ACE inhibitor로서의 epoxide 유도체의 합성 및 생리활성 연구

Abstract

A lot of angiotensin-converting enzyme (ACE) inhibitors, e.g captopril and enalapril, have been used for the treatment of hypertension in man. In this study, a series of epoxy compounds were synthesized and evaluated as ACE inhibitors with pseudomechanism-based inactivation mechanism. Since BEBA (2-Benzy1-3,4-epoxybutanoic acid) is known as a pseudomechanism-based inactivator against Carboxypeptidase A which served as a prototype enzyme for ACE, compounds similar to BEER but have one more amide bond than BEBA were synthesized. Also, ester and ketone derivatives were synthesized to evaluate the importance of amide bond. The synthetic route for the epoxide derivatives was as follow. The corresponding unsaturated fatty acids were converted into their acid chloride, then reacted with various amino acids and α-hydroxy carboxylic acids. These amides, esters, and ketone were reacted with dimethyl-dioxirane to give corresponding epoxides. Their activity and structure-activity relationships were investigated and concluded that (1) the α-methyl group of a carbonyl group and the hydrophobic group(phenyl group, indoline group, etc) are necessary for the hydrophobic interaction with ACE (2) rigidity of a amide bond is essential to binding with ACE. Molecular dynamics simulation was practiced for N-(2-methyl-3,4-epoxy-butanoyl) indoline-2-carboxylic acid in order to obtain the good condition for simulation to explain the experimental structure-activity relationships. In conclusion, S_(C_(11))-R_(C_(12)) configuration is necessary for biological activity.;Angiotensin converting enzyme (ACE)와 공유결합하여 효소 활성억제효과를 나타내는 새로운 mechanism (pseudomechanism-based inactivation)의 ACE 억제제로 다양한 epoxide 유도체들을 개발하였다. 이 epoxide 유도체들은 2-Benzyl- 3,4-epoxy-butanoic acid (BEBA)가 carboxypeptidase A에 대하여 pseudomechanism-based inactivator)로 작용한다는 결과 (김 동한, J.Am.Chem.Soc., 113, 3200, 1991)를 토대로 하여 개발된 BEBA 유사구조의 화합물들이다. 본 연구에서는 2-Benzyl-3,4-epoxytanoic acid보다 1개의 amide결합을 더 갖는 화합물, amide결합 대신 ester결합을 갖는 화합물, amide결합의 N대신 C를 도입한 ketone유도체 등의 epoxide 유도체들을 합성하였으며, 그 결합형태의 차이가 ACE 저해효과에 미치는 영향을 살펴보았다. 합성경로는 불포화 지방산을 출발물질로 하여 acid chloride로 전환, 여러 가지 amino acid, phenyllactic acid등과의 결합 및 oxone을 이용한 epoxidation이었다. 합성된 화합물의 ACE에 대한 IC_(50)을 측정 결과로 부터 carbonyl기의 α 위치 탄소의 methyl group과 hydrophobic group에 의한 hydrophobic interaction이 효소 활성억제효과 발현에 중요한 역할을 하는 것을 알 수 있었다. 또, β,γ-Epoxy compound유도체에 대한 분자동력학적인 연구 결과 5(C_(ll))-R(C_(l2))형태의 stereoisomer가 생리활성을 갖는다는 것을 알 수 있었다.