We 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.

2-Pyridineacetamides: a novel class of Tyrosine Kinases Inhibitors / A. Contini, P. Trimarco. ((Intervento presentato al convegno eCheminformatics 2003 tenutosi a Basel nel 2003.

2-Pyridineacetamides: a novel class of Tyrosine Kinases Inhibitors

A. Contini
Primo
;
P. Trimarco
Ultimo
2003-11-27

Abstract

We 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.
Settore CHIM/06 - Chimica Organica
2-Pyridineacetamides: a novel class of Tyrosine Kinases Inhibitors / A. Contini, P. Trimarco. ((Intervento presentato al convegno eCheminformatics 2003 tenutosi a Basel nel 2003.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/174548
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