SYNTHESIS OF ANNONACEOUS ACETOGENINS AND ANALOGUES

甘草苷及其类似物的合成

• 批准号: 6351225
• 负责人: JAMES A MARSHALL
• 金额: $ 21.04万
• 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 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6351225
• 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：(首席调查员的)综合方法 将开发具有代表性的番荔枝内酯。这些 植物衍生材料具有广泛的生物活性。的 特别令人感兴趣的是他们对实体人体肿瘤非常高的ED50‘S 细胞系及其对肿瘤的选择性毒性高于正常细胞。这个 活性化合物抑制哺乳动物NADH：泛醌还原酶 线粒体因此导致氧化磷酸化的关闭。 有趣的是，它们能特异性地抑制泛醌：NADH氧化酶系统 在癌细胞的质膜中。他们还被发现 表现出免疫抑制活性并刺激钾的运输 通过一种类似于离子载体抗生素的机制从淋巴细胞中释放离子。这个 番荔枝属植物及其食用果实在民间医药中的应用 表明其中的乙酸根素对人体毒性不高。这个 合成方法将使用手性烯丙基和烯类有机金属 引入同时形成立体感中心的试剂 碳-碳键。

项目成果

Total synthesis and structure confirmation of the annonaceous acetogenins 30(S)-hydroxybullatacin, uvarigrandin a, and 5(R)-uvarigrandin a (narumicin I?).

• DOI: 10.1021/jo0266137
• 发表时间: 2003-02
• 期刊: The Journal of organic chemistry
• 作者: J. Marshall;Arnaud Piettre;M. Paige;F. Valeriote

Total synthesis of the cytotoxic threo, trans, threo, trans, threo annonaceous acetogenin asimin and its C-10 epimer: unambiguous confirmation of absolute stereochemistry.

细胞毒性苏式、反式、苏式、反式、苏式乙酰基阿西明及其 C-10 差向异构体的全合成：绝对立体化学的明确证实。

• DOI: 10.1021/np990132
• 发表时间: 1999
• 期刊: Journal of natural products.
• 作者: Marshall,JA;Jiang,H
• 通讯作者: Jiang,H