Photoresponsive azo-combretastatin A-4 analogues

Abstract

Colchicine analogues in which an azo group is incorporated into a molecule containing the key pharmacophore of colchicine, have found particular utility as switchable tubulin binding chemotherapeutics. Combretastatin is a related compound containing a stilbene fragment that shows different bioactivity for the cis and trans isomers. We have performed cell assays on 17 new compounds structurally related to a previously reported azo-analogue of combretastatin. One of these compounds showed enhanced potency against HeLa (IC₅₀ = 0.11 μM) and H157 cells (IC₅₀ = 0.20 μM) for cell studies under 400 nm irradiation and the highest photoactivity (IC₅₀ with irradiation/IC₅₀ in dark = 550). We have performed docking and physicochemical studies of this new compound (7). Kinetic studies in water reveal a longer half-life for the cis isomer of 7 which may be one factor responsible for the better IC₅₀ values in cell assays and the improved photoresponsive behavior.

Keywords: Azobenzene; Colchicine; Combretastatin; Photopharmacology; Tubulin.