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Drug Design and Synthesis Center (CHIM/08)

Head of Laboratory: Romano Silvestri 
Laboratory: Synthesis and Computational studies (CHIM/08)
Sito web: surf the link 



Main research topics:

The Drug Design and Synthesis Center (DDSC) research activity is focused on the achievement of new chemical entities in the areas of antiviral, anticancer and CNS agents to develop new potential drugs.
1- Development on Anticancer Agents:
 the strategy of inducing cell death through an interference with the dynamics of microtubules has proved to be successful in the design of effective antitumor drugs. Aim of this project is the design and synthesis of new microtubule targeting agents as inhibitors of tubulin polymerization to develop drug candidate for cancer treatment, including breast cancer, glioblastoma and leukemia.
2- Novel Antiviral Agents: the overall goal is to design novel inhibitors for different viruses and to develop them into potent lead candidates for antiviral therapy. Current research projects are focused on HIV-1, Norovirus, Dengue, and Zika viruses.
3- Novel CNS Agents: this research project has been focused on the development of highly effective CNS agents as monoamine oxidase inhibitors and CB1endocannabinoid receptor ligands.
4- DDSC Computational Drug Design Platform: DDSC can support a wide variety of drug discovery research projects by means of modern computational methodologies to guide the hit-to-lead optimization process and to develop them into drug candidates.
5- Microwave-assisted synthesis: The work is focused on the development of new procedures for microwave-assisted synthesis of heterocyclic compounds of pharmaceutical interest.



National and International Collaborations: 


Anticancer agents:
Ernest Hamel, National Cancer Institute, National Institutes of Health, Frederick, USA;
Andrea Brancale,Cardiff University, Cardiff, UK;
Carmela Mazzoccoli, IRCCS, C. di Riferimento Oncologico della Basilicata, Rionero in V., It;
Patrizia Lavia, Istituto di Biologia Molecolare del CNR, Roma, It;
Daniel Merk, Goethe-University, Frankfurt, De.
Antiviral agents: 
José A. Esté, IrsiCaixa, Universitat Autonóma de Barcelona, Badalona, Es;
Giovanni Maga, Istituto di Genetica Molecolare, CNR, Pavia, It;
Johan Neyts, KU Leuven, Be;
Jin-Ching Lee, Kaohsiung Medical University, Taiwan, Tw;
Eloise Mastrangelo, CNR-IBF, Milano, It;
Daniele Castagnolo, King's College, London, UK.
Endocannabinoid ligands: 
Vincenzo di Marzo, Istituto di Chimica Biomolecolare, CNR, Pozzuoli, It;
Giancarlo Colombo, Istituto di Neuroscienza, CNR, Cagliari, It.

Facilities:

Synthetic unit: CEM Discover SP single-mode reactor equipped with an Explorer 72 autosampler, PerkinElmer Spectrum 100 FT-IR spectrophotometer equipped with ATR accessory, NMR Bruker Avance (400 MHz) spectrometer equipped with 12-position autosampler, Thermo Fisher Scientific Inc. Dionex UltiMate 3000 HPLC system. Computational unit: Schrodinger suite; GOLD, PLANTS and Autodock (docking); AMBER, Gromacs (Molecular Dynamics); LeadIt (core hopping and rebranching); MolInspiration (ADME prediction).

ERC panels:
Pharmacology, pharmacogenomics, drug discovery and design, drug therapy (LS7_3)
Organic chemistry (PE5_17)
Cardiovascular diseases (LS4_7)
Food sciences (including food technology, nutrition) (LS9_5)
Cancer and its biological basis (LS4_6)

