State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Chemistry and Biomedicine Innovation Center (ChemBIC), ChemBioMed Inter-disciplinary Research Center, Nanjing University, Nanjing, 210023, China.
Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, 475004, China.
Nat Commun. 2024 Nov 27;15(1):10288. doi: 10.1038/s41467-024-54765-2.
Hydrogen sulfide (HS) is an important endogenous gasotransmitter, but the bioorthogonal reaction triggered HS donors are still rare. Here we show one type of bioorthogonal HS donors, sydnthiones (1,2,3-oxadiazol-3-ium-5-thiolate derivatives), which was designed with the aid of density functional theory (DFT) calculations. The reactions between sydnthiones and strained alkynes provide a platform for controllable, tunable and mitochondria-targeted release of HS. We investigate the reactivity of sydnthiones‒dibenzoazacyclooctyne (DIBAC) reactions and their orthogonality with two other bioorthogonal cycloaddition pairs: tetrazine‒norbornene (Nor) and tetrazine‒monohydroxylated cyclooctyne (MOHO). By taking advantage of these mutually orthogonal reactions, we can realize selective labeling or drug release. Furthermore, we explore the role of HS, which is released from the sydnthione-DIBAC reaction, on doxorubicin-induced cytotoxicity. The results demonstrate that the viability of H9c2 cells can be significantly improved by pretreating with sydnthione 1b and DIBAC for 6 h prior to exposure to Dox.
硫化氢 (HS) 是一种重要的内源性气体递质，但生物正交反应触发的 HS 供体仍然很少。在这里，我们展示了一类生物正交 HS 供体，即 sydnthiones（1,2,3-噁二唑-3-硫醇盐衍生物），它们是在密度泛函理论 (DFT) 计算的帮助下设计的。sydnthiones 与应变炔烃之间的反应为 HS 的可控、可调谐和靶向线粒体释放提供了一个平台。我们研究了 sydnthiones-二苯并氮杂环辛炔 (DIBAC) 反应的反应性及其与另外两种生物正交环加成对的正交性：四嗪-降冰片烯 (Nor) 和四嗪-单羟基化环辛炔 (MOHO)。通过利用这些相互正交的反应，我们可以实现选择性标记或药物释放。此外，我们还探讨了 HS 的作用，HS 是从 sydnthione-DIBAC 反应中释放出来的，对阿霉素诱导的细胞毒性的影响。结果表明，在暴露于 Dox 之前，用 sydnthione 1b 和 DIBAC 预处理 H9c2 细胞 6 小时，可以显著提高细胞活力。
