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

Hadfield, JA; Rossington, SB; Wallace, TW; Shnyder, SD; Williams, KJ

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.

Citation

Hadfield, J., Rossington, S., Wallace, T., Shnyder, S., & Williams, K. (2017). Tubulin-binding dibenz[c,e]oxepines: Part 2 Structural variation and biological evaluation as tumour vasculature disrupting agents. Bioorganic and Medicinal Chemistry, 25(5), 1630-1642. https://doi.org/10.1016/j.bmc.2017.01.027

• Journal Article Type: Article
• Acceptance Date: Jan 17, 2017
• Online Publication Date: Jan 19, 2017
• Publication Date: Mar 1, 2017
• Deposit Date: Jan 30, 2017
• Publicly Available Date: Jan 17, 2018
• Journal: Bioorganic and Medicinal Chemistry
• Print ISSN: 0968-0896
• Electronic ISSN: 1464-3391
• Publisher: Elsevier
• Volume: 25
• Issue: 5
• Pages: 1630-1642
• DOI: https://doi.org/10.1016/j.bmc.2017.01.027
• Publisher URL: http://dx.doi.org/10.1016/j.bmc.2017.01.027
• Related Public URLs: https://www.journals.elsevier.com/bioorganic-and-medicinal-chemistry/
• Additional Information: Funders : UMIP