Amanpour Tayebeh, Wang Rui
York University, Department of Biology, Faculty of Science, 151B Farquharson Life Sciences Building, 4700 Keele Street, Toronto, Ontario M3J 1P3, Canada.
ACS Omega. 2025 Aug 27;10(35):39517-39529. doi: 10.1021/acsomega.5c00702. eCollection 2025 Sep 9.
Metformin (1,1-dimethylbiguanide) is an effective insulin sensitizer for diabetes management and an antiaging compound. Hydrogen sulfide (HS) as a gasotransmitter also plays an important role in the regulation of diabetes and longevity. The interaction of these two molecules may find applications in various areas of cell biology. In this study, different preparations of hydrogen sulfide (HS) were used to interact with metformin to form a metformin hydrosulfide (MetfHS), including HS saturated tetrahydrofuran (THF) solution. HS demonstrates greater stability in tetrahydrofuran (THF) than in acetone due to THF's moderate polarity, lower evaporation rate, and inert nature, which enhance its solubility and reduce undesired reactions. These properties facilitate controlled HS release and improved reaction efficiency, making THF a more suitable solvent for HS-related synthesis processes. Initially, metallic sodium was introduced into anhydrous ethanol under an inert atmosphere, and it reacted to form sodium ethoxide in situ. This freshly generated sodium ethoxide then acted as a strong base, deprotonating metformin hydrochloride to yield the free base form of metformin (1,1-dimethylbiguanide), which precipitated as a white solid after purification steps. This purified compound was subsequently converted into 1,1-dimethylbiguanide hydrosulfide (MetfHS) by reacting with a HS in THF, yielding a slightly odorous, pale-yellow product. HS release from the MetfHS salt was tested in two different solutions, HO and Dulbecco's Modified Eagle Medium (DMEM), qualified and quantified with a lead acetate paper and a methylene blue spectrophotometry assay, respectively. The results show a higher release of HS in DMEM than in HO, likely due to the different solution buffering capacity and ionic strength. The dual functionality of MetfHS, combining metformin's own therapeutic properties with the controlled release of HS, makes it a novel candidate for treating different diseases like diabetes and cardiovascular disorders.
二甲双胍（1,1 - 二甲基双胍）是一种用于糖尿病管理的有效胰岛素增敏剂，也是一种抗衰老化合物。硫化氢（HS）作为一种气体信号分子，在糖尿病和寿命调节中也起着重要作用。这两种分子的相互作用可能在细胞生物学的各个领域得到应用。在本研究中，使用了不同的硫化氢（HS）制剂与二甲双胍相互作用，形成二甲双胍氢硫化物（MetfHS），包括HS饱和四氢呋喃（THF）溶液。由于THF具有适度的极性、较低的蒸发速率和惰性性质，HS在四氢呋喃（THF）中比在丙酮中表现出更高的稳定性，这些性质增强了其溶解性并减少了不必要的反应。这些特性有助于控制HS的释放并提高反应效率，使THF成为与HS相关合成过程更合适的溶剂。最初，在惰性气氛下将金属钠引入无水乙醇中，它原位反应形成乙醇钠。这种新生成的乙醇钠随后作为强碱，使盐酸二甲双胍去质子化，生成二甲双胍（1,1 - 二甲基双胍）的游离碱形式，经过纯化步骤后沉淀为白色固体。随后，通过与THF中的HS反应，将这种纯化的化合物转化为1,1 - 二甲基双胍氢硫化物（MetfHS），得到一种略带气味的淡黄色产物。在两种不同的溶液，即水（HO）和杜氏改良 Eagle 培养基（DMEM）中测试了MetfHS盐中HS的释放，分别用醋酸铅试纸和亚甲基蓝分光光度法进行了定性和定量。结果表明，DMEM中HS的释放量高于HO，这可能是由于不同溶液的缓冲能力和离子强度不同。MetfHS的双重功能，将二甲双胍自身的治疗特性与HS的可控释放相结合，使其成为治疗糖尿病和心血管疾病等不同疾病的新型候选药物。
