title: Tubulin-binding dibenz[c,e]oxepines: Part 2. Structural variation and biological evaluation as tumour vasculature disrupting agents.
abstract: 5,7-Dihydro-3,9,10,11-tetramethoxybenz[c,e]oxepin-4-ol 1, prepared from a dibenzyl ether precursor via Pd-catalysed intramolecular direct arylation, possesses broad-spectrum in vitro cytotoxicity towards various tumour cell lines, and induces vascular shutdown, necrosis and growth delay in tumour xenografts in mice at sub-toxic doses. The biological properties of 1 and related compounds can be attributed to their ability to inhibit microtubule assembly at the micromolar level, by binding reversibly to the same site of the tubulin αβ-heterodimer as colchicine 2 and the allocolchinol, N-acetylcolchinol 4.
authors.affiliation: School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Rossington
authors.affiliation: School of Environment and Life Sciences, University of Salford, Salford M5 4WT, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Hadfield
authors.affiliation: Institute of Cancer Therapeutics, University of Bradford, Richmond Road, Bradford BD7 1DP, UK.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shnyder
authors.affiliation: School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK. Electronic address: tim.wallace@manchester.ac.uk.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Wallace
authors.affiliation: Manchester Pharmacy School, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Kaye J
authors.initials: KJ
authors.lastname: Williams
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003990:Dibenzoxepins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D064593:Heterografts; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms / Q000098:blood supply*; D014404:Tubulin / Q000378:metabolism*
chemical_list: D003990:Dibenzoxepins; D014404:Tubulin
keywords: Colchicinoid; Dibenz[c,e]oxepine; Intramolecular direct arylation; Tubulin targeting; Tumour growth inhibition; Vascular shutdown