Drug Design and Synthesis Center (CHIM/08)

Attività di ricerca

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.

Collaborazioni nazionali e internazionali

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.

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).
Settori ERC
  • 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)


22-03-2010 - 22-09-2012 (30 months), Drug design, synthesis and biological evaluation of antitumor agents targeting mitosis, PRIN, Italian MIUR, Principal Investigator

01-02-2013 - 01-02-2016 (36 months) Drug design, synthesis and biological studies of innovative drugs againts cancer. PRIN, Italian MIUR, Principal Investigator
05-02-2017 - 05-02-2020 (36 months) New perspectives treatment to treat glioblastoma multiforme trhogh a multitarget approach, PRIN, Italian MIUR, Principal Investigator
2009-2011 (36 months), Drug design and synthesis of non-nucleoside inhibitors of both HIV-1 wild type and resistant mutant strains reverse transcriptase, and coxsackie B4 virus, Istitute Pasteur Italy, Principal Investigator
2012 - 2015 (36 months), New non-nucleoside antiviral agents targeting HIV-1 reverse transcriptase . Istitute Pasteur Italy, Principal Investigator
23-06-2011 - 23-06-2015, (48 months), The molecular basis of the diseases, FIRB, Italian, Research Unit Coordinator
01-12-2014 - 31-12-2015, (13 months), Design and synthesis of a series of N-(piperidin-4-ylmethyl)-1H-indazole-3-carboxamide derivatives, A.C.R.A.F. SpA, Italy, Principal Investigator
01-04-2016 - 01-02-2017 (10 months), Synthesis of a series of tetrahydro-1H-pyrazolopyridine and imidazopyridine derivatives, A.C.R.A.F. SpA, Italy, Principal Investigator
22-06-2012 - 29-03-2013 - 13-12-2013 (24 months) Synthesis of scaffolds useful for targeted chemical libraries, European Institute of Oncology, Italy, Principal Investigator

Publication (2019-2021)

1. Nardella, C., Visconti, L., Malagrinò, F., Pagano, L., Bufano, M., Nalli, M., Coluccia, A., La Regina, G., Silvestri, R., Gianni, S., Toto, A.
Targeting PDZ domains as potential treatment for viral infections, neurodegeneration and cancer
(2021) 16 (1), art. no. 15, .

2. Puxeddu, M., Shen, H., Bai, R., Coluccia, A., Bufano, M., Nalli, M., Sebastiani, J., Brancaccio, D., Da Pozzo, E., Tremolanti, C., Martini, C., Orlando, V., Biagioni, S., Sinicropi, M.S., Ceramella, J., Iacopetta, D., Coluccia, A.M.L., Hamel, E., Liu, T., Silvestri, R., La Regina, G.
Discovery of pyrrole derivatives for the treatment of glioblastoma and chronic myeloid leukemia
(2021) 221, art. no. 113532, .

3. Van Dycke, J., Puxeddu, M., La Regina, G., Mastrangelo, E., Tarantino, D., Rymenants, J., Sebastiani, J., Nalli, M., Matthijnssens, J., Neyts, J., Silvestri, R., Rocha-Pereira, J.
Discovery of a novel class of norovirus inhibitors with high barrier of resistance
(2021) 14 (10), art. no. 1006, .

4. Li, S., Xu, A., Li, Y., Tan, C., La Regina, G., Silvestri, R., Wang, H., Qi, W.
RS4651 suppresses lung fibroblast activation via the TGF-β1/SMAD signalling pathway
(2021) 903, art. no. 174135, .

5. Daniele, S., La Pietra, V., Piccarducci, R., Pietrobono, D., Cavallini, C., D'Amore, V.M., Cerofolini, L., Giuntini, S., Russomanno, P., Puxeddu, M., Nalli, M., Pedrini, M., Fragai, M., Luchinat, C., Novellino, E., Taliani, S., La Regina, G., Silvestri, R., Martini, C., Marinelli, L.
CXCR4 antagonism sensitizes cancer cells to novel indole-based MDM2/4 inhibitors in glioblastoma multiforme
(2021) 897, art. no. 173936, .

6. Liu, T., Wu, J., Han, C., Gong, Z., Regina, G.L., Chen, J., Dou, F., Silvestri, R., Chen, C., Yu, Z.
Rs-5645 attenuates inflammatory cytokine storm induced by sars-cov-2 spike protein and lps by modulating pulmonary microbiota
(2021) 17 (13), pp. 3305-3319.

