- Structure-based optimization of tyrosine kinase inhibitor CLM3. design, synthesis, functional evaluation, and molecular modeling studies.
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Recent advances in the knowledge of thyroid carcinomas development identified receptor tyrosine kinases, like VEGFR2 and RET, as viable and promising targets. Accordingly, their inhibition is emerging as the major therapeutic strategy to treat these pathologies. In this study we describe the synthesis and the functional evaluation of three different series of 4-substituted pyrazolo[3,4-d]pyrimidine derivatives, 8a-g, 9a-g, and 10a-g, designed exploiting a structure-based optimization of the previously developed inhibitor CLM3. Compared to the lead, the novel compounds markedly improved both their inhibitory profile against the target proteins, VEGFR2 and RET, and their antiproliferative efficacy against the medullary thyroid cancer cell line TT. Significantly, compounds 8b, 9c, and 10c proved to block the kinase activity of the mutant RETV804L, which still lacks effective inhibitors.
- Sartini, Stefania,Coviello, Vito,Bruno, Agostino,La Pietra, Valeria,Marinelli, Luciana,Simorini, Francesca,Taliani, Sabrina,Salerno, Silvia,Marini, Anna Maria,Fioravanti, Anna,Orlandi, Paola,Antonelli, Alessandro,Da Settimo, Federico,Novellino, Ettore,Bocci, Guido,La Motta, Concettina
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p. 1225 - 1235
(2014/03/21)
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- Organoruthenium antagonists of human A3 adenosine receptors
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Human A3 adenosine receptor (hA3AR) is a membrane-bound G protein-coupled receptor implicated in a number of severe pathological conditions, including cancer, in which it acts as a potential therapeutic target. To derive structure-activity relationships on pyrazolo-triazolo-pyrimidine (PTP)-based A3AR antagonists, we developed a new class of organometallic inhibitors through replacement of the triazolo moiety with an organoruthenium fragment. The objective was to introduce by design structural diversity into the PTP scaffold in order to tune their binding efficacy toward the target receptor. These novel organoruthenium antagonists displayed good aquatic stability and moderate binding affinity toward the hA3 receptor in the low micromolar range. The assembly of these complexes through a template-driven approach with selective ligand replacement at the metal center to control their steric and receptor-binding properties is discussed. Scaffold design: A novel class of ruthenium(II)-arene complexes containing chelating N,N-pyrazolo-pyrimidine ligands was rationally developed to be selective antagonists of human A3 adenosine receptors based on the proven pyrazolo-triazolo-pyrimidine design (see figure). Copyright
- Paira, Priyankar,Chow, Mun Juinn,Venkatesan, Gopalakrishnan,Kosaraju, Vamsi Krishna,Cheong, Siew Lee,Klotz, Karl-Norbert,Ang, Wee Han,Pastorin, Giorgia
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p. 8321 - 8330
(2013/07/27)
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- Does the combination of optimal substitutions at the C2-, N 5- and N8-positions of the pyrazolo-triazolo-pyrimidine scaffold guarantee selective modulation of the human A3 adenosine receptors?
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In an attempt to study the optimal combination of a phenyl ring at the C2-position and different substituents at the N5- and N8-positions towards the selective modulation of human A3 adenosine receptors (hA3AR), we synthesized a new series of 2-para-(un)substituted-phenyl-pyrazolo-triazolo-pyrimidines bearing either a methyl or phenylethyl at N8 and chains of variable length at N 5. Through biological evaluation, it was found that the majority of the compounds had good affinities towards the hA3AR in the low nanomolar range. Compound 16 possessed the best hA3AR affinity and selectivity profile (KihA3 = 1.33 nM; hA 1/hA3 = 4880; hA2A/hA3 = 1100) in the present series of 2-(substituted)phenyl-pyrazolo-triazolo-pyrimidine derivatives. In addition to pharmacological characterization, a molecular modeling investigation on these compounds further elucidated the effect of different substituents at the pyrazolo-triazolo-pyrimidine scaffold on affinity and selectivity to hA3AR.
- Cheong, Siew Lee,Dolzhenko, Anton V.,Paoletta, Silvia,Lee, Evelyn Pei Rong,Kachler, Sonja,Federico, Stephanie,Klotz, Karl-Norbert,Dolzhenko, Anna V.,Spalluto, Giampiero,Moro, Stefano,Pastorin, Giorgia
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scheme or table
p. 6120 - 6134
(2011/11/07)
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- Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives: Potent and selective A2A adenosine antagonists
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A series of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives (10a-o,q,r), bearing alkyl and aralkyl chains on positions 7 and 8, were synthesized in the attempt to obtain potent and selective antagonists for the A2A adenosine receptor subtype. The compounds were tested in binding and functional assays to evaluate their potency for the A2A compared with the A1 adenosine receptor subtype. In binding studies in rat brain membranes, most of the compounds showed affinity for A2A receptors in the low nanomolar range with a different degree of A2A versus A1 selectivity. Comparison of N7 (10a-d,h-o)- and N8 (10e-g)-substituted pyrazolo derivatives indicates that N7 substitution decreases the A1 affinity with the concomitant increase of A2A selectivity. Specifically, the introduction of a 3-phenylpropyl group at pyrazolo nitrogen in position 7 (101) increased significantly the A2A selectivity, being 210-fold, while the A2A receptor affinity remained high (Ki = 2.4 nM). With regards to the affinity for A2A receptors, also the compound 10n, bearing in the 7-position a β-morpholin-4-ylethyl group, deserves attention (K1 = 5.6 nM) even though the A2A selectivity (84-fold) was not as high as that of 101. Conversely, the compound 10m (N7-4-phenylbutyl derivative) showed a remarkable selectivity (A1/A2A ratio = 129) associated with lower A2A affinity (K1 = 21 nM). In functional studies, most of the compounds examined reversed 5′-(N-ethylcarbamoyl)adenosine-induced inhibition of rabbit platelet aggregation inhibition which is a biological response mediated by the A2A receptor subtype. The compounds are potent and selective A2A antagonists which can be useful to elucidate the pathophysiological role of this adenosine receptor subtype. These compounds deserve to be further developed to assess their potential for treatment of neurodegenerative disorders such as Parkinson's disease.
- Baraldi, Pier Giovanni,Cacciari, Barbara,Spalluto, Giampiero,Pineda De Las Infantas Y Villatoro, Maria José,Zocchi, Cristina,Dionisotti, Silvio,Ongini, Ennio
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p. 1164 - 1171
(2007/10/03)
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