Synthesis of Metformin Hydrosulfide and Its Controlled-Release of H₂S

Metformin (1,1-dimethylbiguanide) is an effective insulin sensitizer for diabetes management and an antiaging compound. Hydrogen sulfide (H₂S) 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 (H₂S) were used to interact with metformin to form a metformin hydrosulfide (Metf⁺HS^-), including H₂S saturated tetrahydrofuran (THF) solution. H₂S 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 H₂S release and improved reaction efficiency, making THF a more suitable solvent for H₂S-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 (Metf⁺HS^-) by reacting with a H₂S in THF, yielding a slightly odorous, pale-yellow product. H₂S release from the Metf⁺HS^- salt was tested in two different solutions, H₂O 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 H₂S in DMEM than in H₂O, likely due to the different solution buffering capacity and ionic strength. The dual functionality of Metf⁺HS^-, combining metformin's own therapeutic properties with the controlled release of H₂S, makes it a novel candidate for treating different diseases like diabetes and cardiovascular disorders.