Microsoft word - $asq9548df2a244b4df4801468f8757749984fb076b1d7904356aa18ec17aa620152a1f865657a7e4044b04a57ea83879aea

Nome programma:Nucleic acids as drugs and drug targets: development of oligonucleotide-based drugsand characterization of the mechanism of action of nucleic acid- and kinase-targetedcompounds Obiettivi specifici del programmaThe goals of this program focuses on the following lines of research: 1. The development of nucleic acids as drugs employing the technique known as SELEX, or Systematic Evolution of Ligands by Exponential enrichment, and 2. the design and study of novel drugs selectively targeting nucleic acids, alone or in complex with specific protein, with potential applications in antitumor,antibacterial or antiviral chemotherapy.
3. the design, synthesis and biophysical/biochemical investigation of new Ser/Thr inhibitors aimed at contributing to better understanding/influencing the signaltransduction process.
Line 1:
Project 1.1: Identification of ssDNA aptamers for plasmin. The goal is to isolate
single-stranded DNA aptamers for plasmin by SELEX.
Project 1.2: Identification of RNA aptamers for folic acid. The goal is to isolate
RNA aptamers for folic acid by SELEX.
Project 1.3: Identification of ssDNA aptamers for cathepsin G. The goal is to isolate
single-stranded DNA aptamers for cathepsin G for cathepsin B by SELEX.
Line 2:
Project 2.1: Design and investigation of new nucleic acid-selective ligands.
Our aim is to design and investigate new synthetic ligands targeted at specific structural
contexts in DNA/RNA chains, in particular those relevant for therapeutic treatment
(TAR-RNA of the HIV genome, quadruplex DNA of the human telomeric sequence or
of oncogenes). We characterize the physico-chemical parameters of DNA/RNA
recognition of established or potential drugs and clarify the mechanism of action of the
new compounds in terms of recognition of specific nucleic acid sequences and
interference with the activity of essential helix-tracking enzymes.
Project 2.2: Mechanism of action of clerocidin. Clerocidin (CL) is an effective
topoisomerase II-poison, which has been shown to produce DNA depurination and
strand breaks per se at the guanine level. We investigate the mechanism of action of CL
toward DNA and the modulation effect of mammalian and bacterial topoisomerases
towards CL activity at specific sequences and nucleotides.
Project 2.3: Novel DNA-gyrase and DNA-topoisomerase IV targeted antibacterials.
Combinatorial biosynthesis is used for the generation of novel bacterial topoisomerase-
inhibiting drugs derived from known and powerful natural inhibitors (especially
aminocoumarins, angucyclinones and cyclothialidins) produced by various
Streptomyces strains. This approach allows the generation of a variety of new
compounds by the use of recombinant DNA technology. The new derivatives are
investigated in view of their use against bacterial strains resistant to existing drugs.
Project 2.4: Novel DNA-topoisomerase I targeted anticancer agents.
The design and synthesis of new molecules targeted to the DNA-topoisomerase I
complex will enlighten the mechanism of the process and make it possible to plan
better anticancer drugs.
Line 3:
Project 3.1: Design, synthesis and investigation of new ATP-site agonists/
antagonists for Ser/Thr kinases. Kinases are key enzymes in the process of signal
transduction and amplification within the cell. Our aim is to develop selective ligands
as potential new drugs.
Risorse personaleManlio Palumbo (Full Professor)Giuseppe Zagotto (Associate Professor)Barbara Gatto (Assistant Professor)Claudia Sissi (Assistant Professor)Elena Vianini (PhD student)Erika Cecchin (PhD student)Bosio Silvia (PhD student)Cadamuro Sergio (PhD student)Giulia Giaretta (PhD student)Elisabetta Leo (PhD student)Lorena Lucatello (PhD student)Claudia Pivetta (PhD student)Standen Steven (Post-doc)Huber Florian (Post-doc) Risorse finanziarie [media quinquennale]In the period 2001-2005, the program received through the Department a mean of € 125000 per year.
