title: Synthesis and biological evaluation of 1,4-diaryl-2-azetidinones as specific anticancer agents: activation of adenosine monophosphate activated protein kinase and induction of apoptosis.
abstract: A series of novel 1,4-diaryl-2-azetidinones were synthesized and evaluated for antiproliferative activity, cell cycle effects, and apoptosis induction. Strong cytotoxicity was observed with the best compounds (±)-trans-20, (±)-trans-21, and enantiomers (+)-trans-20 and (+)-trans-21, which exhibited IC(50) values of 3-13 nM against duodenal adenocarcinoma cells. They induced inhibition of tubulin polymerization and subsequent G2/M arrest. This effect was accompanied by activation of AMP-activated protein kinase (AMPK), activation of caspase-3, and induction of apoptosis. Additionally, the most potent compounds displayed antiproliferative activity against different colon cancer cell lines, opening the route to a new class of potential therapeutic agents against colon cancer.
authors.affiliation: Department of Biotechnology and Biosciences, University of Milan-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy.
authors.forename: Farida
authors.initials: F
authors.lastname: Tripodi
authors.forename: Roberto
authors.initials: R
authors.lastname: Pagliarin
authors.forename: Gabriele
authors.initials: G
authors.lastname: Fumagalli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bigi
authors.forename: Paola
authors.initials: P
authors.lastname: Fusi
authors.forename: Fulvia
authors.initials: F
authors.lastname: Orsini
authors.forename: Milo
authors.initials: M
authors.lastname: Frattini
authors.forename: Paola
authors.initials: P
authors.lastname: Coccetti
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001384:Azetidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms; D004354:Drug Screening Assays, Antitumor; D004379:Duodenal Neoplasms; D020536:Enzyme Activators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001384:Azetidines; D020536:Enzyme Activators; D050257:Tubulin Modulators; D055372:AMP-Activated Protein Kinases; D053148:Caspase 3