7. Nalli, M., Armijos Rivera, J.I., Masci, D., Coluccia, A., Badia, R., Riveira-Muñoz, E., Brambilla, A., Cinquina, E., Turriziani, O., Falasca, F., Catalano, M., Limatola, C., Esté, J.A., Maga, G., Silvestri, R., Crespan, E., La Regina, G.
New indolylarylsulfone non-nucleoside reverse transcriptase inhibitors show low nanomolar inhibition of single and double HIV-1 mutant strains
(2020) 208, art. no. 112696, .

8. Di Magno, L., Di Pastena, F., Puxeddu, M., La Regina, G., Coluccia, A., Ciogli, A., Manetto, S., Maroder, M., Canettieri, G., Silvestri, R., Nalli, M.
Sulfonamide Inhibitors of β-Catenin Signaling as Anticancer Agents with Different Output on c-MYC
(2020) 15 (23), pp. 2264-2268.

9. Scala, R., Di Matteo, A., Coluccia, A., Lo Sciuto, A., Federici, L., Travaglini-Allocatelli, C., Visca, P., Silvestri, R., Imperi, F.
Mutational analysis of the essential lipopolysaccharide-transport protein LptH of Pseudomonas aeruginosa to uncover critical oligomerization sites
(2020) 10 (1), art. no. 11276, .

10. Malagrinò, F., Coluccia, A., Bufano, M., Regina, G., Puxeddu, M., Toto, A., Visconti, L., Paone, A., Magnifico, M.C., Troilo, F., Cutruzzolà, F., Silvestri, R., Gianni, S.
Targeting the Interaction between the SH3 Domain of Grb2 and Gab2
(2020) 9 (11), .

11. Bufano, M., Laudette, M., Blondeau, J.-P., Lezoualc’h, F., Nalli, M., Silvestri, R., Brancale, A., Coluccia, A.
Modeling Epac1 interactions with the allosteric inhibitor AM-001 by co-solvent molecular dynamics
(2020) 34 (11), pp. 1171-1179.

12. Coluccia, A., Puxeddu, M., Nalli, M., Wei, C.-K., Wu, Y.-H., Mastrangelo, E., Elamin, T., Tarantino, D., Bugert, J.J., Schreiner, B., Nolte, J., Schwarze, F., La Regina, G., Lee, J.-C., Silvestri, R.
Discovery of Zika Virus NS2B/NS3 Inhibitors That Prevent Mice from Life-Threatening Infection and Brain Damage
(2020) 11 (10), pp. 1869-1874.

13. La Regina, G., Puxeddu, M., Nalli, M., Vullo, D., Gratteri, P., Supuran, C.T., Nocentini, A., Silvestri, R.
Discovery of New 1,1′-Biphenyl-4-sulfonamides as Selective Subnanomolar Human Carbonic Anhydrase II Inhibitors
(2020) 11 (5), pp. 633-637.

14. Capdevielle, C., Desplat, A., Charpentier, J., Sagliocco, F., Thiebaud, P., Thézé, N., Fédou, S., Hooks, K.B., Silvestri, R., Guyonnet-Duperat, V., Petrel, M., Raymond, A.-A., Dupuy, J.-W., Grosset, C.F., Hagedorn, M.
HDAC inhibition induces expression of scaffolding proteins critical for tumor progression in pediatric glioma: Focus on EBP50 and IRSp53
(2020) 22 (4), pp. 550-562.

15. Spizzichino, S., Mattedi, G., Lauder, K., Valle, C., Aouadi, W., Canard, B., Decroly, E., Kaptein, S.J.F., Neyts, J., Graham, C., Sule, Z., Barlow, D.J., Silvestri, R., Castagnolo, D.
Design, Synthesis and Discovery of N,N’-Carbazoyl-aryl-urea Inhibitors of Zika NS5 Methyltransferase and Virus Replication
(2020) 15 (4), pp. 385-390.

16. Filipović, N.R., Bjelogrlić, S.K., Pelliccia, S., Jovanović, V.B., Kojić, M., Senćanski, M., La Regina, G., Silvestri, R., Muller, C.D., Todorović, T.R.
Selenotriapine – An isostere of the most studied thiosemicarbazone with pronounced pro-apoptotic activity, low toxicity and ability to challenge phenotype reprogramming of 3-D mammary adenocarcinoma tumors
(2020) 13 (1), pp. 1466-1489.

