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Tautomeric equilibria of benzopyranoimidazoles: useful insights from quantum chemical calculation and NMR
No full textThe development of novel syntetic strategies for achieving compounds containing the coumarin nucleus condensed to several heterocycles has been the subject of our research for the latter few years. [1] Such heterocycles are pharmacologically relevant as CNS depressants, [2] growth inhibitors of mammalian cancer [3] and also phosphodiesterase VII inhibitors for treatment of immunity-associated diseases. [4]
Recently we reported the synthesis of some substituted benzopyranoimidazolones, and we pointed out the possibility of such heterocycles to exist in solution in at least two tautomeric forms, the N3-H and the N1-H tautomers (Fig. 1). [5] The study and quantitative evaluation of prototropic tautomerism in heterocyclic compounds is of primary interest, influencing both reactivity and biological behavior, for example the ability of a drug to bind the active site of a target enzyme [6]. Unfortunately literature does not report any reliable structural information and neither experimental data concerning tautomerism on pyranoimidazolone nucleus. Furthermore RT NMR experiments conducted by us so far were able to evidence the presence of at least two tautomers only for compound 4d and the attempts previously reported by us to unequivocally assign the preferred tautomeric structure by NMR were unsuccessful. The only result was obtained by N-methylation of compound 4d, were just the N3-CH3 product was isolated both at high and low reaction temperatures. However the reaction condition adopted could have influenced the tautomeric equilibrium. On the other hand tautomerism has been successfully described on various substituted imidazoles by ab-initio and DFT calculations in both gas-phase and solution within the continuum solvent model or evaluating explicit solvent interactions. [7]
In our previous work, where the main object was the development of a synthetic strategy for benzopiranoimidazoles, preliminary quantum chemical calculations explained only in part the tautomeric behavior observed, thus the need of a throughout theoretical and experimental investigation. The relative stability of all the possible tautomers for [1]benzopyrano[3,4-d]imidazol-4(3H)-ones, namely the N3-H (alpha tautomer), N1-H (beta tautomer), coumarin O-H (gamma tautomer) and C2-H (delta tautomer), has been evaluated by mean of HF and B3LYP calculations, including the solvent contribution by the SCRF PCM model. Furthermore the 13C and 1H chemical shifts were calculated by GIAO technique at the HF/6-311+G(2d,p) and B3LYP/TZVP levels of theory both in gas phase and in solution by using the PCM model for DMSO. The calculation of 13C chemical shifts by GIAO technique and the comparison with the experimental has been reported as one of the most reliable methods for the investigation of tautomeric equilibria in solution [8]. Finally, 1H NMR spectra were recorded in CD3COCD3 at 500 Mhz at variable temperature in a range from RT to –60°C in order to evidence the presence of the most probable tautomers by progressively lowering their interconversion rates.
The combination of the above mentioned theoretical techniques and experimental NMR allowed us to demonstrate that:
1.The only relevant tautomeric equilibrium for benzopyranoimidazolones is between alpha and beta forms.
2.All compounds 4a-e are able to exhibit tautomeric equilibrium in polar solvents.
3.The interconversion rate between alpha and beta tautomers is fast, thus by NMR is possibile to detect the presence of both tautomers only at low temperatures, otherwise averaged signals are recorded.
Bibliography
1.[a] E.M. Beccalli, A. Contini and P. Trimarco, Eur. J. Org. Chem., 2003, 3976-3984, [b] E.M. Beccalli, A. Contini and P. Trimarco, Tetrahedron Letters, 2004, 45, 3447-3449.
2.V. L. Savel’ev, N. T. Pryanishnikova, V. A. Zagorevskii, I. V. Chernyakova, O.S. Artamonova, V. V. Shavyrina, L. I. Malysheva, Khim. Farm. Zh. 1983, 17, 697-700; see Chem. Abstr. 1983, 99, 158325.
3.M. Trkovnik, V. Kalaj, D. Kitan, Org. Prep. Proced. Int., 1987, 19, 450-455
4.M. Eggenweiler, J. Rochus, M. Wolf, M. Gassen, O. Poeschke, Merck Patent Gmbh, Germany, PCT Int. Appl. 2001; see Chem. Abstr. 2001, 134, 331619.