Rapporti con altri istituti di ricerca a livello locale, nazionale e internazionale Dipartimento di Chimica e Tecnologia del Farmaco, University of Perugia, Italy Department of Histology, Microbiology and Medical Biotechnologies, Section of Microbiology and Virology, University of Padova, Italy (PRIN) University of Bologna, Biochemistry Dept, Bologna, Italy (PRIN) Department of Biochemistry, University of Padova, Italy (PRIN) Institute of Chemistry ad Biochemistry “Ronzoni”, Milan, Italy (FIRB) University of London, Dept. Medicinal Chemistry, London, UK (UE) Polytechnic University of Barcelona, Dept. Chemical Engineering, Barcelona, University of Southhampton, Dept. of Biochemistry, Southhampton, UK (UE) University of Tübingen, Pharmaceutical Institute, Tübingen, Germany (UE) University of Oviedo, Microbiology Dept., Oviedo, Spain (UE) University of Freiburg, Dept. of Pharmacy, Freiburg, Germany (UE) John Innes Centre, Dept. Biological Chemistry, Norwich, UK (UE) Department of Chemical Sciences, University of Camerino, Italy Department of Pharmacology, University of Padova, Italy Division of Rheumatology, Department of Medical and Surgical Sciences, Centro di Riferimento Oncologico, Aviano, Italy Associazioni Industriali di Vicenza, Italy Department of Chemistry and Biochemistry, University of Maryland, Baltimore Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Department of Basic Medical Sciences, St. George’s, University of London, Altre attività rilevanti per la ricerca, a livello di Programma Invited Lectures
10 invited lectures at international meetings Articles
G. Zagotto, B. Gatto, S. Moro, C. Sissi, M. Palumbo, Anthracyclines: recent
developments in their separation and quantitation. J. Chrom., B. 764, 161-171, 2001. IF
2.085
B. Gatto, S. Richter, S. Moro, G. Capranico, M. Palumbo, The topoisomerase II poison
clerocidin alkylates non-paired guanines of DNA: implications for the irreversible
stimulation of DNA cleavage. Nucleic Acids Res. 29, 4224-4230, 2001. IF 6.575
M.G. Ferlin, B. Gatto, G.F. Chiarelotto, M. Palumbo, Novel pyrrolo [3,2-f]quinolines:
synthesis and antiproliferative activity. Bioorg. Med. Chem. 9, 1843-1848, 2001. IF
2.043
F. Meggio, S. Moro, A.D. Deana, D. Dal Ben, S. Sarno, G. Zagotto, L.A. Pinna,
Molecular features of selective polyphenolic inhibitors of protein kinase ck2. Cell. Mol.
