A new synthesis of 2-pyridineacetamides was developed 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. Such compounds have been pharmacologically tested on smooth muscular cells proliferation and resulted active with an IC50 ranging from 40 to 0.7 µM. With the aid of molecular modeling tools a potential mechanism of action has been proposed. The pharmacological activity seems to be due to tyrosine kinase receptors inhibition. In silico experiments shows a notable 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). 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.

Synthesis, in silico and pharmacological evaluation of 2-pyridin-acetamides as tyrosine kinase inhibitors / A. Contini ; tutor: P. Trimarco ; coordinatore: C. De Micheli. ISTITUTO DI CHIMICA ORGANICA "ALESSANDRO MARCHESINI", 2003 May 26. 15. ciclo, Anno Accademico 2002/2003. [10.13130/contini-alessandro_phd2003-05-26].

Synthesis, in silico and pharmacological evaluation of 2-pyridin-acetamides as tyrosine kinase inhibitors

A. Contini
2003

Abstract

A new synthesis of 2-pyridineacetamides was developed 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. Such compounds have been pharmacologically tested on smooth muscular cells proliferation and resulted active with an IC50 ranging from 40 to 0.7 µM. With the aid of molecular modeling tools a potential mechanism of action has been proposed. The pharmacological activity seems to be due to tyrosine kinase receptors inhibition. In silico experiments shows a notable 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). 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.
26-mag-2003
Settore CHIM/06 - Chimica Organica
Settore CHIM/08 - Chimica Farmaceutica
TRIMARCO, PASQUALINA
DE MICHELI, CARLO
Doctoral Thesis
Synthesis, in silico and pharmacological evaluation of 2-pyridin-acetamides as tyrosine kinase inhibitors / A. Contini ; tutor: P. Trimarco ; coordinatore: C. De Micheli. ISTITUTO DI CHIMICA ORGANICA "ALESSANDRO MARCHESINI", 2003 May 26. 15. ciclo, Anno Accademico 2002/2003. [10.13130/contini-alessandro_phd2003-05-26].
File in questo prodotto:
File Dimensione Formato  
Thesis.pdf

accesso aperto

Tipologia: Pre-print (manoscritto inviato all'editore)
Dimensione 1.98 MB
Formato Adobe PDF
1.98 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/174341
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact