Synthesis of Helminthosporol Analogs as ACAT Inhibitors

描述(由申请人提供)：在美国，冠心病是主要的死亡原因。导致这种情况的主要因素之一是动脉粥样硬化斑块导致的动脉硬化和狭窄。这些斑块主要来自巨噬细胞来源的泡沫细胞，这些细胞储存了高浓度的酯化胆固醇。酰基辅酶A胆固醇酰基转移酶(ACAT)催化细胞内胆固醇与长链辅酶A激活的脂肪酸的酯化反应。因此，ACAT可能在膳食胆固醇的吸收中起重要作用。一种有效的ACAT抑制剂有可能通过减少胆固醇的吸收和限制巨噬细胞向胆固醇酯饱和的泡沫细胞的转化来发挥抗动脉粥样硬化剂的治疗作用。 本项目的目的是基于蠕孢子酚的基本结构，开发一种有效的ACAT抑制剂。蠕孢子酚是一种已显示出中等抑制活性的植物毒素。揭示对抑制活性最重要的结构特征将是开发治疗剂的核心。因此，蠕虫孢子醇、两种与生物遗传相关的代谢物前蠕孢子醇和索洛卡宁，以及几个最小化的类似物将通过全化学合成来制备。对所有这些目标的综合访问将从一条一般路线开始，该路线可以在中后期阶段改道，以准备每一种模拟。这种常见的合成方法基本上是基于一系列的步骤：i)硅基导向的纳扎罗夫环化反应，ii)乙烯基环丙烷缩合反应，以及iii)二乙烯基环丙烷重排反应，以制备组成蠕虫孢子醇天然产物的[3.2.1]-双环辛烷核。一旦天然产物和类似物已经准备好，使用14C标记油酸盐的体外实验将被用来确定ACAT在巨噬细胞中的抑制程度。

DESCRIPTION (provided by applicant): Coronary disease is the leading cause of death in the United States. One of the major factors leading to this condition is the hardening and narrowing of arteries by atherosclerotic plaques. These plaques originate principally from macrophage-derived foam cells, which store elevated concentrations of esterifled cholesterol. Acyl-CoA cholesterol acyltransferase (ACAT) catalyzes the intracellular esterification of cholesterol with long chain coenzyme A-activated fatty acids. Therefore, ACAT may play an important role in the absorption of dietary cholesterol. An efficient ACAT inhibitor has the potential to function therapeutically as an anti-atherosclerotic agent by decreasing cholesterol absorption and limiting the conversion of macrophages into cholesterol ester-saturated foam cells. The purpose of this project is to develop an effective inhibitor for ACAT based upon the fundamental structure of helminthosporol, a phytotoxin that has shown moderate inhibitory activity. Unmasking the structural features most important to inhibitory activity will be central to the development of a therapeutic agent. Therefore, helminthosporol, two biogenetically-related metabolites known as prehelminthosporol and sorokinianin, and several minimized analogs will be prepared by total chemical synthesis. Synthetic access to all these targets will originate from a general route that can be diverted in the middle to late stages to prepare each analog. This common synthesis is based fundamentally upon a sequence of i) silyl-directed Nazarov cyclization, ii) vinylogous Darzen's condensation, and iii) divinylcyclopropane rearrangement to prepare the [3.2.1]-bicyclooctane nucleus that composes the helminthosporol natural products. Once the natural product and analogs have been prepared, a well-precedented in vitro assay that employs 14C-labeled-oleate will be used to determine the extent of ACAT inhibition in macrophages.