SYNTHESIS OF ANNONACEOUS ACETOGENINS AND ANALOGUES

甘草苷及其类似物的合成

• 批准号: 6151191
• 负责人: JAMES A MARSHALL
• 金额: $ 20.43万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6151191
• 关键词: antimetabolites; antineoplastics; drug design /synthesis /production; enzyme inhibitors; immunosuppression; oxidative phosphorylation; plant extracts; stereochemistry

DESCRIPTION: (Principal Investigator's) Synthetic approaches to representative Annonaceous acetogenins will be developed. These plant-derived materials exhibit a wide range of biological activities. Of special interest is their remarkably high ED50's against solid human tumor cell lines and their selective toxicity to tumor over normal cells. The active compounds inhibit mammalian NADH:ubiquinone reductase at Complex I in the mitochondria thereby causing shutdown of oxidative phosphorylation. Interestingly, they specifically inhibit the ubiquinone:NADH oxidase system in the plasma membranes of cancerous cells. They have also been found to exhibit immunosuppressant activity and to stimulate transport of potassium ions from lymphocytes by a mechanism similar to ionophore antibiotics. The use of the Annonaceous plants and their edible fruits in folk medicine suggest that the acetogenins therein are not highly toxic to humans. The synthetic approach will employ chiral allylic and allenic organometal reagents to introduce stereogenic centers with concurrent formation of carbon-carbon bonds.

描述：（主要研究者）合成方法， 将开发代表性的番荔枝内酯。 这些 植物来源的材料表现出广泛的生物活性。 的 特别令人感兴趣是它们对实体人肿瘤的显著高的ED 50 细胞系及其对肿瘤的选择性毒性超过正常细胞。 的 活性化合物抑制哺乳动物NADH：泛醌还原酶在复合物I中的表达， 线粒体从而引起氧化磷酸化的停止。 有趣的是，它们特异性抑制泛醌：NADH氧化酶系统 在癌细胞的质膜上。 也发现它们 表现出免疫抑制活性并刺激钾的转运 通过类似于离子载体抗生素的机制从淋巴细胞中释放离子。 的 番荔枝科植物及其食用果实在民间医药中的应用 表明其中的乙酸配基对人没有高毒性。 的 合成方法将使用手性烯丙基和联烯有机金属 引入立体中心并同时形成 碳碳键