67 results on '"Pugliesi I"'
Search Results
2. A novel ultra-broadband transient spectrometer with microsecond measurement range based on a supercontinuum fiber laser
- Author
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Schriever, C., Pugliesi, I., and Riedle, E.
- Published
- 2009
- Full Text
- View/download PDF
3. Sub-50 fs broadband absorption spectroscopy with tunable excitation: putting the analysis of ultrafast molecular dynamics on solid ground
- Author
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Megerle, U., Pugliesi, I., Schriever, C., Sailer, C. F., and Riedle, E.
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- 2009
- Full Text
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4. Modulation of PAR1 signalling by benzimidazole compounds
- Author
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Asteriti, S, Daniele, S, Porchia, F, Dellʼ Anno, MT, Fazzini, A, Pugliesi, I, Trincavelli, ML, Taliani, S, Martini, C, Mazzoni, MR, and Gilchrist, A
- Published
- 2012
- Full Text
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5. Modulation of PAR(1) signaling by benzimidazole compounds
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Asteriti, Sabrina, Daniele, Simona, Porchia, F, Dell'Anno, Mt, Fazzini, A, Pugliesi, I, Trincavelli, MARIA LETIZIA, Taliani, Sabrina, Martini, Claudia, Mazzoni, MARIA ROSA, and Gilchrist, A.
- Published
- 2012
6. THIOAMIDE, IMINOTHIOETHER AND ISOTHIOCYANATE DERIVATIVES: CHEMOTYPES OF SLOW H2S-RELEASING AGENTS
- Author
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Martelli, Alma, Testai, Lara, Marino, Alice, Pugliesi, I, Taliani, Sabrina, Nesi, Giulia, Rapposelli, Simona, DA SETTIMO PASSETTI, Federico, Citi, Valentina, Breschi, MARIA CRISTINA, and Calderone, Vincenzo
- Published
- 2012
7. Indole-based modulators of p53/MDM2 interaction as antitumoral agents
- Author
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Elisabetta Barresi, Pugliesi, I., SABRINA TALIANI, FEDERICO DA SETTIMO PASSETTI, La Pietra, V., Marinelli, L., Novellino, E., Baratta, C., Eleonora Da Pozzo, BARBARA COSTA, and Claudia Martini
- Published
- 2012
8. Design and synthesis of novel indolylglyoxylamide derivatives as molecular probes for 18 KDa translocator protein (TSPO)
- Author
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Elisabetta Barresi, Pugliesi, I., SABRINA TALIANI, FEDERICO DA SETTIMO PASSETTI, Eleonora Da Pozzo, BARBARA COSTA, Bendinelli, S., and Claudia Martini
- Published
- 2012
9. H2S-RELEASING PROPERTIES OF NEW THIOAMIDE, IMINOTHIOETHER AND ISOTHIOCYANATE DERIVATIVES
- Author
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Calderone, Vincenzo, Martelli, Alma, Testai, Lara, Marino, Alice, Pugliesi, I, Taliani, Sabrina, Nesi, Giulia, Rapposelli, Simona, DA SETTIMO PASSETTI, Federico, and Breschi, MARIA CRISTINA
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- 2012
10. Evaluation of Novel N1-Methyl-2-phenylindol-3-ylglyoxylamides as a New Chemotype 2 of 18 kDa Translocator Protein-Selective Ligand Suitable for the Development 3 of Positron Emission Tomography Radioligands
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Pike, Vw, Taliani, Sabrina, Lohith, Tg, Owen, R, Pugliesi, I, DA POZZO, Eleonora, Hong, J, Zoghbi, Ss, Gunn, R, Parker, Ca, Rabiner, Ea, Fujita, M, Innis, Rb, Martini, Claudia, and DA SETTIMO PASSETTI, Federico
- Published
- 2011
11. Derivatives of benzimidazol-2-yl-quinoline and benzimidazol-2-yl-isoquinoline as selective antagonists at A1 adenosine receptors with stimulant actions on human colon motility
- Author
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Cosimelli, B, Taliani, Sabrina, Greco, G, Novellino, E, Sala, A, Severi, E, DA SETTIMO PASSETTI, Federico, LA MOTTA, Concettina, Pugliesi, I, Antonioli, Luca, Fornai, Matteo, COLUCCI ROCCHINA, L, Blandizzi, Corrado, Daniele, Simona, Trincavelli, MARIA LETIZIA, and Martini, Claudia
- Published
- 2011
12. Lead optimization of a novel molecular scaffold in search for novel MMP-13 inhibitors
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Taliani, Sabrina, Pugliesi, I., Barresi, Elisabetta, Simorini, Francesca, Salerno, Silvia, LA MOTTA, Concettina, Marini, ANNA MARIA, Nuti, Elisa, La Pietra, V., Cosconati, S., Marinelli, L., Rossello, Armando, DA SETTIMO PASSETTI, Federico, and Novellino, E.
- Published
- 2010
13. Two-dimensional Fourier transform spectroscopy in the ultraviolet with sub-20 fs pump pulses and 250-720nm supercontinuum probe.
- Author
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Krebs, N., Pugliesi, I., Hauer, J., and Riedle, E.
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FOURIER transform infrared spectroscopy , *SPECTRUM analysis , *FOURIER analysis , *BROADBAND communication systems , *DATA transmission systems , *RADIO frequency modulation , *ULTRAVIOLET radiation - Abstract
Experimental realizations of two-dimensional (2D) electronic spectroscopy in the ultraviolet (UV) must so far contend with a limited bandwidth in both the excitation and particularly the probe frequency. The pump bandwidth is at best 1500 cm-1 (full width at half maximum) at a fixed wavelength of 267 nm or 400 cm-1 for tunable pulses. The use of a replica of the pump pulse as a probe limits the observation of photochemical processes to the excitation region and makes the disentanglement of overlapping signal contributions difficult. We show that 2D Fourier transform spectroscopy can be conducted in a shaper-assisted collinear setup comprising fully tunable UV pulse pairs and supercontinuum probe spanning 250-720 nm. The pump pulses are broadened up to a useable spectral coverage of 2000 cm-1 (25 nm at 316 nm) by self-phase modulation in bulk CaF2 and compressed to 18 fs. By referencing the white light probe and eliminating pump stray light contributions, high signal-to-noise ratios even for weak probe intensities are achieved. Data acquisition times as short as 4 min for a selected population time allow the rapid recording of 2D spectra for photolabile biological samples even with the employed 1 kHz laser system. The potential of the setup is demonstrated on two representative molecules: pyrene and 2,2-diphenyl-5,6-benzo(2H)chromene. Well-resolved cross-peaks are observed and the excitation energy dependence of the relaxation processes is revealed. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
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14. Modulation of PAR1 signalling by benzimidazole compounds.
- Author
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Asteriti, S, Daniele, S, Porchia, F, Dell' Anno, MT, Fazzini, A, Pugliesi, I, Trincavelli, ML, Taliani, S, Martini, C, Mazzoni, MR, and Gilchrist, A
- Subjects
BENZIMIDAZOLE derivatives ,CELLULAR signal transduction ,DRUG interactions ,PHARMACOLOGY ,ENDOTHELIAL cells ,INTRACELLULAR calcium ,DRUG development - Abstract
BACKGROUND AND PURPOSE Recently, a small molecule (Q94) was reported to selectively block PAR
1 /Gαq interaction and signalling. Here, we describe the pharmacological properties of Q94 and two analogues that share its benzimidazole scaffold (Q109, Q89). Q109 presents a modest variation from Q94 in the substituent group at the 2-position, while Q89 has quite different groups at the 1- and 2-positions. EXPERIMENTAL APPROACH Using human microvascular endothelial cells, we examined intracellular Ca2+ mobilization and inositol 1,4,5-trisphosphate accumulation as well as isoprenaline- or forskolin-stimulated cAMP production in response to thrombin. KEY RESULTS Q89 (10 µM) produced a leftward shift in the thrombin-mediated intracellular Ca2+ mobilization concentration-response curve while having no effect on the Emax . Both Q94 (10 µM) and Q109 (10 µM) reduced intracellular Ca2+ mobilization, leading to a decrease in Emax and an increase in EC50 values. Experiments utilizing receptor-specific activating peptides confirmed that Q94 and Q109 were selective for PAR1 as they did not alter the Ca2+ response mediated by a PAR2 activating peptide. Consistent with our Ca2+ results, micromolar concentrations of either Q94 or Q109 significantly reduced thrombin-induced inositol 1,4,5-trisphosphate production. Neither Q94 nor Q109 diminished the inhibitory effects of thrombin on cAMP production, indicating they inhibit signalling selectively through the Gq pathway. Our results also suggest the 1,2-disubstituted benzimidazole derivatives act as 'allosteric agonists' of PAR1 . CONCLUSIONS AND IMPLICATIONS The Q94 and Q109 benzimidazole derivatives represent a novel scaffold for the development of new PAR1 inhibitors and provide a starting point to develop dual signalling pathway-selective positive/negative modulators of PAR1 . [ABSTRACT FROM AUTHOR]- Published
- 2012
- Full Text
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15. Noise-Induced Förster Resonant Energy Transfer between Orthogonal Dipoles in Photoexcited Molecules.
