일후박으로부터 분리된 Acyl-CoA

Abstract

Acyl CoA:Cholesterol Acyltransferase is responsible for catalyzing the intracellular esterification of cholesterol and acyl CoA. ACAT plays various roles in cholesterol metabolism in mammals. ACAT-mediated cholesterol esterification is believed to play a key role in intestinal absorption of cholesterol, hepatic production of lipoproteins, and the deposition of cholesterol esters in atherosclerotic lesions. In both experimental and clinical atherosclerosis, the formation of foam cells derived from macrophages and smooth muscle cells is an important event because foam cells contain a high concentration of cholesterol esters that are derivedfrom cholesterol by the activity of ACAT. Therefore, ACAT inhibitor is an attractive target for prediction and treatment of hypercholesterolemia and atherosclerosis. In these recent years the pharmaceutical experimental data demonstrated that the therapeutical potential of an ACAT inhibitor can be markedly enhanced when the compound directly affects ACAT activity in target tissues such as the liver or the arterial wall. A large number of synthetic and microbial ACAT inhibitors have been reported. However, the inhibitors have not been used clinically because of various side effects including hepatic toxicity. Therefore, new types of ACAT inhibitor are highly demanded to develope as a hypolipidemic as well as antiatherosclerotic agent. In the course of searchinlg ACAT inhibitors from natural sources, new types of ACAT inhibitors were isolated from the extract of Magnolia obolvata leaves, which were identified as obovatol, magnolol, and honokiol. These compounds inhibited ACAT with an IC_(50) of around 12.5-23.2 ㎍/ml. In order to investigate the structure-activity relationships, three derivatives were synthesized and tested for ACAT inhibitory activity. Dimethylobovatol, obovatol diacetate, and o-benzyl eugenol showed similar inhibition activities, compared with obovatol. And, eugenol derivatives from Magnolia officinalis showed effective inhibition activity when it had biphenyl ether bond. Biphenol exhibited relatively higher inhibition activity than monophenol. Activity among biphenolic compounds showed some differences. So, it seems that biphenol and stereochemistry have relation to activity. These results suggest that obovatol, magnolol, and honokiol would be used as antiatherosclerotic agents by inhibition of ACAT.;Acyl CoA:Cholesterol Acyltransferase(ACAT)는 세포안에서 cholesterol과 long-chain fatty acyl coenzyme A를 기질로하여 Cholesterol Ester(CE)를 형성하는 효소로서 소장에서의 cholesteol 흡수, 간에서의 lipoprotein 생성, 혈관 내벽 상처부위 세포에서의 CE의 축적에 관여한다. 따라서, ACAT의 저해로 다량의 CE가 축적되는 것을 막아줌으로써 고콜레스테롤혈증과 동맥경화증의 예방 및 치료에의 응용을 기대해 볼 수 있다. 그동안 ACAT 저해제로서 보고된 것으로는 항고혈압약, 중추신경계약, fibrates, cholesterol 합성 저해제, fatty acyl amides, trisubstituted ureas, cetaben sodium, octimibate, cyclandelate 등의 합성품, 미생물에서 유래된 ACAT 저해제 등이 있으나 부작용과 간독성 때문에 임상적으로 사용되고 있지는 않으므로 새로운 형태의 ACAT 저해제가 요구되고 있다. 천연물로부터 새로운 형태의 ACAT 저해제를 찾기 위한 검색과정중에 일후박잎에서 biphenyl type의 lignan인 obovatol, magnolol, honokiol 등의 ACAT 저해제를 발견하였다. 일후박(Magnolia obovata Thunb.)은 목련과(Magnoliaceae) 식물로 수피부분이 주로 약용되어져 왔으며 중추성 근육이완작용, 항균 작용, 항궤양작용, 위액분비억제작용, 방향성 건위효과가 있다고 보고되어 있고, 이 식물의 성분인 obovatol, magnolol, honokiol은 ACAT에 대해 IC_(50)가 각각 12.5㎍/㎖, 23.2㎍/㎖, 19.4㎍/㎖를 나타내었다. 또한, ACAT 저해활성과 이 성분들의 구조와의 관련성을 알아보기 위해 유도체를 합성하고 여러 가지 합성품들을 가지고 ACAT 저해 활성을 비교해 본 결과, obovatol의 aromatic ring 2, 3위치의 OH기가 methylation된 것과 acetylation된 것 모두 obovatol과 유사한 저해활성도를 보였으며 단일 phenol 화합물들은 200㎍/㎖에서도 저해활성을 보이지 않았으나 biphenol 화합물들은 유의성있는 저해도를 보여주었다. 따라서, biphenol 구조가 ACAT 저해 활성 발현에 중요한 것으로 여겨진다. 이상의 사실들로 미루어 볼 때, ACAT 저해 활성을 나타낸 Obovatol, magnolol, honokiol이 고콜레스테롤혈증과 동맥경화증의 예방 및 치료에 효과적일 것으로 사료된다.