Selective Photorelease of an Organometallic-Containing Enzyme Inhibitor

Histone deacetylases (HDACs) are regarded as promising targets in cancer and a growing number of other diseases due to their crucial involvement in epigenetics and cellular signaling. Many organic HDAC inhibitors are known, and several efficient metal-based analogues have been recently developed. Many of them contain a hydroxamic acid group that binds to the catalytic HDAC zinc center. In this work, a light-activatable organometallic HDAC inhibitor (p-Fc-SAHA) was synthesized and characterized. More specifically, the hydroxamic acid moiety of a known ferrocene-containing HDAC inhibitor (Fc-SAHA) was blocked with a photolabile protecting group (PLPG), namely, 1-(bromomethyl)-4,5-dimethoxy-2-nitrobenzene. Upon UV-A (350 nm) irradiation, Fc-SAHA could be successfully released from p-Fc-SAHA. Importantly, p-Fc-SAHA was significantly less active on HDAC1, HDAC2, and HDAC6 than Fc-SAHA. As expected, the inhibition activity of Fc-SAHA was recovered upon light irradiation. To our knowledge, this is the first study presenting the selective photorelease of an organometallic enzyme inhibitor.