Synthesis of Helminthosporol Analogs as ACAT Inhibitors

作为 ACAT 抑制剂的长蠕孢醇类似物的合成

• 批准号: 6702528
• 负责人: Eduard Casillas
• 金额: $ 14.31万
• 依托单位: VILLANOVA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6702528
• 关键词: acyltransferase; analog; antiatherogenic agent; chemical structure function; chemical synthesis; cholesterol; cholesterol esters; drug design /synthesis /production; enzyme inhibitors; esterification; macrophage; plant poisons

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.

描述（由申请人提供）：冠状动脉疾病是美国的主要死因。导致这种情况的主要因素之一是动脉粥样硬化斑块造成的动脉硬化和狭窄。这些斑块主要来源于巨噬细胞衍生的泡沫细胞，其储存高浓度的胆固醇。酰基辅酶A胆固醇酰基转移酶（ACAT）催化胆固醇与长链辅酶A激活的脂肪酸的细胞内酯化。因此，ACAT可能在膳食胆固醇的吸收中发挥重要作用。有效的ACAT抑制剂具有通过降低胆固醇吸收和限制巨噬细胞转化为胆固醇酯饱和的泡沫细胞而在治疗上作为抗动脉粥样硬化剂发挥作用的潜力。 本项目的目的是基于蠕虫孢酚的基本结构开发一种有效的ACAT抑制剂，蠕虫孢酚是一种具有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，将通过全化学合成来制备蠕虫孢子酚、两种生物遗传学相关的代谢物（称为前蠕虫孢子酚和sorokinianin）和几种最小化的类似物。对所有这些目标的合成访问将源自一条通用路线，该路线可以在中期到后期阶段转向以准备每个模拟。这种常见的合成基本上是基于以下顺序：i）甲硅烷基导向的Nazarov环化，ii）乙烯基Darzen缩合，和iii）二乙烯基环丙烷重排，以制备构成蠕虫孢酚天然产物的[3.2.1]-双环辛烷核。一旦制备了天然产物和类似物，将使用采用14 C标记油酸酯的良好先例体外试验来确定巨噬细胞中ACAT抑制的程度。