Biol. Lett. 6(2B), 265-274, 2001. IF 0.495
M. Palumbo, C. Sissi, B. Gatto, S. Moro, G. Zagotto, Quantitation of Camptothecin and
related compounds. J. Chrom., B. 764, 121-140, 2001. IF 2.085
C. Sissi, S. Moro, S. Richter, B. Gatto, E. Menta, S. Spinelli, A. Krapcho, F. Zunino,
M. Palumbo, DNA-Interactive Anticancer Aza-Anthrapyrazoles: Biophysical and
Biochemical Studies Relevant to the Mechanism of Action. Mol. Pharmacol. 59, 96-
103, 2001. IF 5.650
E. Vianini, M. Palumbo, B. Gatto, In vitro Selection of DNA Aptamers that Bind L-
Tyrosinamide. Bioorg. Med. Chem. 9, 2543-2548,2001. IF 2.185
P. Perego, M. De Cesare, P. De Isabella, N. Carenini, G. Beggiolin, G. Pezzoni, M.
Palumbo, G. Pratesi, C. Pisano, P. Carminati, G. Scheffer, F. Zunino, A novel 7-
modified camptothecin analog overcomes breast cancer resistance protein-associated
resistance in a mitoxantrone-selected colon carcinoma cell line. Cancer Res. 61, 6034-
6037, 2001. IF 7.690
C. Sissi, E. Perdonà, E. Domenici, A. Feriani, A.J. Howells, A. Maxwell, M. Palumbo,
Ciprofloxacin affects conformational equilibria of DNA gyrase A in the presence of
magnesium ions. J. Mol. Biol. 311, 195-203, 2001. IF 5.542
C. Sissi, P. Rossi, F. Felluga, F. Formaggio, M. Palumbo, P. Tecilla, C. Toniolo, P.
Scrimin, Dinuclear Zn2+ complexes of synthetic heptapeptides as artificial nucleases. J.
Am. Chem. Soc. 123, 3168-3170, 2001. IF 6.903
C. Sissi, A. Naggi, G. Torri, M. Palumbo, Effects of Sulfation on Antithrombin-
Thrombin/Factor Xa Interactions in Semisynthetic Low-Molecular Weight Heparins.
Semin. Thromb. Hemost. 27, 483-487, 2001. IF 2.018
R. Supino, D. Polizzi, R. Pavesi, G. Pratesi, G. Capranico, M. Palumbo, C. Sissi, S.
Richter, E. Menta, S. Spinelli, F. Tortoreto, F. Zumino, A Novel 9-Aza-Anthrapyrazole
effective against human prostatic carcinoma Xenografts. Oncology 61, 234-242, 2001.
IF 2.114
I. Antonini, P. Polucci, A. Magnano, B. Gatto, M. Palumbo, E. Menta, N. Pescalli, S.
Martelli, 2,6-Di(-aminoalkyl)-2,5,6,7-tetrahydropyrazolo[3,4,5-mn]pyrimido[5,6,1-
de]acridine-5,7-diones: Novel, Potent, Cytotoxic, and DNA-Binding Agents. J. Med.
Chem. 45, 696-702, 2002. IF 4.820
M. Palumbo, B. Gatto, S. Moro, C. Sissi, G. Zagotto, Sequence specific interaction of
drugs interfering with topoisomerase-DNA cleavage complex. Biochim. Biophys. Acta
1587, 145-154, 2002. IF 2.509
C. Sissi, L. Lucatello, A. Naggi, G. Torri, M. Palumbo, Effects of Ca2+ ions on the
interactions between antithrombin III and factor Xa mediated by variously-sulfated
semi-synthetic low-molecular-weight heparins. Semin. Thromb. Hemost. 28, 355-359,
2002. IF 2.018
S. Sarno, S. Moro, F. Meggio, G. Zagotto, D. Dal Ben, P. Ghisellini, R. Battistutta, G.
Zanotti, L.A. Pinna, Toward the rational design of protein kinase casein kinase-2
inhibitors Pharmacol. Ther. 93, 159-168, 2002. IF 7.496
M.O. Nicoletto, R. Padrini, M. Palumbo, A. Ziade, G. Pratesi, G. Artioli, M. De Cesare,