- Author
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Nalbach, P., Pugliesi, I., Langhals, H., and Thorwart, M.
- Subjects
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ENERGY transfer , *ORTHOGONAL functions , *DIPOLE moments , *FLUCTUATIONS (Physics) , *TEMPERATURE measurements , *PERYLENE - Abstract
We show that Förster resonance energy transfer (FRET) in an orthogonally arranged donor-acceptor pair can be induced by environmental noise, although direct transfer is prohibited. Environmental fluctuations break the strict orthogonal dipole arrangement and cause effective fluctuating excitonic interactions. Using a scaling argument, we show that interaction fluctuations are coupled to those of the energy levels and are strong enough to induce large FRET rates. This mechanism also explains the temperature dependence observed in a recent experiment on a perylene bisimide dyad and predicts a modified distance dependence as compared to standard Förster theory. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
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16. New perspectives on ultrafast Förster Resonant Energy Transfer.
- Author
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Pugliesi, I., Langhals, H., Kauffmann, H., and Riedle, E.
- Subjects
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ENERGY transfer , *PERYLENE , *IMIDES , *DYADS , *ELECTRON donor-acceptor complexes , *DIPOLE-dipole interactions , *ULTRASHORT laser pulses , *FEMTOSECOND pulses - Abstract
We show that perylene diimide dyads based on a donor-spacer-acceptor motif violate Förster's dipole-dipole interaction picture for energy transfer in the low picosecond to sub-100 femtosecond regime. First theoretical explanations are presented. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
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17. Naphthalene Bisimides: on the Way to Ultrafast Opto-electronic Devices.
- Author
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Pugliesi, I., Krok, P., Błaszczyk, A., Mayor, M., and Riedle, E.
- Abstract
For core-substituted naphthalene bisimides and their dimers we observe ultrafast charge transfer and Resonance Energy Transfer processes that change their conduction properties. This makes them suitable candidates for optoelectronic switches with terahertz response times. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
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18. Förster resonant energy transfer (FRET) in orthogonal chromophores.
- Author
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Pugliesi, I., Langhals, H., and Riedle, E.
- Published
- 2011
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19. Ultrafast time-resolved photoelectron spectroscopy with tunable deep UV-pulses.
- Author
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Lang, P., Homann, C., Pugliesi, I., Kienberger, R., and Riedle, E.
- Published
- 2011
- Full Text
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20. New frontiers in ultrafast broadband pump-probe spectroscopy for the investigation of electron transfer processes.
- Author
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Pugliesi, I., Megerle, U., Bradler, M., and Riedle, E.
- Published
- 2009
- Full Text
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21. 3-Aryl-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one: a novel template for the design of highly selective A2B adenosine receptor antagonists
- Author
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Barbara Cosimelli, Federico Da Settimo, Ettore Novellino, Salvatore Di Maro, Sabrina Taliani, Giovanni Greco, Simona Daniele, Claudia Martini, Anna Maria Marini, Silvia Salerno, Francesca Simorini, Maria Letizia Trincavelli, Elisabetta Barresi, Isabella Pugliesi, Luciana Marinelli, Concettina La Motta, Sandro Cosconati, Taliani, S., Pugliesi, I., Barresi, E., Simorini, F., Salerno, S., La Motta, C., Marini, A. M., Cosimelli, Barbara, Cosconati, S., DI MARO, Salvatore, Marinelli, Luciana, Daniele, S., Trincavelli, M. L., Greco, Giovanni, Novellino, Ettore, Martini, C., Da Settimo, F., Taliani, S, Pugliesi, I, Barresi, E, Simorini, F, Salerno, S, La Motta, C, Marini, Am, Cosimelli, B, Cosconati, Sandro, Marinelli, L, Daniele, S, Trincavelli, Ml, Greco, G, Novellino, E, and Martini, C
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Stereochemistry ,Aryl ,Chlorine atom ,antagonist ,Highly selective ,Ring (chemistry) ,Adenosine receptor ,chemistry.chemical_compound ,pharmacology, Benzimidazoles ,chemistry ,Drug Discovery ,Molecular Medicine ,adenosine receptor ,Selectivity ,IC50 - Abstract
In an effort to identify novel ligands possessing high affinity and selectivity for the A2B AR subtype, we further investigated the class of 3-aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones V, previously disclosed by us as selective A1 AR antagonists. Preliminary assays on a number of triazinobenzimidazoles derived from our "in-house" collection revealed that all the derivatives selected showed significant affinity at A 2B AR, no affinity at A3 AR, and various degrees of selectivity toward A1 and A2A ARs. Investigation of a new series featuring modified substituents at the 10-position (4′-chlorophenyl or phenylethyl groups), and a chlorine atom at the 7-position (X) of the triazinobenzimidazole nucleus, yielded highly potent and selective A 2B AR antagonists. The presence of a pendant 3-phenyl ring appears to hamper the interaction with A2A AR, conferring high A 2B/A2A AR selectivity. Derivative 13 (X = Cl, R = C 6H5) is the most potent and selective compound, with an IC50 of 3.10 nM at A2B AR and no affinity at A 1, A2A, and A3 ARs. © 2012 American Chemical Society.
- Published
- 2012
22. Phenylpyrazolo[1,5‑a]quinazolin-5(4H)‑one: a suitable scaffold for the development of noncamptothecin topoisomerase I (Top1) inhibitors
- Author
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Anna Maria Marini, Christophe Marchand, Keli Agama, Luciana Marinelli, Concettina La Motta, Francesco Saverio Di Leva, Sabrina Taliani, Ettore Novellino, Silvia Salerno, Yves Pommier, Roberto Di Santo, Elisabetta Barresi, Federico Da Settimo, Francesca Simorini, Sandro Cosconati, Isabella Pugliesi, Taliani, S, Pugliesi, I, Barresi, E, Salerno, S, Marchand, C, Agama, K, Simorini, F, La Motta, C, Marini, Am, Di Leva, F, Marinelli, L, Cosconati, Sandro, Novellino, E, Pommier, Y, Di Santo, R, Da Settimo, F., Department of Pharmacy, University of Pisa - Università di Pisa, Laboratory of Molecular Pharmacology, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Department of Pharmaceutical Chemistry and Toxicology, Università degli studi di Napoli Federico II, Department of Pharmacy Naples, Université de Naples, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Department of Medicinal Chemistry and Technologies, Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], S., Taliani, I., Pugliesi, E., Barresi, S., Salerno, C., Marchand, K., Agama, F., Simorini, C., La Motta, A. M., Marini, Di Leva, Francesco Saverio, Marinelli, Luciana, S., Cosconati, Novellino, Ettore, Y., Pommier, R., Di Santo, and F., Da Settimo
- Subjects
Protein Conformation ,Stereochemistry ,Topoisomerase-I Inhibitor ,010402 general chemistry ,Cleavage (embryo) ,01 natural sciences ,Molecular Docking Simulation ,Article ,antitumor agents ,chemistry.chemical_compound ,MESH: Protein Conformation ,MESH: Drug Discovery ,Drug Discovery ,inhibitors ,Side chain ,Quinazoline ,MESH: Molecular Docking Simulation ,Humans ,Pyrroles ,MESH: Heterocyclic Compounds, 3-Ring ,topoisomerase ,MESH: Humans ,biology ,010405 organic chemistry ,Drug discovery ,Chemistry ,Topoisomerase ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,0104 chemical sciences ,MESH: Quinazolines ,MESH: Topoisomerase I Inhibitors ,DNA Topoisomerases, Type I ,Docking (molecular) ,Quinazolines ,biology.protein ,MESH: Pyrroles ,Molecular Medicine ,Topoisomerase I Inhibitors ,Heterocyclic Compounds, 3-Ring ,MESH: DNA Topoisomerases, Type I - Abstract
In search for a novel chemotype to develop topoisomerase I (Top1) inhibitors, the pyrazolo[1,5-a]quinazoline nucleus, structurally related to the indenoisoquinoline system precursor of well-known Top1 poisons, was variously decorated (i.e., a substituted phenyl ring at 2- or 3-position, a protonable side chain at 4- or 5-position), affording a number of Top1 inhibitors with cleavage patterns common to CPT and MJ-III-65. SARs data were rationalized by means of an advanced docking protocol. © 2013 American Chemical Society.