Grants (2015-2018):
A.C.R.A.F. S.p.A. Synthesis of a series of tetrahydro-1H-pyrazolopyridine and imidazopyridine derivatives" (cod. 132CS16122).
PRIN 2015. Research project entitled “New prospects to treat glioblastoma multiforme (GBM) through a multi-target approach".
Sapienza University 2017. Research project entitled “New 3-aroyl-1,4diarypyrroles as inhibitors of cancer cell as chronic myeloid leukaemia cells thought interaction with tubulin”.
Finanziamenti di Ateneo 2017, Sapienza Università di Roma: Hit to lead optimization of arylthioindoles and aroylindoles as modern anticancer agents (RP11715C7D1CF0D1).
Ricerche Universitarie 2015, Sapienza Università di Roma: New inhibitors of tubulin polymerization as anticancer agents endowed with stimulation of natural killer cell cytotoxic activity and repression of Hedgehog signalling pathway (C26A15J3BB).
Finanziamenti Ateneo 2016, Sapienza Università di Roma: Targeting colchicine binding site of tubulin by indole- and pyrrole-based anticancer agents (RG116154CF287B95).

Laboratory Members:

Romano Silvestri
Synthetic unit:
Giuseppe La Regina, 
Marianna Nalli, 
Valentina Naccarato, PhD student
Domiziana Masci, PhD student
Computational unit
Antonio Coluccia, 
Chiara Esposito, graduate fellow

Publication 2015-2018

1. D. Manvar,S. Pelliccia, G. La Regina, V. Famiglini, A. Coluccia, A. Ruggieri, S. Anticoli,J.-C. Lee, A. Basu, O. Cevik,L. Nencioni, A. T. Palamara,C. Zamperini, M. Botta,J. Neyts, P. Leyssen,N. Kaushik-Basu, R. Silvestri. New 1-phenyl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides inhibit Hepatitis C virus replication via suppression of cyclooxygenase-2. Eur. J. Med. Chem.2015, 90, 497-506 (doi: 10.1016/j.ejmech.2014.11.042, ISI IF 2014: 3.447).

2. S. Generoso, M. Giustiniano, G. La Regina, S. Passacantilli, H. Cassese, A.o Bruno, M. Mallardo, R. Silvestri, L. Marinelli, S. Bonatti, E. Novellino, M. Stornaiuolo. Folding rescue, Wnt antagonism and anticancer potential of the first small molecules addressing Frizzled4 receptor. Nat. Chem. Biol. 2015, 11, 280-286 (doi: 10.1038/nchembio.1770, ISI IF 2014: 12.996

3. M. Stornaiuolo, G. La Regina, S. Passacantilli, G. Grassia, A. Coluccia, V. La Pietra, M. Giustiniano, H. Cassese, S. di Maro, D. Brancaccio, S. Taliani, A. Ialenti, R. Silvestri, C. Martini, E. Novellino, L. Marinelli. Structure-based lead optimization and biological evaluation of BAX direct activators as novel potential anticancer agents. J. Med. Chem.2015, 58, 2135-2148. (doi: 10.1021/jm501123r, ISI IF 2014: 5.447)

4. Pinto, A.; Lucia Tamborini, L.; Pennacchietti, E.; Coluccia, E.; Silvestri, R.; De Micheli, C.; Conti, P.; De Biase, D. Bicyclic γ-amino acids as inhibitors of γ-aminobutyrate aminotransferase. J. Enzyme Inhib. and Med. Chem.2015, 31, 295-301. (doi: 10.3109/14756366.2015.1021251, ISI IF 2014: 2.332)

5. S. Santamaria, E. Nuti, G. Cercignani, G. La Regina, R. Silvestri, C. T. Supuran, A. Rossello. Kinetic characterization of 4,4’-biphenylsulfonamides as selective non zinc binding MMP inhibitors.J. Enzyme Inhib. and Med. Chem.2015, 30, 947-954 (doi: 10.3109/14756366.2014.1000889, ISI IF 2014: 2.332).

6. Carradori, S.; Silvestri, R. New frontiers in selective human MAO-B inhibitors. Perspective article, J. Med. Chem.2015, 58, 6717-6732 (doi: 10.1021/jm501690r, ISI IF 2015: 5.589).

