Visible-Light-Controlled Histone Deacetylase Inhibitors for Targeted Cancer Therapy

The lack of selectivity of anticancer drugs limits current
chemotherapy.
Light-activatable drugs, whose activity can be precisely controlled
with external light, could provide a more localized action of the
drugs in the tumor, thus decreasing side effects and increasing efficacy.
Herein, we introduce a series of photoswitchable azobenzene histone
deacetylase inhibitors (HDACis) whose activity can be controlled by
external visible light. Initial HDACis isomerized under ultraviolet
light and were up to >50-fold more active under illumination than
in the dark in enzyme assays. These were then optimized toward compounds
responding to more permeable and less harmful green light by introducing o-halogen atoms into the azobenzene. Selected compounds
decreased cell viability only under illumination in four different
cancer cell lines. Overall, we present photoswitchable HDACis with
optimized activation wavelengths, which inhibit enzyme activity and
cell viability only upon illumination with visible light, contributing
to the still limited toolbox of photoswitchable anticancer drugs.