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.

Automated summary

The lack of selectivity in anticancer drugs restricts their efficacy in chemotherapy. This study introduces a series of photoswitchable azobenzene histone deacetylase inhibitors (HDACis) that can be controlled by external visible light. These compounds showed significantly increased activity under ultraviolet light and were optimized to respond to more permeable and less harmful green light. They exhibited inhibitory effects on cancer cell viability only under illumination with visible light.