7. Céline Lacroix, Samuela Laconi, Fabrizio Angius, Raffaello Pompei, Antonio Coluccia, Romano Silvestri, Johan Neyts, Pieter Leyssen. In vitrocharacterisation of a pleconaril/pirodavir-like compound with potent activity against rhinoviruses.Virology Journal2015, 12, 106-112 (doi:10.1186/s12985-015-0330-4, ISI IF 2014: 2.101)

8. G. La Regina, R. Bai, A. Coluccia, V. Famiglini, S. Pelliccia, S. Passacantilli, C. Mazzoccoli,V. Ruggieri,A. Verrico,A. Miele, L. Monti,M. Nalli,R. Alfonsi, L. Di Marcotullio, A. Gulino, B. Ricci,A. Soriani,A. Santoni, M. Caraglia, S. Porto, E. Da Pozzo, C. Martini, A. Brancale, L. Marinelli, E. Novellino, S. Vultaggio, M. Varasi, C. Mercurio, G. Dondio, C. Bigogno, E. Hamel, P. Lavia, R. Silvestri. New indole tubulin assembly inhibitors cause stable arrest of mitotic progression, enhanced stimulation of natural killer cell cytotoxic activity and repression of Hedgehog-dependent cancer. J. Med. Chem.2015, 58, 5789-5807 (doi: 10.1021/acs.jmedchem.5b00310, ISI IF 2015: 5.589).

9. Cawston, E.; Connor, M.; Di Marzo, V.; Silvestri, R.; Glass, M. Distinct temporal fingerprint for cyclic adenosine monophosphate (cAMP) signalling of indole-2-carboxamides as allosteric modulators of the cannabinoid receptors. J. Med. Chem.2015, 58, 5979-5988 (doi: 10.1021/acs.jmedchem.5b00579, ISI IF 2015: 5.589).

10. A. A. Philchenkov, M. P. Zavelevich, V. P. Tryndyak, L. M. Kuiava, D. Y.. Blokhin, K. Miura, R. Silvestri, I. P. Pogribny. Antiproliferative and proapoptotic effects of a pyrrole containing arylthioindole in human Jurkat leukaemia cell line and multidrug-resistant Jurkat/A4 cells. Cancer Biology and Therapy 2015, 16, 1820-1829 (ISI IF 2014: 3.872).

11. Laura Masuelli; Fabrizio Pantanella; Giuseppe La Regina; Monica Benvenuto; Massimo Fantini; Rosanna Mattera; Enrica Di Stefano; Maurizio Mattei; Romano Silvestri; Serena Schippa; Vittorio Manzari; Andrea Modesti; Roberto Bei. Violacein, an indole-derived purple-colored natural pigment produced by Janthinobacterium lividum, inhibits the growth of head and neck carcinoma cell lines both in vitro and in vivo. Tumor Biology2015, accepted (ISI IF 2014: 3.611).

12. G. La Regina, A. Coluccia, V. Famiglini, S. Pelliccia, L. Monti, D. Vullo, E. Nuti, P. Pan, S. Parkkila, S. Monti, V. Alterio, G. De Simone, C. T. Supuran, A. Rossello, R. Silvestri. Discovery of 1,1’-biphenyl-4-sulfonamides as a new class of potent and selective carbonic anhydrase XIV inhibitors.J. Med. Chem.2015, 58, 8564-8572 (doi: 10.1021/acs.jmedchem.5b01144, ISI IF 2015: 5.589).

13. L. Marinelli, M. Stornaiuolo, A. Bruno, L. Botta, G. La Regina, S. Cosconati, R. Silvestri, , E. Novellino. Endogenous vs Exogenous Allosteric Modulators in GPCRs: A dispute for shuttling CB1 among different membrane microenvironmentsSci Rep.2015, 2015 Oct 20;5:15453 (doi: 10.1038/srep15453M, ISI IF 2014: 5.578).

