title: Synthesis and Biochemical Evaluation of 3-Phenoxy-1,4-diarylazetidin-2-ones as Tubulin-Targeting Antitumor Agents.
abstract: Structure-activity relationships for a series of 3-phenoxy-1,4-diarylazetidin-2-ones were investigated, leading to the discovery of a number of potent antiproliferative compounds, including trans-4-(3-hydroxy-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (78b) and trans-4-(3-amino-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (90b). X-ray crystallography studies indicate the potential importance of the torsional angle between the 1-phenyl "A" ring and 4-phenyl "B" ring for potent antiproliferative activity and that a trans configuration between the 3-phenoxy and 4-phenyl rings is generally optimal. These compounds displayed IC50 values of 38 and 19 nM, respectively, in MCF-7 breast cancer cells, inhibited the polymerization of isolated tubulin in vitro, disrupted the microtubular structure in MCF-7 cells as visualized by confocal microscopy, and caused G2/M arrest and apoptosis. Compound 90b possessed a mean GI50 value of 22 nM in the NCI60 cell line screen, displayed minimal cytotoxicity, and was shown to interact at the colchicine-binding site on β-tubulin. Phosphate and amino acid prodrugs of both 78b and 90b were synthesized, of which the alanine amide 102b retained potency and is a promising candidate for further clinical development.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin , Dublin 2, Ireland.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Greene
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin , Dublin 2, Ireland.
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.affiliation: School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin , 152-160 Pearse Street, Dublin 2, Ireland.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Greene
authors.affiliation: School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin , 152-160 Pearse Street, Dublin 2, Ireland.
authors.forename: Seema M
authors.initials: SM
authors.lastname: Nathwani
authors.affiliation: School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin , 152-160 Pearse Street, Dublin 2, Ireland.
authors.forename: Jade K
authors.initials: JK
authors.lastname: Pollock
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin , Dublin 2, Ireland.
authors.forename: Azizah M
authors.initials: AM
authors.lastname: Malebari
authors.affiliation: School of Chemistry, Trinity College Dublin , Dublin 2, Ireland.
authors.forename: Thomas
authors.initials: T
authors.lastname: McCabe
authors.affiliation: School of Chemistry, Trinity College Dublin , Dublin 2, Ireland.
authors.forename: Brendan
authors.initials: B
authors.lastname: Twamley
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin , Dublin 2, Ireland.|School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin , 152-160 Pearse Street, Dublin 2, Ireland.
authors.forename: Niamh M
authors.initials: NM
authors.lastname: O'Boyle
authors.affiliation: School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin , 152-160 Pearse Street, Dublin 2, Ireland.
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Zisterer
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin , Dublin 2, Ireland.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Meegan
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001384:Azetidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000187:drug effects*; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000494:pharmacology*; D047090:beta-Lactams / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001384:Azetidines; D014404:Tubulin; D050257:Tubulin Modulators; D047090:beta-Lactams