A ROS-Responsive Dual-Functional H₂S Donor for Synergistic Cardioprotection.

Authors

Rong-Hong Zhang, Jin-Feng Long, Yi-Ying Lian, Ting Chen, Long-Fa Yang, Hong-Fu Liu, Heng-Pei Ran, Yong-Long Zhao, Shang-Gao Liao, Chengli Yang, Yong-Jun Li, Meng Zhou

Published in

Journal of medicinal chemistry. Jul 27, 2026. Epub Jul 27, 2026.

Abstract

The therapeutic utility of H₂S donors in myocardial ischemia/reperfusion injury (MIRI) is hampered by the lack of spatiotemporally controlled release at the site of injury and the poor molecular economy of donor scaffolds. Herein, we designed ROS-responsive dual-functional H₂S donors by conjugating a cardioprotective β-carboline with an H₂O₂-cleavable arylboronate H₂S donor. Lead donor 7j undergoes H₂O₂-triggered cascade hydrolysis to corelease H₂S and active β-carboline 5j. In H9c2 cardiomyoblasts, 7j concentration-dependently mitigated H₂O₂-induced oxidative stress, effectively suppressed apoptotic cell death, preserved mitochondrial membrane potential, and enhanced SOD/GSH-Px activities. 7j also protected HUVECs from oxidative damage, promoted migration, and restored VEGFA expression with Bax/Bcl-2 modulation. In a rat MIRI model, 7j (50 mg/kg) significantly reduced myocardial infarct size from 46.67% to 15.30%. This work establishes a synergistic molecular strategy that leverages the pathological ROS microenvironment to achieve targeted codelivery of H₂S and a bioactive β-carboline, thereby offering a promising therapeutic approach for MIRI.

PMID:
42504501
Bibliographic data and abstract were imported from PubMed on 27 Jul 2026.

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