Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 44, Issue 9, Pages 3471-3479Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2009.01.035
Keywords
Hydantoin; Antiproliferative activity; EGFR; A549 cell line; Cell cycle
Categories
Funding
- Italian MIUR
- Regione Emilia Romagna
- Associazione Chiara Tasson, Parma
- A.VO.PRO.RI.T., Parma
- Associazione Davide Rodella, Montichiari
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Benzylidene hydantoins have been recently reported as a new class of EGFR inhibitors. We describe here a simple and efficient methodology for the parallel solution-phase synthesis of a library of 5-benzylidene hydantoins, which were evaluated for anti proliferative activity on the human lung adenocarcinoma A549 cell line. Various substituents at positions 1, 3 and 5 on the hydantoin nucleus were examined. In the presence of a 5-benzylidene group and of a lipophilic substituent at position 1, most of the tested compounds inhibited cell proliferation at a concentration of 20 mu M. Compound 7 (UPR1024), bearing 1-phenethyl and (E)-5-p-OH-benzylidene substituents, was found to be the most active derivative of the series. It inhibited EGFR autophosphorylation and induced DNA damage in A549 cells. Compound 7 and other synthesized 5-benzylidene hydantoin derivatives increased p53 levels, suggesting that the dual mechanism of action was a common feature shared by compound 7 and other member of the series. (C) 2009 Elsevier Masson SAS. All rights reserved.
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