S-Adenosyl-L-methionine의 합성법 개발

Abstract

S-Adenosyl-L-methionine(SAMe)은 DNA, RNA, phospholipids, proteins 등의 분자 물질에 methyl group을 제공함으로써 우울증과 골 관절염 치료효과 등 중요한 생물학적 치료효과를 제공하는 것으로 알려져 있다. 본 연구에서는 보호기를 도입한 adenosine을 출발물질로 사용한 기존에 알려진 방법과는 달리 adenosine을 보호기 없이 chlorination하여 얻은 5'-chloro-5'-deoxyadenosine (16)을 S-benzyl-L-homocysteine (15)과 반응시켜 S-adenosyl-L-homocysteine (10)을 합성하였다. 화합물 10의 methylation reagent로 1-methyloxiranium tetrafluoroborate (12)를 이용하여 ion exchange resin의 정제 없이도 순수한 S-adenosyl-L-methionine (1)을 합성하였다. 또한, S-adenosyl-L-methionine cation을 안정화시킬 수 있는 counter ion으로 chloride, sulfate, tosylate를 도입한 salt형의 화합물 17-20을 합성하였다.; S-Adenosyl-L-methionine, known as SAMe, is the main biological donor of methyl group and it has several important therapeutic applications. As a substance existing in the living body, SAMe has been found to possess various pharmacological actions such as improvement of energy state of ischemic brain, improvement of cerebral energy metabolism and acidosis of the model with recirculated blood flow following ischemia. S-Adenosyl-L-homocysteine (10) has been prepared from the reaction of unprotected 5'-chloro-5'-deoxyadenosine (16) with S-benzyl-L-homocysteine (15) obtained from L-methionine using the liquid ammonia as the solvent with good yield. The main object of the invention is to develop a chemical method for large scale manufacturing of S-adenosyl-L-homocysteine (10) from adenosine and L-methionine as well as to develop a chemical approach for the regioselective methylation of SAH, with a different methylating agent. Another objective of invention is to develop a chemical approach for methylation of SAH using methylating agent, which avoids hazardous gases like dimethyl ether, and without ion exchange resin. The various methylation to the methionine sulfur atom in compound 17- 20 have been tried.