title: Design, synthesis and biological evaluation of arylcinnamide hybrid derivatives as novel anticancer agents.
abstract: The combination of two pharmacophores into a single molecule represents one of the methods that can be adopted for the synthesis of new anticancer molecules. A series of novel antiproliferative agents designed by a pharmacophore hybridization approach, combining the arylcinnamide skeleton and an α-bromoacryloyl moiety, was synthesized and evaluated for its antiproliferative activity against a panel of seven human cancer cell lines. In addition, the new derivatives were also active on multidrug-resistant cell lines over-expressing P-glycoprotein. The biological effects of various substituents on the N-phenyl ring of the benzamide portion were also described. In order to study the possible mechanism of action, we observed that 4p slightly increased the Reactive Oxygen Species (ROS) production in HeLa cells, but, more importantly, a remarkable decrease of intracellular reduced glutathione content was detected in treated cells compared with controls. These results were confirmed by the observation that only thiol-containing antioxidants were able to significantly protect the cells from induced cell death. Altogether our results indicate that the new derivatives are endowed with good anticancer activity in vitro, and their properties may result in the development of new cancer therapeutic strategies.
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17, Università di Ferrara, 44121 Ferrara, Italy. Electronic address: rmr@unife.it.
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17, Università di Ferrara, 44121 Ferrara, Italy. Electronic address: pgb@unife.it.
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Maria Kimatrai
authors.initials: MK
authors.lastname: Salvador
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Mariem
authors.initials: M
authors.lastname: Chayah
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: M Encarnacion
authors.initials: ME
authors.lastname: Camacho
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Prencipe
authors.affiliation: Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Consolaro
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy. Electronic address: giampietro.viola1@unipd.it.
authors.forename: Giampietro
authors.initials: G
authors.lastname: Viola
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D061986:MCF-7 Cells; D015394:Molecular Structure; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D002934:Cinnamates; D017382:Reactive Oxygen Species
keywords: Apoptosis; GSH depletion; In vitro antiproliferative activity; Michael acceptor; Oxidative stress; Phenylcinnamides