- Published
- 2013
23. Synthesis and biological evaluation of 4-phenylquinazoline-2-carboxamides designed as a novel class of potent ligands of the translocator protein
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Ciro Milite, Giorgio Stefancich, Claudia Martini, Elisa Rizzetto, Eleonora Da Pozzo, S Bendinelli, Federico Da Settimo, Barbara Costa, Sabrina Taliani, Sandro Cosconati, Giovanni Greco, Isabella Pugliesi, Ettore Novellino, Gianluca Sbardella, Sabrina Castellano, Castellano, S, Taliani, S, Milite, C, Pugliesi, I, Da Pozzo, E, Rizzetto, E, Bendinelli, S, Costa, B, Cosconati, Sandro, Greco, G, Novellino, E, Sbardella, G, Stefancich, G, Martini, C, Da, Settimo, Castellano, Sabrina, Taliani, Sabrina, Milite, Ciro, Pugliesi, Isabella, Da Pozzo, Eleonora, Rizzetto, Elisa, Bendinelli, Sara, Costa, Barbara, Greco, Giovanni, Novellino, Ettore, Sbardella, Gianluca, Stefancich, Giorgio, Martini, Claudia, and Da Settimo, Federico
- Subjects
18 KDA ,Cell Survival ,Pharmaceutical Science ,Binding, Competitive ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,chemistry.chemical_compound ,PERIPHERAL BENZODIAZEPINE-RECEPTOR, 18 KDA, GLIOBLASTOMA CELLS, APOPTOSIS, BINDING, BIOSYNTHESIS, RADIOLIGANDS, DERIVATIVES, TSPO ,Biosynthesis ,Cell Line, Tumor ,Drug Discovery ,BINDING ,Translocator protein ,Animals ,Structure–activity relationship ,PERIPHERAL BENZODIAZEPINE-RECEPTOR ,BIOSYNTHESIS ,Receptor ,Biological evaluation ,Molecular Structure ,biology ,Animal ,Ligand ,GLIOBLASTOMA CELLS ,DERIVATIVES ,Quinazoline ,Receptors, GABA-A ,Combinatorial chemistry ,Rats ,APOPTOSIS ,chemistry ,RADIOLIGANDS ,Quinazolines ,biology.protein ,Rat ,Molecular Medicine ,Pharmacophore ,Carrier Proteins ,Carrier Protein ,Selectivity ,TSPO - Abstract
A series of novel 4-phenylquinazoline-2-carboxamides (1-58) were designed as aza-isosters of PK11195, the well-known 18 kDa translocator protein (TSPO) reference ligand, and synthesized by means of a very simple and efficient procedure. A number of these derivatives bind to the TSPO with K i values in the nanomolar/subnanomolar range, show selectivity toward the central benzodiazepine receptor (BzR) and exhibit structure-affinity relationships consistent with a previously published pharmacophore/topological model of ligand-TSPO interaction. © 2012 American Chemical Society.
- Published
- 2012
24. 3-(Fur-2-yl)-10-(2-Phenylethyl)-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one, a Novel Adenosine Receptor Antagonist with (2A)-Mediated Neuroprotective EffeCTS
- Author
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Alessia Scatena, Federico Da Settimo, Claudia Martini, Francesco Fornai, Isabella Pugliesi, Sabrina Taliani, Sandro Cosconati, Simona Daniele, Maria Letizia Trincavelli, Scatena, A, Fornai, F, Trincavelli, Ml, Taliani, S, Daniele, S, Pugliesi, I, Cosconati, Sandro, Martini, C, and Da Settimo, F.
- Subjects
Cell viability ,1-Methyl-4-phenylpyridinium ,Physiology ,Pharmacology ,Biochemistry ,PC12 Cells ,Methamphetamine ,chemistry.chemical_compound ,Cricetinae ,AR antagonist ,Cyclic AMP ,PC12 cell ,Cell Death ,Triazines ,General Medicine ,Neuroprotection ,Adenosine A2 Receptor Antagonists ,Neuroprotective Agents ,Trypan blue ,Agonist ,Receptor, Adenosine A2A ,medicine.drug_class ,Cell Survival ,Cognitive Neuroscience ,Neurotoxins ,CHO Cells ,Adenosine receptor antagonist ,Receptors, N-Methyl-D-Aspartate ,medicine ,Animals ,Humans ,Computer Simulation ,Viability assay ,2A ,Membranes ,Human neuroblastoma cell ,Receptor, Adenosine A1 ,Receptors, Dopamine D2 ,Antagonist ,Cell Biology ,Meth ,Receptors, GABA-A ,Adenosine receptor ,Rats ,chemistry ,Benzimidazoles ,Indicators and Reagents ,Neurotoxin - Abstract
In this study, compound FTBI (3-(2-furyl)-10-(2-phenylethyl)[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one) was selected from a small library of triazinobenzimidazole derivatives as a potent A(2A) adenosine receptor (AR) antagonist and tested for its neuroprotective effects against two different kinds of dopaminergic neurotoxins, 1-methyl-4-phenylpyridinium (MPP+) and methamphetamine (METH), in rat PC12 and in human neuroblastoma SH-SY5Y cell lines. FTBI, in a concentration range corresponding to its affinity for A(2A) AR subtype, significantly increased the number of viable PC12 cells after their exposure to METH and, to a similar extent, to MPP+, as demonstrated in both trypan blue exclusion assay and in cytological staining. These neuroprotective effects were also observed with a classical A(2A) AR antagonist, ZM241385, and appeared to be completely counteracted by the AR agonist, NECA, supporting A(2A) ARs are directly involved in FTBI-mediated effects. Similarly, in human SH-SY5Y cells, FTBI was able to prevent cell toxicity induced by MPP+ and METH, showing that this A(2A) AR antagonist has a neuroprotective effect independently by the specific cell model. Altogether these results demonstrate that the A(2A) AR blockade mediates cell protection against neurotoxicity induced by dopaminergic neurotoxins in dopamine containing cells, supporting the potential use of A(2A) AR antagonists in dopaminergic degenerative diseases including Parkinson's disease.
- Published
- 2011
25. Hole-transfer induced energy transfer in perylene diimide dyads with a donor-spacer-acceptor motif.
- Author
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Kölle P, Pugliesi I, Langhals H, Wilcken R, Esterbauer AJ, de Vivie-Riedle R, and Riedle E
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- Electron Transport, Electrons, Perylene chemistry, Quantum Theory, Fluorescence Resonance Energy Transfer, Imides chemistry, Perylene analogs & derivatives
- Abstract
We investigate the photoinduced dynamics of perylene diimide dyads based on a donor-spacer-acceptor motif with polyyne spacers of varying length by pump-probe spectroscopy, time resolved fluorescence, chemical variation and quantum chemistry. While the dyads with pyridine based polyyne spacers undergo energy transfer with near-unity quantum efficiency, in the dyads with phenyl based polyyne spacers the energy transfer efficiency drops below 50%. This suggests the presence of a competing electron transfer process from the spacer to the energy donor as the excitation sink. Transient absorption spectra, however, reveal that the spacer actually mediates the energy transfer dynamics. The ground state bleach features of the polyyne spacers appear due to the electron transfer decay with the same time constant present in the rise of the ground state bleach and stimulated emission of the perylene energy acceptor. Although the electron transfer process initially quenches the fluorescence of the donor it does not inhibit energy transfer to the perylene energy acceptor. The transient signatures reveal that electron and energy transfer processes are sequential and indicate that the donor-spacer electron transfer state itself is responsible for the energy transfer. Through the introduction of a Dexter blocker unit into the spacer we can clearly exclude any through bond Dexter-type energy transfer. Ab initio calculations on the donor-spacer and the donor-spacer-acceptor systems reveal the existence of a bright charge transfer state that is close in energy to the locally excited state of the acceptor. Multipole-multipole interactions between the bright charge transfer state and the acceptor state enable the energy transfer. We term this mechanism coupled hole-transfer FRET. These dyads represent a first example that shows how electron transfer can be connected to energy transfer for use in novel photovoltaic and optoelectronic devices.
- Published
- 2015
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26. Vibrations of the S1 state of fluorobenzene-h5 and fluorobenzene-d5 via resonance-enhanced multiphoton ionization (REMPI) spectroscopy.
- Author
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Harris JP, Andrejeva A, Tuttle WD, Pugliesi I, Schriever C, and Wright TG
- Subjects
- Models, Chemical, Quantum Theory, Spectrum Analysis, Vibration, Fluorobenzenes chemistry
- Abstract
We report resonance-enhanced multiphoton ionization spectra of the isotopologues fluorobenzene-h5 and fluorobenzene-d5. By making use of quantum chemical calculations, the changes in the wavenumber of the vibrational modes upon deuteration are examined. Additionally, the mixing of vibrational modes both between isotopologues and also between the two electronic states is discussed. The isotopic shifts lead to dramatic changes in the appearance of the spectrum as vibrations shift in and out of Fermi resonance. Assignments of the majority of the fluorobenzene-d5 observed bands are provided, aided by previous results on fluorobenzene-h5.