F. Zunino, Intralesional topotecan in advanced ovarian cancer: A clinical report, based
on a preclinical study. Oncol. Rep. 9, 1351-1354, 2002. . IF 1.356
I. Antonini, P. Polucci, A. Magnano, B. Gatto, M. Palumbo, E. Menta, N. Pescalli, S.
Martelli, Design, Synthesis and Biological Properties of New bis(acridine-4-
carboxamides) as anticancer agents. J. Med. Chem. 46, 3109-3115, 2003. IF 4.820
C. Parolin, B. Gatto, T. Pecere, E. Tramontano, V. Cecchetti, A. Fravolini, S. Masiero,
M. Palumbo, G. Palù, New anti-human immunodeficiency virus type 1 6-
aminoquinolones: characterization of the mechanism of action. Antimicrob. Agents
Chemother. 47, 889-896, 2003. IF 4.246
T. Pecere, F. Sarinella, C. Salata, B. Gatto, A. Bet, F. Dalla Vecchia, A. Diaspro, M.
Carli, M. Palumbo, G. Palù, Involvement of p53 in specific anti-neuroectodermal tumor
activity of aloe-emodin. Int. J. Cancer 106, 836-847, 2003. IF 4.375
S. Richter, B. Gatto, D. Fabris, Ki. Takao, S. Kobayashi, M. Palumbo, Clerocidin
alkylates DNA through its epoxide function: evidence for a fine tuned mechanism of
action. Nucleic Acids Res. 31, 5149-5156, 2003. IF 6.575
S. Moro, D. Dal Ben, G. Zagotto, F. Meggio, S. Sarno, L.A. Pinna, Rational design of
new competitive inhibitors of human CK2 activity. Cell. Mol. Biol. 8, 598, 2003. IF
0.873
E. De Moliner, S. Moro, S. Sarno, G. Zagotto, G. Zanotti, L.A. Pinna, R. Battistutta,
Inhibition of Protein kinase CK2 by anthraquinone-related compounds. A structural
insight. J. Biol. Chem. 278, 1831-1836, 2003. IF 6.482.
A. Cavaggioni, C. Mucignat, G. Zagotto, Absolute configuration of 2-sec-butyl-4,5-
dihydrothiazole in male mouse urine Chem. Senses. 28, 791-797, 2003. IF 2.594.
P. Carampin, S. Rosan, D. Dalzoppo, G. Zagotto, P. Zatta, Some biochemical
properties of melatonin and the characterization of a relevant metabolite arising from its
interaction with H2O2 J. Pineal Res. 34, 134-142, 2003. IF 3.426.
B. Gatto, E. Leo, Drugs acting on the beta isoform of human topoisomerase II (p180).
Curr. Med. Chem. 3, 173-185,2003. IF 4.409
Yu. Yevdokimov, V. Salyanov, Yu. Nechipurenko, S. Skuridin, M. Zakharov, F.
Spener, M. Palumbo, Molecular Constructions (Superstructures) with adjustable
properties based on double-stranded nucleic acids. Mol. Biol. 37, 293-306 (2003). IF
0.693
C. Sissi, M. Palumbo, The quinolone family: from antibacterial to anticancer agents.
Curr. Med. Chem. 3, 439-450, 2003. IF 4.382
S. Richter, M. Palumbo, Alternative Approaches to the Discovery and Development of
Telomerase-targeted Anticancer Agents. Mini-Rev. Med. Chem. 3, 37-49, 2003. IF n.a.
Sissi, C., Naggi, A., Torri, G., Palumbo M. Modulation of Antithrombin-protease
interactions by semi-synthetic low-molecular weight heparins with different sulfation
patterns Sem. Thromb. Hemost. 29, 661-670. (2003). IF 2.018
M. Zaffaroni, C. Mucignat, T. Pecere, G. Zagotto, R. Frapolli, M. D'Incalci, M.
Zucchetti, High-performance liquid chromatographic assay for the determination of
Aloe Emodin in mouse plasma J. Chrom., B. 796, 113-119, 2003. IF 2.176
S. Richter, D. Fabris, M. Binaschi, B. Gatto, G. Capranico, M. Palumbo, Effects of
Common Buffer Systems on Drug Activity: The Case of Clerocidin. Chem. Res.
