二甲双胍硫化氢盐的合成、结构鉴定和稳定性研究
收稿日期: 2018-11-26
修回日期: 2018-12-26
网络出版日期: 2019-01-10
基金资助
石药集团心脑血管药物创新综合平台建设基金（No.2013ZX09402103-1）资助项目.
Synthesis, Structural Characterization and Stability Evaluation of Metformin Hydrosulfide
Received date: 2018-11-26
Revised date: 2018-12-26
Online published: 2019-01-10
Supported by
Project supported by the Construction of a Comprehensive Platform for the Innovation of Cardio-cerebrovascular Drugs in Shijiazhuang Pharmaceutical Group Company Limited (No. 2013ZX09402103-1).
随着硫化氢作为人体内重要内源性气体信号分子研究的不断深入，有机小分子硫化氢供体的研究也取得了较大的进展，但目前尚无一种硫化氢供体药物上市.二甲双胍是临床上治疗糖尿病的一线药物，近年来被报道还具有减肥、抗癌、抗衰老等多种生理活性.鉴于硫化氢和二甲双胍在重大疾病治疗中的良好前景，设计了一种全新的硫化氢供体二甲双胍硫化氢盐，前人对该类有机碱硫化氢盐的系统研究几乎为空白，更无将其作为硫化氢供体的报道.首先将二甲双胍盐酸盐处理得到二甲双胍游离碱，再与硫化氢反应形成二甲双胍硫化氢盐.通过氢谱、碳谱、元素分析及X单晶衍射对其进行了结构确证.采用碘量法、醋酸铅法和荧光亚甲蓝法测定了二甲双胍硫化氢盐中硫化氢的含量，均大于96.00%；采用高效液相色谱（HPLC）测定了二甲双胍硫化氢盐中二甲双胍的含量大于98.50%，且二甲双胍硫化氢盐的溶液及固体均相对稳定.上述研究结果表明，二甲双胍硫化氢盐有望作为一种新结构类型的硫化氢供体进行深入的研究和开发.
胡曰富 , 崔桂玲 , 黄文才 , 杨黎 , 齐庆蓉 . 二甲双胍硫化氢盐的合成、结构鉴定和稳定性研究[J]. 有机化学, 2019 , 39(5) : 1503 -1508 . DOI: 10.6023/cjoc201811031
Hydrogen sulfide (H2S), the third gas signal molecule in mammals is studied more and more deeply, and great progress has been made on organic small molecule hydrogen sulfide donors. However, no hydrogen sulfide donor has been marketed as a drug yet. Metformin is a first-line drug for the treatment of diabetes. And some other biological activities such as anti-obesity, anticancer, and anti-aging have been disclosed in recent years. H2S donor has also shown promising prospect in antitumor, cardiovascular protection, anti-inflammation, ion channel regulation and anti-oxidation activities. In view of the potential of hydrogen sulfide and metformin for treatment of diseases, a novel hydrogen sulfide donor, metformin hydrosulfide, was thus designed. Till now, there is no report of this type of hydrogen sulfide donor. In our work, metformin hydrochloride was first basified to obtain metformin, followed by reaction with hydrogen sulfide to afford metformin hydrosulfide. The structure was fully characterized by 1H NMR, 13C NMR, elemental analysis and X-ray crystal. The content of hydrogen sulfide was determined by iodometry method, lead acetate test and methylene blue spectrophotometric method to be more than 96.00%. The metformin level was determined by high-pressure liquid chromatography (HPLC) to be more than 98.50%. The stability of metformin hydrosulfide was evaluated by iodometry method in solution and solid, respectively. The results indicate that metformin hydrosulfide is a promising new type of hydrogen sulfide donor which deserves further research and development.
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