- Published
- 2014
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27. Allosteric modulators of human A2B adenosine receptor.
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Trincavelli ML, Giacomelli C, Daniele S, Taliani S, Cosimelli B, Laneri S, Severi E, Barresi E, Pugliesi I, Greco G, Novellino E, Da Settimo F, and Martini C
- Subjects
- Adenosine-5'-(N-ethylcarboxamide) pharmacology, Allosteric Regulation, Cyclic AMP physiology, Guanosine 5'-O-(3-Thiotriphosphate) metabolism, Humans, Receptor, Adenosine A2B metabolism, Receptor, Adenosine A2B drug effects
- Abstract
Background: Among adenosine receptors (ARs) the A2B subtype exhibits low affinity for the endogenous agonist compared with the A1, A2A, and A3 subtypes and is therefore activated when concentrations of adenosine increase to a large extent following tissue damages (e.g. ischemia, inflammation). For this reason, A2B AR represents an important pharmacological target., Methods: We evaluated seven 1-benzyl-3-ketoindole derivatives (7-9) for their ability to act as positive or negative allosteric modulators of human A2B AR through binding and functional assays using CHO cells expressing human A1, A2A, A2B, and A3 ARs., Results: The investigated compounds behaved as specific positive or negative allosteric modulators of human A2B AR depending on small differences in their structures. The positive allosteric modulators 7a,b and 8a increased agonist efficacy without any effect on agonist potency. The negative allosteric modulators 8b,c and 9a,b reduced agonist potency and efficacy., Conclusions: A number of 1-benzyl-3-ketoindole derivatives were pharmacologically characterized as selective positive (7a,b) or negative (8c, 9a,b) allosteric modulators of human A2B AR., General Significance: The 1-benzyl-3-ketoindole derivatives 7-9 acting as positive or negative allosteric modulators of human A2B AR represent new pharmacological tools useful for the development of therapeutic agents to treat pathological conditions related to an altered functionality of A2B AR., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2014
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28. Modulation of A2B adenosine receptor by 1-Benzyl-3-ketoindole derivatives.
- Author
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Taliani S, Trincavelli ML, Cosimelli B, Laneri S, Severi E, Barresi E, Pugliesi I, Daniele S, Giacomelli C, Greco G, Novellino E, Martini C, and Da Settimo F
- Subjects
- Animals, CHO Cells, Cricetulus, Dose-Response Relationship, Drug, Humans, Indoles chemical synthesis, Indoles chemistry, Molecular Structure, Structure-Activity Relationship, Indoles pharmacology, Receptor, Adenosine A2B metabolism
- Abstract
We have disclosed a series of 1-benzyl-3-ketoindole derivatives acting as either positive or negative modulators of the human A(2B) adenosine receptor (A(2B) AR) depending on small differences in their side chain. The new compounds were designed taking into account structural similarities between AR antagonists and ligands of the GABA(A)/benzodiazepine receptor. All compounds resulted totally inactive at A(2A) and A₃ ARs and showed small (8a,b) or none (7a,b, 8c and 9a,b) affinity for A₁ AR. When tested on A(2B) AR-transfected CHO cells, 7a,b and 8a acted as positive modulators, whereas 8b,c and 9a,b acted as negative modulators, enhancing or weakening the NECA-induced increase of cAMP levels, respectively. Compounds 7-9 might be regarded as useful biological and pharmacological tools to explore the therapeutic potential of A(2B) AR modulators, while their 3-ketoindole scaffold might be taken as a reference to design new analogs., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)
- Published
- 2013
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29. Phenylpyrazolo[1,5-a]quinazolin-5(4H)-one: a suitable scaffold for the development of noncamptothecin topoisomerase I (Top1) inhibitors.
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Taliani S, Pugliesi I, Barresi E, Salerno S, Marchand C, Agama K, Simorini F, La Motta C, Marini AM, Di Leva FS, Marinelli L, Cosconati S, Novellino E, Pommier Y, Di Santo R, and Da Settimo F
- Subjects
- DNA Topoisomerases, Type I chemistry, Heterocyclic Compounds, 3-Ring chemistry, Heterocyclic Compounds, 3-Ring metabolism, Humans, Molecular Docking Simulation, Protein Conformation, Pyrroles metabolism, Quinazolines metabolism, Topoisomerase I Inhibitors metabolism, DNA Topoisomerases, Type I metabolism, Drug Discovery, Heterocyclic Compounds, 3-Ring pharmacology, Pyrroles chemistry, Pyrroles pharmacology, Quinazolines chemistry, Quinazolines pharmacology, Topoisomerase I Inhibitors chemistry, Topoisomerase I Inhibitors pharmacology
- Abstract
In search for a novel chemotype to develop topoisomerase I (Top1) inhibitors, the pyrazolo[1,5-a]quinazoline nucleus, structurally related to the indenoisoquinoline system precursor of well-known Top1 poisons, was variously decorated (i.e., a substituted phenyl ring at 2- or 3-position, a protonable side chain at 4- or 5-position), affording a number of Top1 inhibitors with cleavage patterns common to CPT and MJ-III-65. SARs data were rationalized by means of an advanced docking protocol.
- Published
- 2013
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30. Arylthioamides as H2S Donors: l-Cysteine-Activated Releasing Properties and Vascular Effects in Vitro and in Vivo.
- Author
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Martelli A, Testai L, Citi V, Marino A, Pugliesi I, Barresi E, Nesi G, Rapposelli S, Taliani S, Da Settimo F, Breschi MC, and Calderone V
- Abstract
A small library of arylthioamides 1-12 was easily synthesized, and their H2S-releasing properties were evaluated both in the absence or in the presence of an organic thiol such as l-cysteine. A number of arylthioamides (1-3 and 7) showed a slow and l-cysteine-dependent H2S-releasing mechanism, similar to that exhibited by the reference slow H2S-releasing agents, such as diallyl disulfide (DADS) and the phosphinodithioate derivative GYY 4137. Compound 1 strongly abolished the noradrenaline-induced vasoconstriction in isolated rat aortic rings and hyperpolarized the membranes of human vascular smooth muscle cells in a concentration-dependent fashion. Finally, a significant reduction of the systolic blood pressure of anesthetized normotensive rats was observed after its oral administration. Altogether these results highlighted the potential of arylthioamides 1-3 and 7 as H2S-donors for basic studies, and for the rational design/development of promising pharmacotherapeutic agents to treat cardiovascular diseases.
- Published
- 2013
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31. A comprehensive microscopic picture of the benzhydryl radical and cation photogeneration and interconversion through electron transfer.
- Author
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Sailer CF, Thallmair S, Fingerhut BP, Nolte C, Ammer J, Mayr H, Pugliesi I, de Vivie-Riedle R, and Riedle E
- Subjects
- Cations chemistry, Electron Transport, Free Radicals chemistry, Molecular Structure, Photochemical Processes, Quantum Theory, Spectrophotometry, Ultraviolet, Benzhydryl Compounds chemistry
- Abstract
Bond cleavage and bond formation are central to organic chemistry. Carbocations play a key role in our understanding of nucleophilic substitution reactions that involve both processes. The precise understanding of the mechanism and dynamics of the photogeneration of carbocations and carbon radicals is therefore an important quest. In particular, the role of electron transfer for the generation of carbocations from the radical pair is still unclear. A quantitative femtosecond absorption study is presented, with ultrabroad probing on selected donor and acceptor substituted benzhydryl chlorides irradiated with 270 nm (35 fs) pulses. The ultrafast bond cleavage within 300 fs is almost exclusively homolytic, thus leading to a radical pair. The carbocations observable in the nanosecond regime are generated from these radicals by electron transfer from the benzhydryl to the chlorine radical within the first tens of picoseconds. Their concentration is reduced by geminate recombination within hundreds of picoseconds. In moderately polar solvents this depletion almost extinguishes the cation population; in highly polar solvents free ions are still observable on the nanosecond timescale. The explanation of the experimental findings requires the microscopic realm of the intermediates to be accounted for, including their spatial and environmental distributions. The distance dependent electron transfer described by Marcus theory is combined with Smoluchowski diffusion. The depletion of the radical pair distribution at small distances causes a temporal increase of the mean distance and the observed stretched exponential electron transfer. A close accord with experiment can only be reached for a broad distribution of the nascent radical pairs. The increase in the inter-radical and inter-ion pair distance is measured directly as a shift of the UV/Vis absorption of the products. The results demonstrate that, at least for aprotic solvents, traditional descriptions of reaction mechanisms based on the concept of contact and solvent-separated pairs have to be reassessed., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2013
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32. Electronic transient spectroscopy from the deep UV to the NIR: unambiguous disentanglement of complex processes.
