Study On The Mechanism Of Phosphorothioate Releasing Hydrogen Sulfide

Although hydrogen sulfide is a traditional environmental pollutant,it is directly related to various diseases and has important physiological and pharmacological research value.Hydrogen sulfide is a newly recognized gas transport agent.Due to its anti-inflammatory,anti-cancer,lowering blood pressure,anti-oxidation and other physiological functions,it has shown great therapeutic potential in biomedical research.Due to the inherent physical and chemical properties of hydrogen sulfide,its controlled delivery has become a difficult challenge.In order to solve this problem,a variety of hydrogen sulfide donors have been designed and developed to serve as carriers for hydrogen sulfide transmission and release hydrogen sulfide at appropriate locations.Therefore,designing efficient hydrogen sulfide donors and carrying out physiological function research has become one of the hot research fields recently.Although a variety of hydrogen sulfide donors have been developed,there are still problems such as low selectivity and uncontrolled release at the target site.The lack of research on the mechanism of hydrogen sulfide release from hydrogen sulfide donors has hindered the development of more efficient hydrogen sulfide donors.In this paper,a series of thiophosphate hydrogen sulfide donors(named JK-n,n =1,2,3,4)were selected as the research objects.The quantum chemistry calculation method is used to study the microscopic reaction mechanism of hydrogen sulfide release,explore the hydrogen proton transfer process assisted by water or hydrogen sulfide,reveal stereoselectivity and substituent effects.At the level of M06-2x/6-31G(d,p),the internal cyclization reaction of phosphorothioate to release hydrogen sulfide was studied.The reaction went through three steps,namely hydrogen proton transfer,carboxylate anion to phosphorus atom nucleophilic attack and breaking of phosphorus-sulfur bonds.In the hydrogen proton transfer process,the two isomers of thiophosphates react and change from the stable phosphorus sulfur double bond state,which is not easy to break the phosphorus sulfur bond,to the phosphorus sulfur single bond state,which is favorable to break the phosphorus sulfur bond;Then the carboxylic acid anion attacked the phosphorus atom and formed a five membered ring intermediate,which weakened the strength of the phosphorus sulfur single bond.Finally,the phosphorus sulfur single bond broke and released HS-anion.Single point energy correction and solvation effect calculation were carried out for all key structures in the reaction path,and the reaction potential energy surface was constructed.The potential energy surface shows that the proton transfer process is thedecisive step of the total reaction,but its activation energy is too high to react under physiological conditions.The introduction of water molecules and hydrogen sulfide into the proton transfer process resulted in a more stable six membered ring transition state structure,which significantly reduced the activation energy,indicating the role of water molecules and hydrogen sulfide in promoting the reaction.In addition,the effects of different substituents and chiral isomers on the release of hydrogen sulfide in the internal cyclization were also revealed.The relevant research results provide theoretical and technical basis for the design and development of efficient hydrogen sulfide donors.