerare:1) M. Vecellio, F. Spallotta, S. Nanni, C. Colussi, C. Cencioni, A. Derlet, B. Bassetti, M. Tilenni, M. C. Carena, A. Farsetti, GIANLUCA SBARDELLA, SABRINA CASTELLANO, A. Mai, F. Martelli, G. Pompilio, M. C. Capogrossi, A. Rossini, S. Dimmeler, A. M. Zeiher, C. GaetanoThe Histone Acetylase Activator Pentadecylidenemalonate 1b Rescues Proliferation and Differentiation in Human Cardiac Mesenchymal Cells of Type 2 Diabetic Patients, Diabetes, 2014, 63, 2132–2147. DOI: 10.2337/db13-0731IF: 8,474; FC: 1; Tot: 8,4742) SABRINA CASTELLANO, S. Taliani, C. Milite, I. Pugliesi, E. Da Pozzo, E. Rizzetto, S. Bendinelli, B. Costa, S. Cosconati, G. Greco, E. Novellino, GIANLUCA SBARDELLA, G. Stefancich, C. Martini, and F. Da Settimo, Synthesis and Biological Evaluation of 4-Phenylquinazoline-2-carboxamides Designed as a Novel Class of Potent Ligands of the Translocator Protein J. Med. Chem. 2012, 55, 4506–4510. doi: 10.1021/jm201703kIF: 5,48; FC:1,5; Tot: 8,223) SABRINA CASTELLANO, A. Spannhoff, C. Milite, F. Dal Piaz, D. Cheng, A. Tosco, M. Viviano, A. Yamani, A. Cianciulli, M. Sala, V. Cura, J. Cavarelli, E. Novellino, A. Mai, M. T. Bedford, and GIANLUCA SBARDELLA*,Identification of Small-Molecule Enhancers of Arginine Methylation Catalyzed by Coactivator-Associated Arginine Methyltransferase 1J. Med. Chem. 2012, 55, 9875–9890. DOI: 10.1021/jm301097pIF: 5,48; FC:1,5; Tot: 8,224) SABRINA CASTELLANO, S. Taliani, M. Viviano, C. Milite, E. Da Pozzo, B. Costa, E. Barresi, A. Bruno, S. Cosconati, L. Marinelli, G. Greco, E. Novellino, GIANLUCA SBARDELLA, F. Da Settimo, C. MartiniStructure–Activity Relationship Refinement and Further Assessment of 4-phenylquinazoline-2-carboxamide Translocator Protein (TSPO) Ligands as Antiproliferative Agents in Human Glioblastoma Tumors.J. Med. Chem. 2014, 57, 2413–2428. DOI: 10.1021/jm401721hIF: 5,48; FC:1,5; Tot: 8,225) E. Calabrese, SABRINA CASTELLANO*, M. Santoriello, C. Sgherri, M. Quartacci, L. Calucci, A. Warrilow, D. Lamb, S. Kelly, C. Milite, I. Granata, GIANLUCA SBARDELLA, G. Stefancich, B. Maresca, A. PortaAntifungal Activity of Azole Compounds CPA18 and CPA109 against Azole-Susceptible and -Resistant Strains of J. Antimicrob. Chemother. 2013, 68(5), 1111–1119. DOI: 10.1093/jac/dks506.IF: 5,439; FC: 1,5; Tot: 8,1585