5-Benzylidene-hydantoins: Synthesis and antiproliferative activity on A549 lung cancer cell line
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- 作者：Valentina Zuliani ; Caterina Carmi ; Mirko Rivara ; Marco Fantini ; Alessio Lodola ; Federica Vacondio ; Fabrizio Bordi ; Pier Vincenzo Plazzi ; Andrea Cavazzoni ; Maricla Galetti ; Roberta R. Alfieri ; Pier Giorgio Petronini ; Marco Mor
- 关键词：Hydantoin ; Antiproliferative activity ; EGFR ; A549 cell line ; Cell cycle
- 刊名：European Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：September 2009
- 年：2009
- 卷：44
- 期：9
- 页码：3471-3479
- 全文大小：373 K
文摘
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 antiproliferative 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 μM. 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.