Design of a Fluorogenic Probe Based on Intramolecular Condensation for Specific Detection of HDAC3

It is crucial to develop fluorogenic probes for selective targeting of HDACs to explore the roles of HDACs in the tumor onset and progression as well as HDAC-related drug development. However, considerable non-specific signals were produced by spontaneous hydrolysis and undesirable intermolecular attack of the unstable caging moiety in the detection of HDACs with previous probes. To improve the detection specificity, we proposed an intramolecular condensation strategy by the replacement of the traditional acetamide moiety with a trans-enamide unit. Upon deacetylation by HDACs, rapid intramolecular condensation reaction between newly formed terminal aldehyde and hydrazine moiety would occur to afford highly fluorescent hydrazone product. Systematic studies demonstrated that the probe exhibited an extraordinary selectivity for HDAC3 over other HDAC isoforms and interfering substances. The stability and specificity of the indicator make it a powerful tool for HDAC3 activity detection and HDAC3-related drug development.