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
  • 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: [email protected].
  • 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.