Drug Design and Synthesis Center

Notizie generali
Responsabile scientifico / Coordinatore: 
Settori ERC: 
LS7_3 - Pharmacology, pharmacogenomics, drug discovery and design, drug therapy
PE5_17 - Organic chemistry
PE6_12 - Scientific computing, simulation and modelling tools
Attivita di ricerca: 

Progettazione e sintesi di nuove entità chimiche di interesse farmaceutico.

Aree di interesse
  1. Antiviral agents (HIV, HCV)
  2. Antifungal agents (azole)
  3. Antitumor agents (tubulin, kinase, protein-protein)
  4. Antiinflammatory drugs
  5. CNS agents (endocannabinoid, MAO)
Progetti di ricerca
  • Design and Synthesis of Tubulin polymerization inhibitors. Drugs able to modulate the microtubule assembly either by inhibition of tubulin polymerization or blocking microtubule disassembly are of great interest in anticancer therapy. Arylthioindoles (ATIs) bearing a 5-member heterocyclic nucleus at position 2 of the indole strongly inhibit tubulin polymerization and cancer cell growth. These compounds induce mitotic arrest and apoptosis at a similar level as combretastatin A-4 and vinblastine, and trigger caspase-3 expression in a significant fraction of cells in both p53-proficient and p53-defective cell lines. These ATIs are highly effective as growth inhibitors of the P-glycoprotein-overexpressing NCI/ADR-RES cells, and show good pharmacokinetic properties. We have carried out a computer-aided drug design lead optimization project.
  • Antiviral agents. HIV-1 non-nucleoside reverse transcriptase inhibitors. The anti-HIV-1 activity of indolyl aryl sulfones (IASs) against the NNRTI-resistant mutants is correlated to the presence of a 3-(3,5-dimethylphenyl)sulfonyl moiety. The antiretroviral potency may be modulated by the substituents at the nitrogen of the 2-carboxamide and at the positions 4-7 of the indole. The aim of this research project is to optimise the IAS structure to obtain novel agents endowed with broad spectrum of activity against HIV-1 WT and mutant strains carrying the most common resistance mutations.
  • HCV agents. The goal of this research is the drug design and synthesis of potent inhibitors of the HCV NS5B polymerase. Specifically, we carry out computational studies into the HCV NS5B polymerase binding site, which is characterized by crystallographic studies. The docking results are compared with the co-crystallized poses of the most active HCV NS5B polymerase inhibitors.
  • Allosteric Modulators of the Cannabinoid CB1 Receptor. The identification of the CB1 allosteric binding site has prompted the search for other allosteric ligands as new therapeutic tools. Allosteric enhancers of the CB1 receptor may lead to useful agents without the CNS side effects that are characteristic of direct receptor agonism because they would be inactive per se and potentiate the effects of endogenous ligands. This project aims to investigate SARs of CB1 allosteric ligands using a medicinal chemistry approach.
  • Microwave Synthesis. Pursuing our interest in organic synthesis of heterocyclic compounds, the aim of this project is the achievement of small libraries of agents of biological interest under microwave-assisted venting-while-heating synthesis.
Pubblicazioni
  • Open vessel and cooling while heating microwave-assisted synthesis of pyridinyl N-aryl hydrazones. La Regina, G.; Gatti, V.; Piscitelli, F.; Silvestri R. ACS Combinatorial Science 2011, 13, 2-6.
  • Indolylarylsulfones as HIV-1 non-nucleoside reverse transcriptase inhibitors. New cyclic substituents at the indole-2-carboxamide. La Regina, G.; Coluccia, A.; Brancale, A.; Piscitelli, F.; Gatti, V.; Maga, G.; Samuele, A.; Pannecouque, C.; Schols, D.; Balzarini, J.; Novellino, E.; Silvestri, R. J. Med. Chem. 2011, 54, 1587-1598.
  • Mechanism of interaction of novel indolyl arylsulfone derivatives with K103N and Y181I mutant HIV-1 reverse transcriptase in complex with its substrates. Samuele, A.; Bisi, S.; Kataropoulou, A.; La Regina, G.; Piscitelli, F.; Gatti, V.; Silvestri, R.; Maga G. Antiviral Chem. Chemoth. 2011, 22, 107-118.
  • Drug induced inhibition of tubulin polymerization induces mitochondrion-mediated apoptosis in yeast. Palermo, V.; Silvestri, R.; La Regina, G.; Falcone, C.; Mazzoni, C. Cell Cycle 2011, 10, 3208-3209.
