title: 5-Benzylidene-hydantoins: synthesis and antiproliferative activity on A549 lung cancer cell line.
abstract: 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 microM. 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.
authors.affiliation: Dipartimento Farmaceutico, Università degli Studi di Parma, V.le G.P. Usberti 27/A, I-43100 Parma, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuliani
authors.forename: Caterina
authors.initials: C
authors.lastname: Carmi
authors.forename: Mirko
authors.initials: M
authors.lastname: Rivara
authors.forename: Marco
authors.initials: M
authors.lastname: Fantini
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bordi
authors.forename: Pier Vincenzo
authors.initials: PV
authors.lastname: Plazzi
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavazzoni
authors.forename: Maricla
authors.initials: M
authors.lastname: Galetti
authors.forename: Roberta R
authors.initials: RR
authors.lastname: Alfieri
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Petronini
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001597:Benzylidene Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D006827:Hydantoins; D016159:Tumor Suppressor Protein p53; C512478:EGFR protein, human; D066246:ErbB Receptors