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Riedle E, Bradler M, Wenninger M, Sailer CF, and Pugliesi I
- Abstract
Complex multi-stage relaxation and reaction pathways after the optical excitation of molecules makes the disentanglement of the underlying mechanisms challenging. We present four examples that a new transient spectrometer with excitation fully tunable from the deep UV to the IR and 225 to 1700 nm probing allows for an analysis with greatly reduced ambiguity. The temporal resolution of about 50 fs allows us to resolve all relevant processes. For each example there is a new twist in the sequence of relaxation steps that had previously been overlooked. In malachite green it appears that the importance of the phenyl twisting has been overemphasized and rather a charge transfer state should be considered. In TINUVIN-P the predicted twisting as the driving motion for the ultrafast IC is confirmed and leads to a resolution of the earlier puzzle that the sub-5 ps regime shows kinetics deviating from a pure cooling process despite the sub-ps proton transfer cycle. For the bond cleavage of Ph2CH-Cl and Ph2CH-Br the degree of electron transfer within the radical pair can now be determined quantitatively and leads to a profound understanding of the long-term cation yield. For the first time coherent wavepacket motion in the photoproducts is reported. Last but not least the measurement of the GSB recovery in the deep UV allows for the surprising result, that even after S2 excitation of cyclopentenones the triplet states are reached with near unity probability within a few picoseconds.
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- 2013
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33. Molecular model of the ring-opening and ring-closure reaction of a fluorinated indolylfulgide.
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Nenov A, Schreier WJ, Koller FO, Braun M, de Vivie-Riedle R, Zinth W, and Pugliesi I
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- Anhydrides chemistry, Halogenation, Isomerism, Kinetics, Light, Photochemical Processes, Quantum Theory, Spectrophotometry, Infrared, Static Electricity, Thermodynamics, Time Factors, Electrons, Indoles chemistry, Models, Molecular
- Abstract
A combination of experimental and theoretical techniques is used to study the photoinduced ring-opening/closure of a trifluoromethyl-indolylfulgide. Time-resolved UV/vis pump and IR probe measurements are performed in the subpicosecond to 50 ps time range. Probing in the mid-IR between 1200 and 1900 cm(-1) provides mode-specific dynamics and reveals photochemical reaction dynamics as well as the presence of a noncyclizable conformer. Ring-opening occurs with about 3 ps. Experiments on the open isomer confirm that the ring-closure occurs on the subpicosecond time scale. They also show a 10 ps transient that can be assigned to internal conversion of a noncyclizable conformer. Quantum chemical calculations with multireference methods are used to explore the complex potential energy landscape in the excited electronic state showing paths for ring-opening and closure reactions as well as for competing side-reactions. The calculations reveal that photoexcitation induces a charge transfer from the indole to the anhydride. The same charge transfer drives the system toward a low-energy conical intersection seam spreading from the closed to the open ring side and is responsible for the ultrafast relaxation to the ground state. The ultrafast photoreactivity comes at the expense of selectivity.
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- 2012
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34. Ultrafast photo-induced charge transfer unveiled by two-dimensional electronic spectroscopy.
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Bixner O, Lukeš V, Mančal T, Hauer J, Milota F, Fischer M, Pugliesi I, Bradler M, Schmid W, Riedle E, Kauffmann HF, and Christensson N
- Subjects
- Dimerization, Isoindoles, Models, Molecular, Spectrum Analysis methods, Time Factors, Electrons, Indoles chemistry, Lutetium chemistry, Quaternary Ammonium Compounds chemistry
- Abstract
The interaction of exciton and charge transfer (CT) states plays a central role in photo-induced CT processes in chemistry, biology, and physics. In this work, we use a combination of two-dimensional electronic spectroscopy (2D-ES), pump-probe measurements, and quantum chemistry to investigate the ultrafast CT dynamics in a lutetium bisphthalocyanine dimer in different oxidation states. It is found that in the anionic form, the combination of strong CT-exciton interaction and electronic asymmetry induced by a counter-ion enables CT between the two macrocycles of the complex on a 30 fs timescale. Following optical excitation, a chain of electron and hole transfer steps gives rise to characteristic cross-peak dynamics in the electronic 2D spectra, and we monitor how the excited state charge density ultimately localizes on the macrocycle closest to the counter-ion within 100 fs. A comparison with the dynamics in the radical species further elucidates how CT states modulate the electronic structure and tune fs-reaction dynamics. Our experiments demonstrate the unique capability of 2D-ES in combination with other methods to decipher ultrafast CT dynamics.
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- 2012
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35. Synthesis and biological evaluation of 4-phenylquinazoline-2-carboxamides designed as a novel class of potent ligands of the translocator protein.
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Castellano S, Taliani S, Milite C, Pugliesi I, Da Pozzo E, Rizzetto E, Bendinelli S, Costa B, Cosconati S, Greco G, Novellino E, Sbardella G, Stefancich G, Martini C, and Da Settimo F
- Subjects
- Animals, Binding, Competitive, Cell Line, Tumor, Cell Survival drug effects, Inhibitory Concentration 50, Molecular Structure, Quinazolines pharmacology, Rats, Structure-Activity Relationship, Carrier Proteins metabolism, Quinazolines chemical synthesis, Receptors, GABA-A metabolism
- Abstract
A series of novel 4-phenylquinazoline-2-carboxamides (1-58) were designed as aza-isosters of PK11195, the well-known 18 kDa translocator protein (TSPO) reference ligand, and synthesized by means of a very simple and efficient procedure. A number of these derivatives bind to the TSPO with K(i) values in the nanomolar/subnanomolar range, show selectivity toward the central benzodiazepine receptor (BzR) and exhibit structure-affinity relationships consistent with a previously published pharmacophore/topological model of ligand-TSPO interaction.
- Published
- 2012
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36. 3-aryl-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one: a novel template for the design of highly selective A₂B adenosine receptor antagonists.
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Taliani S, Pugliesi I, Barresi E, Simorini F, Salerno S, La Motta C, Marini AM, Cosimelli B, Cosconati S, Di Maro S, Marinelli L, Daniele S, Trincavelli ML, Greco G, Novellino E, Martini C, and Da Settimo F
- Subjects
- Adenosine A2 Receptor Antagonists chemistry, Adenosine A2 Receptor Antagonists pharmacology, Animals, Benzimidazoles chemistry, Benzimidazoles pharmacology, CHO Cells, Caco-2 Cells, Cell Survival drug effects, Cricetinae, Cricetulus, Cyclic AMP metabolism, Drug Design, Humans, Models, Molecular, Radioligand Assay, Structure-Activity Relationship, Triazines chemistry, Triazines pharmacology, Adenosine A2 Receptor Antagonists chemical synthesis, Benzimidazoles chemical synthesis, Receptor, Adenosine A2B metabolism, Triazines chemical synthesis
- Abstract
In an effort to identify novel ligands possessing high affinity and selectivity for the A(2B) AR subtype, we further investigated the class of 3-aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones V, previously disclosed by us as selective A(1) AR antagonists. Preliminary assays on a number of triazinobenzimidazoles derived from our "in-house" collection revealed that all the derivatives selected showed significant affinity at A(2B) AR, no affinity at A(3) AR, and various degrees of selectivity toward A(1) and A(2A) ARs. Investigation of a new series featuring modified substituents at the 10-position (4'-chlorophenyl or phenylethyl groups), and a chlorine atom at the 7-position (X) of the triazinobenzimidazole nucleus, yielded highly potent and selective A(2B) AR antagonists. The presence of a pendant 3-phenyl ring appears to hamper the interaction with A(2A) AR, conferring high A(2B)/A(2A) AR selectivity. Derivative 13 (X = Cl, R = C(6)H(5)) is the most potent and selective compound, with an IC(50) of 3.10 nM at A(2B) AR and no affinity at A(1), A(2A), and A(3) ARs.
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- 2012
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37. Identification of novel molecular scaffolds for the design of MMP-13 inhibitors: a first round of lead optimization.
