2. Academic Validation
  3. Tubulin-binding dibenz[c,e]oxepines: Part 2. Structural variation and biological evaluation as tumour vasculature disrupting agents

Tubulin-binding dibenz[c,e]oxepines: Part 2. Structural variation and biological evaluation as tumour vasculature disrupting agents

  • Bioorg Med Chem. 2017 Mar 1;25(5):1630-1642. doi: 10.1016/j.bmc.2017.01.027.
Steven B Rossington 1,  John A Hadfield 2,  Steven D Shnyder 3,  Timothy W Wallace 4,  Kaye J Williams 5
Affiliations

Affiliations

  • 1 School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
  • 2 School of Environment and Life Sciences, University of Salford, Salford M5 4WT, UK.
  • 3 Institute of Cancer Therapeutics, University of Bradford, Richmond Road, Bradford BD7 1DP, UK.
  • 4 School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK. Electronic address: tim.wallace@manchester.ac.uk.
  • 5 Manchester Pharmacy School, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
PMID: 28143677 DOI: 10.1016/j.bmc.2017.01.027
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.

Keywords

Colchicinoid; Dibenz[c,e]oxepine; Intramolecular direct arylation; Tubulin targeting; Tumour growth inhibition; Vascular shutdown.

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