17. Laudette, M., Coluccia, A., Sainte-Marie, Y., Solari, A., Fazal, L., Sicard, P., Silvestri, R., Mialet-Perez, J., Pons, S., Ghaleh, B., Blondeau, J.-P., Lezoualc'H, F.
Identification of a pharmacological inhibitor of Epac1 that protects the heart against acute and chronic models of cardiac stress
(2019) 115 (12), pp. 1766-1777.

18. Masci, D., Hind, C., Islam, M.K., Toscani, A., Clifford, M., Coluccia, A., Conforti, I., Touitou, M., Memdouh, S., Wei, X., La Regina, G., Silvestri, R., Sutton, J.M., Castagnolo, D.
Switching on the activity of 1,5-diaryl-pyrrole derivatives against drug-resistant ESKAPE bacteria: Structure-activity relationships and mode of action studies
(2019) 178, pp. 500-514.

19. Cammisotto, V., Carnevale, R., Nocella, C., Stefanini, L., Bartimoccia, S., Coluccia, A., Silvestri, R., Pignatelli, P., Pastori, D., Violi, F.
Nox2-mediated platelet activation by glycoprotein (GP) VI: Effect of rivaroxaban alone and in combination with aspirin
(2019) 163, pp. 111-118.

20. Coluccia, A., La Regina, G., Naccarato, V., Nalli, M., Orlando, V., Biagioni, S., De Angelis, M.L., Baiocchi, M., Gautier, C., Gianni, S., Di Pastena, F., Di Magno, L., Canettieri, G., Coluccia, A.M.L., Silvestri, R.
Drug Design and Synthesis of First in Class PDZ1 Targeting NHERF1 Inhibitors as Anticancer Agents
(2019) 10 (4), pp. 499-503.

21. La Regina, G., Coluccia, A., Naccarato, V., Silvestri, R.
Towards modern anticancer agents that interact with tubulin
(2019) 131, pp. 58-68.

22. Puxeddu, M., Shen, H., Bai, R., Coluccia, A., Nalli, M., Mazzoccoli, C., Da Pozzo, E., Cavallini, C., Martini, C., Orlando, V., Biagioni, S., Mazzoni, C., Coluccia, A.M.L., Hamel, E., Liu, T., Silvestri, R., La Regina, G.
Structure-activity relationship studies and in vitro and in vivo anticancer activity of novel 3-aroyl-1,4-diarylpyrroles against solid tumors and hematological malignancies
(2019) art. no. 111828, .

23. Pippa, S., Mannironi, C., Licursi, V., Bombardi, L., Colotti, G., Cundari, E., Mollica, A., Coluccia, A., Naccarato, V., La Regina, G., Silvestri, R., Negri, R.
Small molecule inhibitors of KDM5 histone demethylases increase the radiosensitivity of breast cancer cells overexpressing JARID1B
(2019) 24 (9), art. no. 1739.


Invited lectures (since 2010)

• Development of new tubulin targeting agents. XX National Meeting on Medicinal Chemistry. Abano Terme, Italy, 12-16-Sep-2010 • Drug design and synthesis of non-nucleoside inhibitors of both HIV-1 wild type and resistant mutant strains reverse transcriptase, and Coxsackie B4 virus. Istitute Pasteur Italy - Fondazione Cenci Bolognetti, Ponzano Romano, Italy, 18-19-Nov-2011 • Development of new tubulin targeting agents. COST Meeting. Warsaw Poland,, 18-21-Sep-2013. • Tubulin Targeting Anti-Cancer Agents, Erberhard Karls Universität Tübingen, Pharmaceutical Chemistry. Tübingen, Germany, 14-Mar-2014 • New Tubulin Targeting Anti-Cancer Agents, Polo Oncologico "Giovanni Paolo II", Lecce, Italy, 22-Oct-2015 • Twenty years of sulfone non-nucleoside HIV-1 reverse transcriptase inhibitors, VI EWDSy, Siena, Italy, 16-19-May-2016 • Discovery of sulfone non-nucleoside HIV-1 reverse transcriptase inhibitors, King's College, London. 10-Aug-2016 • New anti-Cancer Agents through an Interaction with Tubulin. EUFEPS Annual Meeting. Athens, Greece, 26-May-2018 • New Agents Targeting ZIKA Protease or Methyl-Transferases, 16th Medical Biodefense Conference. Munich, Germany, 28-31-Oct-2018 • New anticancer agents through and interaction with tubulin, COST Meeting”Strtagem” (CA17104), Torino, Italy, 29-31-Jan-2019  

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