Toxicol. 17, 492-501, 2004. IF 3.332
S. Richter, C. Parolin, B. Gatto, C. Del Vecchio, E. Brocca-Cofano, A. Fravolini, G.
Palù, M. Palumbo, Inhibition of HIV-1 Tat-TAR interaction by an antiviral quinolone
derivative. Antimicrob. Agents Chemother. 48, 1895-1899, 2004. IF 4.246
B. Gatto, Monoclonal antibodies in cancer therapy. Curr. Med Chem. 4, 411-414, 2004.
IF 4.409
G. Zagotto, C. Sissi, B. Gatto, Aminoacyl-analogues of Mitoxantrone as novel DNA-
damaging cytotoxic agents. Arkivoc V, 204-218, 2004. IF 0.418
O. Tabarrini, M. Stevens, V. Cecchetti, S. Sabatini, M. Delluomo, G. Manfroni, M.
Palumbo, Ch. Pannecouque, E. De Clercq, A. Fravolini. Structure modifications of 6-
Aminoquinolones with potent anti-Hiv activity. J. Med. Chem. 47, 5567-5578, 2004. IF
5.076
M. Palumbo, Anticancer agents: towards the future. Curr. Med. Chem. 4, 425-428,
2004. IF 4.382
S. Richter, C. Parolin, M. Palumbo, G. Palù, Antiviral properties of quinolone-based
drugs. Curr. Drug Targets Infect. Disord. 4, 111-116, 2004. IF 4.104
S. Richter, I. Menegazzo, D. Fabris, M. Palumbo, Concerted bis-alkylating reactivity of
clerocidin towards unpaired cytosine residues in DNA. Nucleic Acids Res. 32, 5658-
5667, 2004. IF 7.260
S. Richter, S. Maggi, S. Colloredo Mels, M. Palumbo, M. Freccero. BINOL quinone
methides as bis-alkylating and DNA cross-linking agents. J. Am. Chem. Soc. 126,
13973-13979, 2004. IF 6.903
C. Sissi, E. Leo, S. Moro, G. Capranico, A. Mancia, E. Menta, A.P. Krapcho, M.
Palumbo, Antitumor Aza-anthrapyrazoles: biophysical and biochemical studies on 8-
and 9-aza regioisomers. Biochem. Pharmacol. 67, 631-642, 2004. IF 3.436
S. Moro, G.L. Beretta, D. Dal Ben, J. Nitiss, M. Palumbo, G. Capranico, An interaction
model for anthracycline activity against DNA topoisomerase II. Biochemistry 43, 7503-
7513, 2004. IF 4.008
F. Meggio, M.A. Pagano, S. Moro, G. Zagotto, M. Ruzzene, S. Sarno, G. Cozza, J.
Bain, M. Elliott, A.D. Deana, A.M. Brunati, L.A. Pinna, Inhibition of protein kinase
CK2 by condensed polyphenolic derivatives. An in vitro and in vivo study.
Biochemistry, 43, 12931-12936, 2004. IF 3.922.
G. Capranico, G. Zagotto, M. Palumbo, Development of DNA of Topoisomerase-
related therapeutics: a short perspective of new challenges. Curr. Med. Chem. 4, 335-
345, 2004. IF 4.382.
S. Richter, B. Gatto, O. Tabarrini, A. Fravolini, M. Palumbo, Antiviral 6-
aminoquinolones: molecular basis for potency and selectivity. Bioorg. Med. Chem.
Lett. 15, 4247-4251. IF 2.182
E. Leo K.A. Gould, X.S. Pan, G. Capranico, M.R. Sanderson, M. Palumbo, L.M.
Fisher, Novel symmetric and asymmetric DNA scission determinants for Streptococcus
pneumoniae topoisomerase IV and gyrase are clustered at the DNA breakage site. J.
Biol. Chem. 280, 14252-14263, 2005. IF 6.355
S. Richter, D. Fabris, S. Moro, M. Palumbo, Dissecting reactivity of Clerocidin towards
common buffer systems by means of selcted drug analogues. Chem. Res. Toxicol. 18,
35-40, 2005. IF 2.797
C. Sissi, E. Marangon, A. Chemello, C.G. Noble, A. Maxwell, M. Palumbo, The effects
of metal ions on the structure and stability of the DNA gyrase B protein. J. Mol. Biol.