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La Pietra V, Marinelli L, Cosconati S, Di Leva FS, Nuti E, Santamaria S, Pugliesi I, Morelli M, Casalini F, Rossello A, La Motta C, Taliani S, Visse R, Nagase H, da Settimo F, and Novellino E
- Subjects
- Catalytic Domain, Crystallography, X-Ray, Drug Evaluation, Preclinical, Humans, Inhibitory Concentration 50, Matrix Metalloproteinase 13 chemistry, User-Computer Interface, Drug Design, Matrix Metalloproteinase Inhibitors, Protease Inhibitors chemistry, Protease Inhibitors pharmacology
- Abstract
Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. Thus, MMP-13-selective inhibitors are promising candidates in osteoarthritis therapy. Recently, we designed an N-isopropoxy-arylsulfonamide-based hydroxamate inhibitor, which showed low nanomolar activity and high selectivity for MMP-13. In parallel to further studies aiming to assess the in vivo activity of our compound, we screened the Life Chemicals database through computational docking to seek for novel scaffolds as zinc-chelating non-hydroxamate inhibitors. Experimental evaluation of 20 selected candidate compounds verified five novel leads with IC(50) in the low μM range. These newly discovered inhibitors are structurally unrelated to the ones known so far and provide useful scaffolds to develop compounds with more desirable properties. Finally, a first round of structure-based optimization on lead 1 was accomplished and led to an increase in potency of more than 5 fold., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)
- Published
- 2012
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38. Medicinal chemistry of indolylglyoxylamide TSPO high affinity ligands with anxiolytic-like effects.
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Simorini F, Marini AM, Taliani S, La Motta C, Salerno S, Pugliesi I, and Da Settimo F
- Subjects
- Amides metabolism, Amides pharmacology, Animals, Anti-Anxiety Agents metabolism, Anti-Anxiety Agents pharmacology, Binding Sites, Brain metabolism, GABA-A Receptor Agonists chemistry, GABA-A Receptor Agonists metabolism, GABA-A Receptor Agonists pharmacology, GABA-A Receptor Antagonists chemistry, GABA-A Receptor Antagonists metabolism, GABA-A Receptor Antagonists pharmacology, Glyoxylates metabolism, Glyoxylates pharmacology, Humans, Indoles metabolism, Indoles pharmacology, Ligands, Neurotransmitter Agents metabolism, Protein Binding, Protein Subunits agonists, Protein Subunits antagonists & inhibitors, Protein Subunits metabolism, Structure-Activity Relationship, Amides chemistry, Anti-Anxiety Agents chemistry, Brain drug effects, Glyoxylates chemistry, Indoles chemistry, Receptors, GABA metabolism, Receptors, GABA-A metabolism
- Abstract
The mitochondrial translocator protein (TSPO) mediates the synthesis of neurosteroids in the CNS, which have been demonstrated to enhance the neurotransmitter GABA response, exhibiting related behavioural properties. Selective TSPO ligands are able to stimulate steroidogenesis with great efficacy, thus representing potential anxiolytic agents. This review describes the development of a class of high affinity ligands to TSPO, N,N-dialkylindol-3-ylglyoxylamides (IGA), from the initial stages of design to the pharmacological characterization of selected compounds for their anxiolytic activity. Affinity data and SARs of the new class of ligands are discussed; the potential applications of compounds characterized by the indolylglyoxylyl scaffold in diagnostic imaging are also pointed out.
- Published
- 2012
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39. Derivatives of benzimidazol-2-ylquinoline and benzimidazol-2-ylisoquinoline as selective A1 adenosine receptor antagonists with stimulant activity on human colon motility.
- Author
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Cosimelli B, Taliani S, Greco G, Novellino E, Sala A, Severi E, Da Settimo F, La Motta C, Pugliesi I, Antonioli L, Fornai M, Colucci R, Blandizzi C, Daniele S, Trincavelli ML, and Martini C
- Subjects
- Actins genetics, Actins metabolism, Adenosine A1 Receptor Antagonists chemistry, Benzimidazoles chemical synthesis, Benzimidazoles pharmacology, Humans, Isoquinolines chemical synthesis, Isoquinolines pharmacology, Muscle, Smooth drug effects, Muscle, Smooth metabolism, Receptor, Adenosine A1 metabolism, Receptor, Adenosine A2A chemistry, Receptor, Adenosine A2A metabolism, Receptor, Adenosine A3 chemistry, Receptor, Adenosine A3 metabolism, Adenosine A1 Receptor Antagonists pharmacology, Benzimidazoles chemistry, Colon drug effects, Isoquinolines chemistry, Quinolines chemistry, Quinolines pharmacology, Receptor, Adenosine A1 chemistry
- Abstract
A number of quinolines and isoquinolines connected in various ways to a substituted benzimidazol-2-yl system were synthesized and evaluated as novel antagonists of adenosine receptors (ARs) by competition experiments using human A(1), A(2A), and A(3) ARs. The new compounds were designed based on derivatives of 2-(benzimidazol-2-yl)quinoxaline, previously reported as potent and selective antagonists of A(1) and A(3) ARs. Among these, 3-[4-(ethylthio)-1H-benzimidazol-2-yl]isoquinoline 4b exhibited the best combination of potency toward the A(1) AR (K(i) =1.4 nM) and selectivity against the A(2A) (K(i) >10 μM), A(2B) (K(i)>10 μM), and A(3) ARs (K(i)>1 μM). Functional experiments in circular smooth muscle preparations of isolated human colon showed that 4b behaves as a potent and selective antagonist of the A(1) AR in the neuromuscular compartment of this intestinal region. Biological and pharmacological data suggest that 4b is a suitable starting point for the development of novel agents endowed with stimulant properties on colonic activity., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2011
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40. 3-(Fur-2-yl)-10-(2-phenylethyl)-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one, a novel adenosine receptor antagonist with A(2A)-mediated neuroprotective effects.
- Author
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Scatena A, Fornai F, Trincavelli ML, Taliani S, Daniele S, Pugliesi I, Cosconati S, Martini C, and Da Settimo F
- Subjects
- 1-Methyl-4-phenylpyridinium toxicity, Adenosine A2 Receptor Antagonists metabolism, Animals, Benzimidazoles metabolism, CHO Cells, Cell Death drug effects, Cell Survival, Computer Simulation, Cricetinae, Cyclic AMP metabolism, Humans, Indicators and Reagents, Membranes metabolism, Methamphetamine toxicity, Neuroprotective Agents metabolism, Neurotoxins antagonists & inhibitors, Neurotoxins toxicity, PC12 Cells, Rats, Receptor, Adenosine A1 metabolism, Receptor, Adenosine A2A metabolism, Receptors, Dopamine D2 metabolism, Receptors, GABA-A metabolism, Receptors, N-Methyl-D-Aspartate metabolism, Triazines metabolism, Adenosine A2 Receptor Antagonists chemical synthesis, Adenosine A2 Receptor Antagonists pharmacology, Benzimidazoles chemical synthesis, Benzimidazoles pharmacology, Neuroprotective Agents chemical synthesis, Neuroprotective Agents pharmacology, Receptor, Adenosine A2A drug effects, Triazines chemical synthesis, Triazines pharmacology
- Abstract
In this study, compound FTBI (3-(2-furyl)-10-(2-phenylethyl)[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one) was selected from a small library of triazinobenzimidazole derivatives as a potent A(2A) adenosine receptor (AR) antagonist and tested for its neuroprotective effects against two different kinds of dopaminergic neurotoxins, 1-methyl-4-phenylpyridinium (MPP+) and methamphetamine (METH), in rat PC12 and in human neuroblastoma SH-SY5Y cell lines. FTBI, in a concentration range corresponding to its affinity for A(2A) AR subtype, significantly increased the number of viable PC12 cells after their exposure to METH and, to a similar extent, to MPP+, as demonstrated in both trypan blue exclusion assay and in cytological staining. These neuroprotective effects were also observed with a classical A(2A) AR antagonist, ZM241385, and appeared to be completely counteracted by the AR agonist, NECA, supporting A(2A) ARs are directly involved in FTBI-mediated effects. Similarly, in human SH-SY5Y cells, FTBI was able to prevent cell toxicity induced by MPP+ and METH, showing that this A(2A) AR antagonist has a neuroprotective effect independently by the specific cell model. Altogether these results demonstrate that the A(2A) AR blockade mediates cell protection against neurotoxicity induced by dopaminergic neurotoxins in dopamine containing cells, supporting the potential use of A(2A) AR antagonists in dopaminergic degenerative diseases including Parkinson's disease.
- Published
- 2011
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41. Vibrational spectra of the ground and the singlet excited ππ* state of 6,7-dimethyl-8-ribityllumazine.