5.See ref 1a
6.P. Pospisil, P. Ballmer, G. Folkers, L. Scapozza, Tautomerism of nucleobase derivatives and their score in virtual screening to thymidine kinase, Abstracts of Papers, 224th ACS National Meeting, Boston, MA, United States, August 18-22, 2002
7.[a] O. V. Shishkin, O. S. Sukhanov, L. Gorb and J. Leszczynski, PCCP, 2002, 4, 5359-5364. [b] G. -S. Li, M. F. Ruiz-Lopez, M. S. Zhang, B. Maigret, J. Mol. Struct. (Theochem), 1998, 422, 197-204. [c] E. D. Raczyńska, Anal. Chim. Acta, 1997, 348, 431-441. [d] G. A. Worth, P. M. King, W. G. Richards, Biochem. Biophys. Acta, 1989, 993, 134-136. [e] G. -S. Li, M. F. Ruiz-Lopez, M. -S. Zhang, B. Maigret, J. Phys. Chem., 1997, 101, 7885-7892. [f] F. J. Luque, J. M. Lopez-Bes, J. Cemeli, M. Aroztegui, M. Orozco, Theor. Chem. Acc., 1997, 96, 105-113.
8.[a] N. E. Campillo, C. Montero, J. A. Páez, J. Mol. Struct. (Theochem), 2004, 678, 83-89. [b] E. Kleinpeter and A. Koch, J. Phys. Org. Chem., 2001, 14, 566-576
2-Pyridineacetamides: a novel class of Tyrosine Kinases Inhibitors
No full textWe developed a new synthesis of 2-pyridineacetamides starting from pyran-2-one N-functionalized amidines. Secondary amines reacted in a sealed tube with the above-mentioned amidines and, by nucleophilic attack on pyran-2-one nucleus and thermal rearrangement, afforded exclusively the desired 2-pyridineacetamide derivatives. Ab-initio electrostatic potential calculations correctly predicted the selectivity of the nucleophilic attack on the pyran-2-one derivatives.
In the context of a blind screening, resulting 2-Pyridineacetamides have been pharmacologically tested on smooth muscular cells proliferation. Some of them resulted active with an IC50 ranging from 40 to 0.7 μM. At this point cheminformatics and bioinformatics tools have been essential for understanding the molecular mechanism of action of our amides. With the aid of Scifinder we searched bioactive molecules presenting substructures similar to our scaffold. Results pointed us toward GF tyrosine kinase receptors. In silico experiments showed us a strong selectivity toward the epidermal derived growth factor receptor kinase (EGFRK) and the platelet derived growth factor receptor kinase (PDGFRK) if compared with the vascular endothelial derived growth factor receptor kinase (VEGFRK) and the fibroblast derived growth factor receptor kinase (FGFRK). We realized that including the water molecule H-bonded to Tyr766 in the EGFR kinase is necessary for reliable docking experiments. Results show that the predicted potency of the 2-pyridineacetamides described in the present study is comparable to that of known EGFRK inhibitor TarcevaTM. Preliminary pharmacological experiments conducted on rat’s aorta smooth muscular cells confirm the observed computational results
Ruolo del solvente negli equilibri tautomerici di benzopiranoimidazoli e 2-nitrometil-4-amminopiridine
No full textI fenomeni di tautomeria prototropica dei composti eterociclici possono influenzarne la reattività chimica e il comportamento biologico1. Risulta quindi importante poter usufruire di modelli teorici in grado di descrivere correttamente gli equilibri tautomerici in fase gassosa e in soluzione. Presentiamo i risultati di calcoli quantomeccanici ab-initio e DFT condotti sui tautomeri più significativi di alcuni derivati benzopiranoimidazolici da noi sintetizzati (fig. 1).2 Le differenze energetiche tra i tautomeri alfa e beta si riducono drasticamente utilizzando il modello solvente PCM, confermando i dati spettroscopici ottenuti mediante 1H e 13C NMR. Riportiamo, inoltre, i risultati di calcoli ab-initio condotti sui tautomeri di derivati di 2-nitrometil-4-amminopiridine (fig. 2). Gli spettri 1H e 13C NMR registrati in C6D6 e CD3OD mostrano la presenza univoca dei tautomeri alfa nel primo solvente e beta nel secondo. I calcoli condotti con modello PCM non confermano le osservazioni sperimentali. Una migliore descrizione del fenomeno si ottiene considerando le interazioni esplicite tra il soluto e un numero limitato di molecole di solvente.
(1) Pospisil, P.; Ballmer, P.; Folkers, G.; Scapozza, L.; Tautomerism of nucleobase derivatives and their score in virtual screening to thymidine kinase, Abstract of Papers, 224th ACS National Meeting, Boston, MA, United States, August 18-22, 2002.
