Sydnthiones are versatile bioorthogonal hydrogen sulfide donors

Area of Science:

• Chemical Biology
• Medicinal Chemistry
• Biochemistry

Background:

• Hydrogen sulfide (H2S) is a crucial endogenous gasotransmitter.
• Development of bioorthogonal H2S donors remains a challenge.
• Existing bioorthogonal systems lack precise control over H2S release.

Purpose of the Study:

• To design and synthesize novel bioorthogonal H2S donors, termed sydnothiones.
• To investigate the controlled and targeted release of H2S using sydnothiones.
• To explore the therapeutic potential of H2S released from sydnothiones in mitigating drug-induced cytotoxicity.

Main Methods:

• Density Functional Theory (DFT) calculations for sydnothione design.
• Bioorthogonal cycloaddition reactions between sydnothiones and strained alkynes (DIBAC).
• Assessment of reaction orthogonality with other bioorthogonal pairs (tetrazine-Nor, tetrazine-MOHO).
• Evaluation of H2S effects on doxorubicin-induced cytotoxicity in H9c2 cells.

Main Results:

• Sydnothiones were successfully designed and synthesized as H2S donors.
• Controllable, tunable, and mitochondria-targeted H2S release was achieved.
• The sydnothione-DIBAC reaction demonstrated orthogonality with other bioorthogonal systems.
• Pretreatment with sydnothione and DIBAC significantly enhanced H9c2 cell viability against doxorubicin.

Conclusions:

• Sydnothiones represent a new class of bioorthogonal H2S donors.
• This platform allows for selective H2S release and potential therapeutic interventions.
• The study highlights the protective role of H2S against doxorubicin-induced cytotoxicity.