- Author
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Schreier WJ, Pugliesi I, Koller FO, Schrader TE, Zinth W, Braun M, Kacprzak S, Weber S, Römisch-Margl W, Bacher A, Illarionov B, and Fischer M
- Subjects
- Hydrogen Bonding, Quantum Theory, Solvents chemistry, Spectrophotometry, Infrared, Vibration, Pteridines chemistry
- Abstract
6,7-Dimethyl-8-ribityllumazine serves as fluorophore in lumazine proteins (LumP) of luminescent bacteria. The molecule exhibits several characteristic vibrational absorption bands between 1300 and 1750 cm(-1) in its electronic ground state. The IR-absorption pattern of the singlet excited ππ* state was monitored via ultrafast infrared spectroscopy after photoexcitation at 404 nm. The comparison of experimentally observed band shifts for a number of isotopologues allows for a clear assignment of several absorption bands--most importantly the two carbonyl bands. This assignment is confirmed by normal-mode calculations by means of either density functional theory (DFT) calculations for the ground state or the configuration interaction singles (CIS) method for the excited singlet state. A good agreement between experiment and calculation is obtained for models including explicitly a first solvation shell. The results provide a basis for further investigations of lumazine protein and demonstrate the necessity of proper accounting for explicit hydrogen bonding in case of strongly polar molecular systems.
- Published
- 2011
- Full Text
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42. Evaluation of novel N1-methyl-2-phenylindol-3-ylglyoxylamides as a new chemotype of 18 kDa translocator protein-selective ligand suitable for the development of positron emission tomography radioligands.
- Author
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Pike VW, Taliani S, Lohith TG, Owen DR, Pugliesi I, Da Pozzo E, Hong J, Zoghbi SS, Gunn RN, Parker CA, Rabiner EA, Fujita M, Innis RB, Martini C, and Da Settimo F
- Subjects
- Amides chemistry, Amides pharmacokinetics, Animals, Binding, Competitive, Brain metabolism, Carbon Radioisotopes, Humans, In Vitro Techniques, Indoles chemistry, Indoles pharmacokinetics, Kidney metabolism, Ligands, Macaca mulatta, Positron-Emission Tomography, Radioligand Assay, Radiopharmaceuticals chemistry, Radiopharmaceuticals pharmacokinetics, Rats, Structure-Activity Relationship, Amides chemical synthesis, Indoles chemical synthesis, Radiopharmaceuticals chemical synthesis, Receptors, GABA metabolism
- Abstract
A novel series of N(1)-methyl-(2-phenylindol-3-yl)glyoxylamides, 19-31, designed in accordance with our previously reported pharmacophore/topological model, showed high affinity for the 18 kDa translocator protein (TSPO) and paved the way for developing a new radiolabeled probe. Thus ligand 31, N,N-di-n-propyl-(N(1)-methyl-2-(4'-nitrophenyl)indol-3-yl)glyoxylamide, featuring the best combination of affinity and lipophilicity, was labeled with carbon-11 for evaluation with positron emission tomography (PET) in monkey. After intravenous injection, [(11)C]31 entered brain to give a high proportion of TSPO-specific binding. These findings augur well for the future application of [(11)C]31 in humans. Consequently, the binding of 31 to human TSPO was tested on samples of brain membranes from deceased subjects who through ethically approved in vitro study had previously been established to be high-affinity binders (HABs), mixed-affinity binders (MABs), or low-affinity binders (LABs) for the known TSPO ligand, PBR28 (2). 31 showed high affinity for HABs, MABs, and LABs. In conclusion, [(11)C]31 represents a promising new chemotype for developing novel TSPO radioligands as biomarkers of neuroinflammation.
- Published
- 2011
- Full Text
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43. Structural requirements to obtain highly potent and selective 18 kDa Translocator Protein (TSPO) Ligands.
- Author
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Taliani S, Pugliesi I, and Da Settimo F
- Subjects
- Anilides chemical synthesis, Anilides pharmacology, Animals, Anti-Anxiety Agents pharmacology, Antineoplastic Agents pharmacology, Benzodiazepines chemical synthesis, Benzodiazepines pharmacology, Humans, Immune System Diseases drug therapy, Immunologic Factors pharmacology, Indoleacetic Acids chemical synthesis, Indoleacetic Acids pharmacology, Isoquinolines chemical synthesis, Isoquinolines pharmacology, Ligands, Mice, Mitochondria drug effects, Mitochondria metabolism, Mitochondrial Membranes drug effects, Mitochondrial Membranes metabolism, Mitochondrial Permeability Transition Pore, Neoplasms drug therapy, Neurodegenerative Diseases drug therapy, Pyridines chemical synthesis, Pyridines pharmacology, Rats, Structure-Activity Relationship, Anti-Anxiety Agents chemical synthesis, Antineoplastic Agents chemical synthesis, Immunologic Factors chemical synthesis, Mitochondrial Membrane Transport Proteins agonists, Mitochondrial Membrane Transport Proteins antagonists & inhibitors, Mitochondrial Membrane Transport Proteins metabolism, Receptors, GABA metabolism
- Abstract
The (18 kDa) Translocator Protein (TSPO), was initially identified in 1977 as peripheral binding site for the benzodiazepine diazepam and named "Peripheral-type benzodiazepine receptor (PBR)". It is an evolutionarily well-conserved protein particularly located at the outer/inner mitochondrial membrane contact sites, in closely association with the 32 kDa voltage-dependent anion channel (VDAC) and the 30 kDa adenine nucleotide translocase (ANT), thus forming the mitochondrial permeability transition pore (MPTP). TSPO is ubiquitary expressed in peripheral tissues (steroid producing tissues, liver, heart, kidney, lung, immune system) and in lower levels in the central nervous system, where it is mainly located in glial cells, and in neurons. TSPO is involved in a variety of biological processes such as cholesterol transport, steroidogenesis, calcium homeostasis, lipid metabolism, mitochondrial oxidation, cell growth and differentiation, apoptosis induction, and regulation of immune functions. In the last decade, many studies have reported that TSPO basal expression is altered in a number of human pathologies, such as cancer and neurodegenerative disorders (Huntington's and Alzheimer's diseases), as well as in various forms of brain injury and inflammation and anxiety. Consequently, TSPO has not only been suggested as a promising drug target for a number of therapeutic applications (anticonvulsant, anxiolytic, immunomodulating, etc.), but also as valid diagnostic marker for related-disease state and progression, prompting the development of specific labelled ligands as powerful tools for imaging techniques. A number of structurally different classes of ligands have been reported, showing high affinity and selectivity towards TSPO. Indeed, most of these ligands have been designed starting from selective CBR ligands which were structurally modified in order to shift their affinity towards TSPO. Extensive structure-activity relationship studies were performed allowing to hypothesize various TSPO pharmacophore models. The purpose of this paper is to highlight the structural requirements needed to obtain TSPO ligands with high affinity and selectivity.
- Published
- 2011
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44. Variation of the ultrafast fluorescence quenching in 2,6-sulfanyl-core-substituted naphthalenediimides by electron transfer.
- Author
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Pugliesi I, Krok P, Lochbrunner S, Błaszczyk A, von Hänisch C, Mayor M, and Riedle E
- Subjects
- Electron Transport, Models, Molecular, Molecular Dynamics Simulation, Molecular Structure, Quantum Theory, Stereoisomerism, Fluorescence, Imides chemistry, Naphthalenes chemistry, Sulfhydryl Compounds chemistry
- Abstract
The ultrafast fluorescence quenching of 2,6-sulfanyl-core-substituted naphthalenediimides was investigated by transient spectroscopy. We find a strong dependence of the relaxation on the chemical structure of the substituent. Direct linking of an aryl rest to the sulfur atom leads to a strong red shift of the fluorescence in 1 ps and the disappearance of the emission in 5-7 ps depending on the polarity and viscosity of the solvent. This complex behavior is interpreted with the help of quantum chemical calculations. The calculations suggest that the initial relaxation corresponds to a planarization of the substituents and an associated partial electron transfer. This is followed by a twisting of the phenylsulfanyl substituents out of the molecular plane that allows a complete localization of the electron-donating orbital on the aryl group. Finally the back transfer happens in another 5-7 ps. For an additional methylene spacer group between the sulfur and the aryl, this sequence of relaxation steps is not possible and a simple exponential decay, slower by about 1 order of magnitude, is found.
- Published
- 2010
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45. Electronic Double-Quantum Coherences and Their Impact on Ultrafast Spectroscopy: The Example of β-Carotene.