14. Mollica, A.; Macedonio, M.; Stefanucci, A.; Costante, R.; Carradori, S.; Cataldi, V.; Di Giulio, M.; Cellini, L.; Silvestri, R.; Giordano, C; Scipioni, A.; Morosetti, S.; Punzi, P.; Mirzaie, S.Arginine- and Lysine-rich peptides: Synthesis, characterization and antimicrobial activity. Lett. Drug Des. Disc.2017,14, 1-7.

15. Famiglini, V.; Silvestri, R. Focus on chirality of HIV-1 non-nucleoside reverse transcriptase inhibitors. Molecules2016(special issue “Chiral Drugs”) 21, 221-240. (doi: doi:10.3390/molecules21020221, IF for Molecules (2014): 2.416).

16. Da Costa, L.; Roche, M.; Scheers, E.; Coluccia, A.; Neyts, J.; Terme, T.; Leyssen, P.; Silvestri, R.; Vanelle, P. VP1 crystal structure-guided exploration and optimization of 4,5-dimethoxybenzene-based inhibitors of rhinovirus 14 infection.Eur. J. Med. Chem.2016, 115, 453-462 (doi: 10.1016/j.ejmech.2016.03.049, ISI IF 2015: 3.902).

17. Filipović, N.; Bjelogrlić, S.; Portalone, G.; Pelliccia, S.; Silvestri, R.; Klisurić, O.; Senćanski, M.; Stanković, D.; Todorović, T. R.; Muller, C. D. Pro-apoptotic and pro-differentiation induction by 8-quinolinecarboxaldehyde selenosemicarbazone and its Co(III) complex in human cancer cell lines. MedChemComm2016, 7, 1604-1616. (10.1039/c6md00199h, ISI IF 2015: ?).

18. Coluccia, G.; La Regina, N. Barilone, M.-N. Lisa, A. Brancale, G.André-Leroux P. M. Alzari, R. Silvestri. Structure-based virtual screening to get new scaffold inhibitors of PknB from Mycobacterium tuberculosis. Lett. Drug Des. Disc. 2016,13, 1012-1018.

19. Coluccia, A.; Passacantilli, S.; Famiglini, V.; Sabatino, M.; Patsilinakos, A.; Ragno, R.; Mazzoccoli, C.; Sisinni, L.; Okuno, Aa; Takikawa, O.; Silvestri, R.; La Regina, G. New inhibitors of indoleamine 2,3-dioxygenase 1: molecular modelling studies, synthesis and biological evaluation. J. Med. Chem.2016, 59, 9760-9773.

20. A. Soriani, C. Borrelli, B. Ricci, A. Zingoni, R. Molfetta, C. Fionda, S. Carnevale, M. Cippitelli, R. Paolini, M. P. Abbruzzese, M. T. Petrucci, M. R. Ricciardi, G. La Regina, P. Lavia, R. Silvestri, A. Santoni. p38MAPK differentially controls NK activating ligands at transcriptional and post-transcriptionallevelon multiple myeloma cells. Oncoimmunology 2016, 2016 Dec 2;6(1):e1264564. doi: 10.1080/2162402X.2016.1264564

21. A. Mollica, S. Pelliccia, V. Famiglini, A. Stefanucci, G. Macedonio, A. Chiavaroli, G. Orlando, L. Brunetti, C. Ferrante, S. Pieretti, E. Novellino, B. Sandor, F. Zador, E. Szucs, R. Samavati, S. Dvrorasko, C. Tomboly, R. Silvestri. Exploring the first Rimonabant analogue-opioid peptide hybrid compound, as bivalent ligand for CB1 and opioid receptors. J. Enz. Inhib. Med. Chem.2017,32, 444-451 (IF 2016: 2.737)

22. Di Cesare, E.; Verrico, A.; Miele, A.; Giubettini, M.; Rovella, P.; Coluccia, A.; Famiglini, V.; La Regina, G.; Cundari, E.; Silvestri, R.; Lavia, P. Mitotic cell death induction by targeting the mitotic spindle with indole derivative tubulin-inhibitory molecules. Oncotarget2017, 8, 19738-19759 (IF 2016: 2.612).