(2) Contini, A.; Beccalli, E.M.; Trimarco, P.; Eur. J. Org. Chem., 2003, in stampa
Synthesis of 4-nitromethylene-1,4-dihydropyrimidine derivatives as pyrimidine nucleoside analogues
No full textThe synthesis of 4-nitromethylene-1,4-dihydropyrimidine derivatives as pyrimidine nucleoside analogues was developed, starting from 3-nitropyran-2-one N-functionalized amidines. Primary amines were reacted with amidines yielding 4-nitromethylene-1,4-dihydropyrimidine derivatives. In an initial survey, several 4-nitromethylene-1,4-dihydropyrimidines turned into 4-nitromethylene-1,2,3,4-tetrahydropyrimidine derivatives under different reduction conditions. The reduction reaction also induced a change in the exocyclic double bond configuration from (E) to (Z), due to an intramolecular hydrogen bond
NEW DERIVATIVES OF 2-PYRIDIN ACETIC ACID AS COMPOUNDS WITH ANTIPROLIFERATIVE ACTIVITY
No full textThe present invention refers to new derivatives of 2-pyridin acetic acid usefully employable as antagonists of the action of some growth factors and therefore their use as drugs active in the treatment and/or prevention of pathologies deriving from uncontrolled cellular proliferation. In particular the present invention refers to the use of a compound of general formula (I), or of its pharmaceutically acceptable salt; (I) for the preparation of a medicament for the treatment and/or prevention of pathologies mediated by uncontrolled cellular proliferation
5(4H)-oxazolones. Part XI. Cycloaddition reaction of oxazolones and munchnones to triphenylvinylphosphonium salts as synthetic equivalents of alkynes
No full text5(4H)-Oxazolones 1 and milnchnones 3 are reacted with triphenylvinylphosphonium bromide 2a to give, through a cycloaddition reaction, pyrrole derivatives 4a-d and 7a-c unsubstituted at C-3 and C-4. The use of substituted vinylphosphonium salts 2b,c and dipoles 1 and 3 allows the isolation of 3-methylpyrroles 4e, f and 7d,e and 3-pyrrolecarboxylic acids 9a-c, respectively. The cycloaddition reactions proceed with high regionelectivity because of the positive interaction of phosphonium group of 2 and carbonyl group of dipoles 1 and 3
New synthetic approach to [1]benzopyrano[4,3-b]pyridin-5-one derivatives
No full textA new synthesis of [1]benzopyrano[4,3-b]pyridin-5-ones 4 was developed starting from 3-formyl-coumarin N-functionalized amidines 3. The reaction is based likely on the intramolecular cyclocondensation of the C-α amidinic carbanion in basic medium on the formyl group
Single step synthesis of 2,3-dialkyl-6-nitro-quinazolin-4(3H)-imines and 3,5-dialkyl-9-nitro-imidazo[1,2-c]quinazolin-2(3H)-ones
No full textAbstract—A single step synthesis of 2,3-dialkyl-6-nitro-quinazolin-4(3H)-imines and 3,5-dialkyl-9-nitro-imidazo-[1,2-c]-quinazolin- 2(3H)-ones from simple carbonyl compounds, primary amines or amino acid methyl esters and 2-azido-5-nitro-benzonitrile was developed. Key intermediates were N,N0-disubstituted amidines obtained by rearrangement of 4,5-dihydrotriazoles; the new heterocyclic rings were formed by spontaneous intramolecular reaction of the amino and cyano groups which are present in the intermediates
Synthesis of 4,5-Dihydro-1H-Imidazole-4-Carboxylates from alfa-Amino Acid Amidines
No full textStarting from serine methyl esters, aldehydes or ketons and tosylazide various beta-hydroxy-substituted amidines were obtained. Via Mitsunobu intramolecular cyclisation, optically pure methyl-2-alkyl-1-tosyl-4,5-dihydro-1H-imidazole-4-carboxylates 5a-d were synthetise
Substituted coumarin amidines: useful building blocks for the preparation of [1]benzopyrano[4,3-b]pyridin-5-one and [1]benzopyrano[4,3-d]pyrimidin-5-one derivatives
No full textThe synthesis of [1]benzopyrano[4,3-b]pyridin-5-ones 4a-f and 4g-j starting from 3-formylcoumarin and 3-cyanocoumarin N-functionalized amidines 3a-f and 3g-j, respectively, was reported. The ring-closure reaction mechanism, under basic or acidic media, was proposed. Furthermore, the reaction of 3-formylamidines 3a,c-f with ammonium acetate gave good yields of 2-substituted [1]benzopyrano[4,3-d]pyrimidin-5-oiies 7. (c) 2005 Elsevier Ltd. All rights reserved
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