title: Lead identification of conformationally restricted benzoxepin type combretastatin analogs: synthesis, antiproliferative activity, and tubulin effects.
abstract: We have synthesized a series of polymethoxylated rigid analogs of combretastatin A-4 which contain a benzoxepin ring in place of the usual ethylene bridge present in the natural combretastatin products. The compounds display antiproliferative activity when evaluated against the MCF-7 and MDA human breast carcinoma cell lines. 5-(3-Hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-2,3-dihydro-benzoxepine (11g) was found to be the most potent product when evaluated against the MCF-7 breast cancer cell line. A brief computational study of the structure-activity relationship for the synthesized compounds is presented. These 4,5-diarylbenzoxepins are identified as potentially useful scaffolds for the further development of antitumor agents which target tubulin.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology, Trinity College Dublin, Dublin, Ireland.
authors.forename: Irene
authors.initials: I
authors.lastname: Barrett
authors.forename: Miriam
authors.initials: M
authors.lastname: Carr
authors.forename: Niamh
authors.initials: N
authors.lastname: O'Boyle
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Greene
authors.forename: Andrew J S
authors.initials: AJ
authors.lastname: Knox
authors.forename: David G
authors.initials: DG
authors.lastname: Lloyd
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Zisterer
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Meegan
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001584:Benzoxepins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015195:Drug Design; D005260:Female; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D013267:Stilbenes / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001584:Benzoxepins; D013267:Stilbenes; D014404:Tubulin; C058728:fosbretabulin