Design and Synthesis of a NTR-Sensitive Fluorescent HS Donor as a Potential Therapeutic Agent for Myocardial Ischemia-Reperfusion Injury.

Myocardial ischemia is a key feature of myocardial ischemia-reperfusion injury (MIRI), which upregulates nitroreductase (NTR) expression. Targeting this mechanism, the design of NTR-responsive prodrugs has emerged as an innovative strategy for MIRI treatment. Herein, we synthesized HSD-NTR-B, a novel NTR-responsive hydrogen sulfide donor. In the presence of NTR and NADH, the nitro group of HSD-NTR-B is reduced to amino groups, triggering decarboxylation reactions to release carbonyl sulfide (COS). COS is rapidly converted to HS by carbonic anhydrase (CA) in biological fluids. The HS release can be quantitatively monitored via self-reported fluorescence signaling. In a rat model of MIRI, HSD-NTR-B significantly improved cardiac structure and function recovery. Mechanistically, its effects stem from inhibiting cardiomyocyte apoptosis and reducing local inflammation. HS donors modulate macrophage polarization by reducing M1 and increasing M2 macrophages, emerging therapeutic targets for MIRI. This NTR-sensitive HS donor shows promise for treating MIRI and other ischemic conditions.