Tubulin-binding dibenz[c,e]oxepines: Part 2.1 Structural variation and biological evaluation as tumour vasculature disrupting agents

Publication date: Available online 19 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Steven B. Rossington, John A. Hadfield, Steven D. Shnyder, Timothy W. Wallace, Kaye J. Williams
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.

Graphical abstract

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