23. Famiglini, V.; Castellano, S.; Silvestri, R. N-Pyrrylarylsulfones with high therapeutic potential. Molecules2017, 22, 434-452 (IF 2016: 2.861)

24. Stirpe, M.; Palermo, V.; Bianchi, M. M.; Silvestri, R.; Falcone, CX.; Tenore, G. C.; Novellino, E.; Mazzoni, C. Annurca apple (M. pumila Miller cv Annurca) extracts act against cellular oxidative stress and ageing. BMC Complementary and Alternative Medicine2017, 17, 200-206 (IF 2016: 2.288)

25. Simona Daniel, Deborah Pietrobono, Barbara Costa,Mariateresa Giustiniano, Valeria La Pietra, Chiara Giacomelli, Giuseppe La Regina, Romano Silvestri,3Maria Letizia Trincavelli, Ettore Novellino, Claudia Martini, Luciana Marinelli.Bax activation blocls self-renewal and induces apoptotis of human glioblastoma stem cells. ACS Chem. Neurosci.2017, 2017 Apr 11. doi: 10.1021/acschemneuro.7b00023 (IF 2016: 3883)

26. La Regina, Giuseppe; Bai, Ruoli; Coluccia, Antonio; Famiglini, Valeria; Passacantilli, Sara; Naccarato, Valentina; Ortar, Giorgio; Mazzoccoli, Carmela; Ruggieri, Vitalba; Agriesti, Francesca ; Piccoli, Claudia; Tataranni, Tiziana; Nalli, Marianna; Brancale, Andrea; Vultaggio, Stefania; Mercurio, Ciro; Varasi, Mario; Saponaro, Concetta; Sergio, Sara; Maffia, Michele; Coluccia, Addolorata; Hamel, Ernest; Silvestri, Romano. 3-Aroyl-1,4-diarylpyrroles inhibit chronic myeloid leukemia cell growth through an interaction with tubulin. ACS Medicinal Chemistry Letters2017, 8, 521-526(doi: 10.1021/acsmedchemlett.7b00022) (IF 2016: 3.746)

27. Valeria Famiglini, Giuseppe La Regina, Antonio Coluccia, Domiziana Masci, Andrea Brancale, Roger Badia, Eva Riveira-Muñoz,José A. Esté, Emmanuele Crespan, Alessandro Brambilla, Giovanni Maga, Myriam Catalano, Cristina Limatola, Francesca Romana Formica, Roberto Cirilli, Ettore Novellino, and Romano Silvestri. Chiral indolylarylsulfone non-nucleoside reverse transcriptase inhibitors as new potent and broad spectrum anti-HIV-1 activity agents. J. Med. Chem.2017, 60, 6528-6547 (IF 2016: 6.259)

28. Sveva Pelliccia, Yu-Hsuan Wu, Antonio Coluccia, Giuseppe La Regina, Chin-Kai Tseng, Valeria Famiglini, Domiziana Masci, John Hiscott, Jin-Ching Lee, Romano Silvestri. Inhibition of Dengue Virus Replication by Novel Inhibitors of RNA-dependent RNA Polymerase and Protease Activities. J. Enz. Inhib Med. Chem. 2017, 32, 1091-1101 (IF 2016: 2.737)

29. Mariateresa Giustiniano, Simona Daniele, Sveva Pelliccia, Valeria La Pietra, Deborah Pietrobono, Diego Brancaccio, Sandro Cosconati, Anna Messere, Stefano Giuntini, Linda Cerofolini, Marco Fragai, Claudio Luchinat, Sabrina Taliani, Federico Da Settimo, Giuseppe La Regina, Romano Silvestri, Claudia Martini, Ettore Novellino, Luciana Marinelli. Computer-aided dentification and lead optimization of dual murine doulbe minute 2 and diuble minute 4 binders: structure-activity relationship studies, and pharmacological activity.J. Med. Chem. 2017,60, 8115-8130.