  • 1-Aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamide: an effective scaffold for the design of either CB1 or CB2 receptor ligands. Piscitelli, F.; Ligresti, A.; La Regina, G.; Gatti, V.; Brizzi, A.; Pasquini, S.; Allarà, M.; Carai, M. A. M.; Novellino, E.; Colombo, G.; Di Marzo, V.; Corelli, F.; Silvestri, R. Eur. J. Med. Chem. 2011, 46, 5641-5653.
  • The tubulin colchicine domain: a molecular modelling perspective. Massarotti, A.; Coluccia, A.; Silvestri, R.; Brancale, A. ChemMedChem 2012, 7, 33-42.
  • Design and synthesis of 2-heterocyclyl-3-arylthio-1H-indoles as potent tubulin polymerization and cell growth inhibitors with improved metabolic stability. La Regina, G.; Bai, R.; Rensen, W.; Coluccia, A.; Piscitelli, F.; Gatti, V.; Bolognesi, A.; Lavecchia, A.; Granata, I.; Porta, A.; Maresca, B.; Soriani, A.; Iannitto, M. L.; Mariani, M.; Santoni, A.; Brancale, A.; Ferlini, C.; Dondio, G.; Varasi, M.; Mercurio, C.; Hamel, E.; Lavia, P.; Novellino, E.; Silvestri, R. J. Med. Chem. 2011, 54, 8394-8406.
  • De novo computer-aided design of novel antiviral agents. Massarotti, A.; Coluccia, A.; Sorba, G.; Silvestri, R.; Brancale, A. Drug Discovery Today, 2011, 9, e213-e218.
  • Venting while heating microwave-assisted synthesis of 3-arylthioindoles. La Regina, G.; Gatti, V.; Famiglini, V.; Piscitelli, F.; Silvestri, R. ACS Comb. Science 2012, 14, 258-262.
  • Indole-2-carboxamides as allosteric modulators of the cannabinoid CB1 receptor. Piscitelli, F.; Ligresti, A.; La Regina, G.; Coluccia, A.; Allarà, M.; Novellino, E.; Di Marzo, V.; Silvestri, R. J. Med. Chem. 2012, 55, 5627-5631.
  • New nitrogen containing substituents at the indole-2-carboxamide yield high potent and broad spectrum indolylarylsulfone HIV-1 non-nucleoside reverse transcriptase inhibitors. La Regina, G.; Coluccia, A.; Brancale, B.; Piscitelli, F.; Gatti, V.; Maga, G.; Samuele, A.; Gonzalez, E.; Clotet, B.; Schols, D.; Esté, J. A.; Novellino, E.; Silvestri, R. J. Med. Chem. 2012, 55, 6634-6638.
  • Apple can acts as anti-aging on yeast cells. Palermo, V.; Mattivi, F.; Silvestri, R.; La Regina, G.; Falcone, C.; Mazzoni, C. Oxidative Med. Cell. Longevity 2012, 1-8.
  • Towards highly potent cancer agents by modulating the C-2 group of the arylthioindole class of tubulin polymerization inhibitors. La Regina, G.; Bai, R.; Rensen, W.M.; Di Cesare, E.; Coluccia, A.; Piscitelli, F.; Famiglini, V.; Reggio, A.; Nalli, M.; Pelliccia, S.; Da Pozzo, E.; Costa, B.; Granata, I.; Porta, A.; Maresca, B.; Soriani, A.; Iannitto, M. L.; Santoni, A.; Li, J.; Miranda Cona, M.; Chen. F.; Ni, Y.; Brancale, A.; Dondio, G.; Vultaggio, S.; Varasi, M.; Mercurio, C.; Martini, C.; Hamel, E.; Lavia, P.; Novellino, E.; Silvestri, R. J. Med. Chem. 2013, 56, 123-149.
  • New prospects for vinblastine analogues as anticancer agents. Silvestri, R. J. Med. Chem. 2013, 56, 625-627.
  • Computer-aided identification, design and synthesis of a novel series of compounds with selective antiviral activity against chikungunya virus. Bassetto, M.; De Burghgraeveb, T.; Delangb, L.; Massarotti, A.; Coluccia, A.; Zonta, N.; Gatti, V.; Colombano, G.; Sorba, G.; Silvestri, R.; Tron, G. C.; Neyts, J.; Leyssen, P.; Brancale, A. Antiviral Research 2013, 98, 12-18.
  • Exploring (4-substituted-thiazol-2-yl)hydrazine derivatives of 2-, 3-, and 4-acetylpyridine as selective and reversible hMAO-B inhibitors. Chimenti, P.; Petzer, A.; Carradori, S.; D’Ascenzio, M.; Silvestri, R.; Alcaro, S.; Ortuso, F.; Petzer, J. J.; Secci, D. Eur. J. Med. Chem. 2013, 66, 221-227.
  • Arylsulfone-based HIV-1 non-nucleoside reverse transcriptase inhibitors. Famiglini, V.; Coluccia, A.; Brancale, A.; La Regina, G.; Silvestri, R. Future Med. Chem. 2013, 5, 2141-2156.
  • Design, synthesis, and biological evaluation of 1-phenylpyrazolo[3,4-e]pyrrolo[3,4-g]indolizine-4,6(1H,5H)-diones as new glycogen synthase kinase-3 inhibitors. La Pietra, V.; La Regina, G.; Coluccia, A.; Famiglini, V.; Pelliccia, S.; Plotkin, B.; Eldar-Finkelman, H.; Brancale, A.; Ballatore, C.; Crowe, A.; Brunden, K. R.; Marinelli, L.; Novellino, E.; Silvestri, R. J. Med. Chem. 2013, 56, 10066-10078.
  • An high-throughput in vivo screening system to select H3K4-specific histone demethylase inhibitors.
    Mannironi, C.; Proietto, M.; Bufalieri, F.; Cundari, E.; Alagia, A.; Danovska, S.; Rinaldi, T.; Famiglini, V.; Coluccia, A.; La Regina, G.; Silvestri, R.; Negri. R. PlosOne 2014, 9, e86002.