- Author
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Christensson N, Milota F, Nemeth A, Pugliesi I, Riedle E, Sperling J, Pullerits T, Kauffmann HF, and Hauer J
- Abstract
The energy level structure and dynamics of biomolecules are important for understanding their photoinduced function. In particular, the role of carotenoids in light-harvesting is heavily studied, yet not fully understood. The conventional approach to investigate these processes involves analysis of the third-order optical polarization in one spectral dimension. Here, we record two-dimensional correlation spectra for different time-orderings to characterize all components of the transient molecular polarization and the optical signal. Single- and double-quantum two-dimensional experiments provide insight into the energy level structure as well as the ultrafast dynamics of solvated β-carotene. By analysis of the lineshapes, we obtain the transition energy and characterize the potential energy surfaces of the involved states. We obtain direct experimental proof for an excited state absorption transition in the visible (S
2 → Sn2 ). The signatures of this transition in pump-probe transients are shown to lead to strongly damped oscillations with characteristic pump and probe frequency dependence.- Published
- 2010
- Full Text
- View/download PDF
46. Förster resonant energy transfer in orthogonally arranged chromophores.
- Author
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Langhals H, Esterbauer AJ, Walter A, Riedle E, and Pugliesi I
- Subjects
- Absorption, Color, Fluorescence Polarization, Kinetics, Motion, Perylene chemistry, Quantum Theory, Temperature, Fluorescence Resonance Energy Transfer, Imides chemistry, Perylene analogs & derivatives
- Abstract
We investigate the ultrafast resonant energy transfer of a perylene bisimide dyad by pump-probe spectroscopy, chemical variation, and calculations. This dyad undergoes transfer with near-unit quantum efficiency, although the transition dipole moments of the donor and acceptor are in a perfectly orthogonal arrangement to each other in the equilibrium geometry. According to the point dipole approximation used in Förster theory, no energy transfer should occur. Experimentally we do, however, find an ultrafast transfer time of 9.4 ps. With the transition density cube approach we show that in the orthogonal arrangement the Coulombic interactions do not contribute to the electronic coupling. Through the change of the spacer in both length and chemical character, we can clearly exclude any Dexter-type energy transfer. The temperature effects on the Förster resonant energy transfer rate demonstrate that energy transfer is enabled through low-frequency ground-state vibrations, which break the orthogonal arrangement of the transition dipole moments. The dyads presented here therefore are a first example that shows with extreme clarity the decisive role vibrational motion plays in energy transfer processes.
- Published
- 2010
- Full Text
- View/download PDF
47. Novel irreversible fluorescent probes targeting the 18 kDa translocator protein: synthesis and biological characterization.
- Author
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Taliani S, Da Pozzo E, Bellandi M, Bendinelli S, Pugliesi I, Simorini F, La Motta C, Salerno S, Marini AM, Da Settimo F, Cosimelli B, Greco G, Novellino E, and Martini C
- Subjects
- 4-Chloro-7-nitrobenzofurazan chemical synthesis, 4-Chloro-7-nitrobenzofurazan chemistry, 4-Chloro-7-nitrobenzofurazan pharmacology, Animals, Binding, Competitive, Cell Line, Tumor, Cell Membrane Permeability, Fluorescent Dyes chemistry, Fluorescent Dyes pharmacology, Humans, In Vitro Techniques, Isothiocyanates chemistry, Isothiocyanates pharmacology, Kidney metabolism, Kinetics, Ligands, Protein Binding, Radioligand Assay, Rats, Spectrometry, Fluorescence, Structure-Activity Relationship, 4-Chloro-7-nitrobenzofurazan analogs & derivatives, Carrier Proteins metabolism, Fluorescent Dyes chemical synthesis, Isothiocyanates chemical synthesis, Mitochondrial Proteins metabolism, Receptors, GABA metabolism, Receptors, GABA-A metabolism
- Abstract
The 18 kDa translocator protein (TSPO) is a mitochondrial protein whose basal density is altered in several diseases, with the result that the evaluation of its expression levels by means of molecular imaging techniques represents a promising diagnostic approach. Experimental procedures using a labeled ligand often cause loss of the bound probe, and consequently high affinity ligands covalently binding the receptor protein are needed to overcome this problem. We have previously described a series of N,N-dialkyl-(2-phenylindol-3-yl)glyoxylamides as potent and selective TSPO ligands. Starting from these derivatives, we designed novel TSPO irreversible ligands bearing an electrophilic isothiocyanato group (7, 8), together with an irreversible NBD-fluorescent probe (18). The TSPO affinity of the new irreversible ligands was measured on rat tissue homogenates by [(3)H]Ro 5-4864 radiobinding kinetic assays, all compounds showing high affinities for the target protein. Further biological characterization of the fluorescent irreversible TSPO probe 18 was carried out by using fluorescent spectroscopy in human glioma cells.
- Published
- 2010
- Full Text
- View/download PDF
48. The role of the methyl group in stabilising the weak N-H...pi hydrogen bond in the 4-fluorotoluene-ammonia complex.
- Author
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Gosling MP, Pugliesi I, and Cockett MC
- Subjects
- Hydrogen chemistry, Hydrogen Bonding, Nitrogen chemistry, Thermodynamics, Ammonia chemistry, Fluorine chemistry, Toluene chemistry
- Abstract
The 4-fluorotoluene-ammonia van der Waals complex has been studied using a combination of resonant two-photon ionisation (R2PI) spectroscopy, ab initio molecular orbital calculations and multidimensional Franck-Condon analysis. The R2PI spectrum shows two sets of features assignable to two distinct conformers: one in which the ammonia binds between the hydrogen meta to the methyl group and the fluorine atom in a planar configuration and the other a pi-bound structure involving one bond between an ammonia hydrogen and the pi-system and another between the ammonia lone pair and the slightly acidic hydrogens on the methyl group. Ground state estimated CCSD(T) interaction energies were computed at the basis-set limit: these calculations yielded very similar interaction energies for the two conformers, whilst zero point energy correction yielded a zero point binding energy for the pi-complex about 10% larger than that of the in-plane, sigma-complex. The results of multidimensional Franck-Condon simulations based on ab initio ground and excited state geometry optimisations and vibrational frequency calculations showed good agreement with experiment, with further improvements achieved using a fitting procedure. The observation of a pi-complex in addition to a sigma-complex supports the intuitive expectation that electron-donating groups should help to increase pi-density and hence stabilise pi-proton acceptor complex formation. In this case, this occurs in spite of the presence of a strongly electron-withdrawing fluorine atom.
- Published
- 2010
- Full Text
- View/download PDF
49. A3 receptor ligands: past, present and future trends.
- Author
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Taliani S, Pugliesi I, Bellandi M, La Motta C, and Da Settimo F
- Subjects
- Animals, Binding Sites, Humans, Ligands, Nucleosides chemistry, Structure-Activity Relationship, Adenosine A3 Receptor Agonists, Adenosine A3 Receptor Antagonists, Nucleosides pharmacology
- Abstract
The A(3) adenosine receptors (A(3) ARs), belonging to the adenosine receptor family of G-protein-coupled receptors (GPCRs), are ubiquitously expressed in a wide variety of tissues in human body, with high levels in peripheral organs and low levels in the brain. The A(3) ARs are involved in a variety of important patho-physiological processes, including modulation of cerebral and cardiac ischemic damage, inflammation, modulation of intraocular pressure, regulation of normal and tumor cell growth, and immunosuppression. Consequently, A(3) AR selective ligands may represent important pharmacological tools in the treatment of a variety of diseases. Indeed, the development of potent and selective A(3) AR ligands has been the subject of medicinal chemistry research for more than two decades. Although to date a considerable number of selective A(3) AR agonists and antagonists have been discovered, much is still to be learned about the exact function of this subtype, due to its enigmatic role in several physiological processes. In the last two decades, numerous medicinal chemistry groups have made intense efforts in searching for ideal ligands for the A(3) AR subtype. The purpose of this review is to summarize the most recent developments made in the field of selective A(3) AR ligands, which have been subdivided on the basis of their main chemical structural features. For each chemical class, attention has been focused on the SARs which determine ligand affinity and selectivity for the target subtype, and on eventually available preclinical data.
- Published
- 2010
- Full Text
- View/download PDF
50. An excited state ab initio and multidimensional Franck-Condon analysis of the A (1)B2 <-- X (1)A1 band system of fluorobenzene.
- Author
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Pugliesi I, Tonge NM, and Cockett MC
- Abstract
This work combines high level ab initio calculations with multidimensional Franck-Condon calculations to refine and augment previous assignments of the lower wavenumber region of the A (1)B(2) <-- X (1)A(1) band system of fluorobenzene. The strength of the assignment has been greatly assisted by the use of zero electron kinetic energy spectroscopy in a series of pump-probe experiments where the response of the molecule to selective excitation in specific modes prior to ionization has been studied. The net result of this analysis is the reassignment of 7 of the 12 previously assigned bands in the region below about 1000 cm(-1) using a strategy that aims to trace the origins of excited state normal modes of fluorobenzene to the well-known Wilson modes of benzene by taking full account of the Duschinsky mixing that accompanies electronic excitation. Duschinsky normal mode analyses of the ground and first excited states of fluorobenzene as well as the electronic ground state of fluorobenzene cation have shown that the common use of the benzene Wilson notation to describe normal modes of this prototypical benzene derivative is highly questionable, particularly following electronic excitation and ionization.
- Published
- 2008
- Full Text
- View/download PDF
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