30. Laurène Da Costa, Els Scheers, Antonio Coluccia, Alessia Rosetti, Manon Roche, Johan Neyts, Thierry Terme, Roberto Cirilli, Carmen Mirabelli, Romano Silvestri, Patrice Vanelle.Heterocyclic pharmacochemistry of new rhinovirusantiviral agents: A combined computational andexperimental study. Eur. J. Med. Chem.2017, 140, 528-541 (IF 2016: 3.902)

31. Valeria Famiglini and Romano Silvestri. Indolylarylsulfones, a fascinating story of highly potent HIV type-1 non-nucleoside reverse transcriptase inhibitors. Antiviral Chem. and Chemoth.2018, 26, 1-19.

32. Filipović, Nenad; Bjelogrlić, Snežana; Pelliccia, Sveva; Jovanović, Vesna ; Kojić, Milan; Senćanski, Milan; La Regina, Giuseppe; Silvestri, Romano; Muller, Christian; Todorović, Tamara. Triapine vs. selenotriapine: a comparative study of anticancer activity in 2-D and 3-D cancer cell models. Arabian J. Chem.2017, in press.

33. Riccio, Gennaro; Bottone, Sara; La Regina, Giuseppe; Badolati, Nadia; Passacantilli, Sara; Rossi, Giovanni; Accardo, Antonella; Dentice, Monica; Silvestri, Romano; Novellino, Ettore; Stornaiuolo, Mariano. A negative allosteric modulator of the WNT receptor Frizzled 4 switches into an allosteric. Biochemistry2018, accepted.

34. Concetta Saponaro, Sara Sergio, Antonio Coluccia, Maria De Luca, Luca Mologni, Daniele Vergar, Michel Salzet, Isabelle Fournier, Cecilia Bucci, Daniela Bonetti, Candice Gautier, Stefano Gianni, Romano Silvestri, Valeria Famiglini, Valentina Naccarato, Carlo Gambacorti Passerini, Michele Maffia, Addolorata M.L. Coluccia. β-Catenin knockdown promotes NHERF1-mediated survival of colorectal cancer cells: implications for a double-targeted therapy. Oncogene2018, accepted.

35. M. S. C. Ambreen, L. Carrassa, D. Passarella, B. Michel, R. Benhida, N. Martinet, A. Hunyadi, E. Ioannou, V. Roussis, L. Musso, S. Dallavalle, R. Silvestri, N. Westwood, M. Mori, C. Ingallina, B. Botta, E. Kavetsou, A. Detsi, Z. Majer, F. Hudecz, S. Bxxsze, B. Kaminska, T. V. Hansen, P. Bertrand, C. M. Athanassopoulos, G. Damia A high-throughput screening of a chemical compound library in ovarian cancer stem cells. Combinatorial Chemistry & High Throughput Screening2018, accepted.

36. R. Carnevale, R. Silvestri, L. Loffred, M. Novo, V. Cammisotto, V. Castellani, S. Bartimoccia, F. Violi. Oleuropein, a component of extra virgin olive oil, lowers post-prandial glycaemia in healthy subjects. British Journal of Clinical Pharmacology2018, accepted.

37. G. La Regina, R. Bai, A. Coluccia, V. Naccarato, V. Famiglini, M. Nalli, D. Masci, A. Verrico, P. Rovella,C. Mazzoccoli, E. Da Pozzo, C. Cavallini, C. Martini, S. Vultaggio, Gi. Dondio, M. Varasi, C. Mercurio, E. Hamel, P. Lavia, R. Silvestri. New 6- and 7-heterocyclyl-1H-indole derivatives as potent tubulin assembly and cancer cell growth inhibitors with potential to treat human liver carcinoma and glioblastoma. Eur. J. Med. Chem.2018, accepted.