353, 1152-1160, 2005. IF 5.542
C. Sissi, F. Mancin, M. Gatos, M. Palumbo, P. Tecilla, U. Tonellato, Efficient plasmid
DNA cleavage by a mononuclear copper(II) complex. Inorg. Chem. 44, 2310, 2005. IF
3.454
International patent
M. Palumbo, B. Gatto, R. Pescador, R. Porta, L. Ferro, DNA-based aptamer for humancathepsin G. 03425428.4. (2003).
Book Chapter
M. Palumbo, B. Gatto, C. Sissi, DNA topoisomerases targeted drugs. In DNA and RNAbinders. M. Demeunynck, C. Bailly, W.D. Wilson (eds.), vol. 2, Wiley-VCH,Weinheim 2003, pp. 503-537.
1) E. Vianini, M. Palumbo, B. Gatto, In vitro Selection of DNA Aptamers that Bind L-Tyrosinamide. Bioorg. Med. Chem. 9, 2543-2548, 2001. IF 2.018
2) C. Sissi, P. Rossi, F. Felluga, F. Formaggio, M. Palumbo, P. Tecilla, C. Toniolo, P. Scrimin, Dinuclear Zn2+ complexes of synthetic heptapeptides as artificial
nucleases. J. Am. Chem. Soc. 123, 3168-3170, 2001. IF: 6.903
3) B. Gatto, S. Richter, S. Moro, G. Capranico, M. Palumbo, The topoisomerase II poison clerocidin alkylates non-paired guanines of DNA: implications for the
irreversible stimulation of DNA cleavage. Nucleic Acids Res. 29, 4224-4230,
4) S. Richter, C. Parolin, B. Gatto, C. Del Vecchio, E. Brocca-Cofano, A.
Fravolini, G. Palù, M. Palumbo, Inhibition of HIV-1 Tat-TAR interaction by an
antiviral quinolone derivative. Antimicrob. Agents Chemother. 48, 1895-1899,
2004. IF 4.246
5) C. Sissi, E. Marangon, A. Chemello, C.G. Noble, A. Maxwell, M. Palumbo, The effects of metal ions on the structure and stability of the DNA gyrase B
protein. J. Mol. Biol. 353, 1152-1160, 2005. IF 5.542
SWOT Analysis
Strenghts
Our program has a strong interdisciplinary character, since the research involves
different disciplines, from synthetic chemistry to molecular biology, and range from
basic research to applied medicinal chemistry and biotechnology.
The specific strong points of this program are:
advanced research in the national and international field; long–time and highly-experienced researchers in the sector, therefore top-level knowledge of issues and related problems excellent possibilities of links and synergies with other sectors for multi-disciplinary research; innovative methodologies in the panorama of national and internationalresearch, with specific expertise rather unique in Italy; possibilities of discussion and collaboration with other universities andinternational research institutes; European funding and insertion in qualified research groups at internationallevel; Weakness
The weaknesses of the program refer to the availability of funds, instruments and
personnel, which are not always adequate for a research requiring very specific levels
of specialisation and many years of investigation.
Hence, the main points of weakness are:
• lack of human resources and uncertainty over human resource exchanges: the personnel involved in long term research and management of each project isrepresented only by few senior investigators; • limited funding, in particular for basic research, with further possible reduction; • lack of continuity of interest and funding in relations with institutional • lack of interest by local Agencies in long-term research does not allow the • lack of possible partners/investors in the local industrial sector does not foster Opportunities
The program has a multidisciplinary character and allows the exchange of ideas andexpertise between scientists with a very different background, with the aim ofcreating knowledge and products aimed at improving human health. The greatinterest in wide sections of society and business outside Italy, in some of theinnovative research topics offers opportunities for future growth. In addition, ourresearch, carried out in collaboration with well-established international groups,allows fruitful exchange programs involving students and post-docs.

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