STRATEGIES FOR TETRODOTOXIN AND AZADIRACHTIN

河豚毒素和印楝素的治疗策略

• 批准号: 2189620
• 负责人: Bertram Oliver Fraser-Reid
• 金额: $ 21.35万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2189620
• 关键词: Diels Alder reaction; biological products; carbopolycyclic compound; chemical structure function; chemical synthesis; dentifrices; free radicals; insecticides; tetrodotoxin; triterpenes

Tetrodotoxin (TTX) and azadirachtin share many common characteristics. Both are legendary in folklore, the former as the potent toxin of the Japanese puffer fish, the latter as the mysterious ingredient of the neem tree, used for thousands of years throughout the Indian subcontinent as a insecticide and germicide. Both compounds defied several decades of effort by eminent chemists on several continents towards structure elucidation, both structures being finally solved by physical rather than chemical methods. TTX exerts its action by blocking ion channels of excitable membranes, and this property is highly valued since it allows biochemists to identify and isolate these poorly understood biological structures. At the present time the puffer fish is the major source of the TTX used in laboratories, and there is a great need for a flexible synthetic approach that will permit the preparation of analogs for use in structure/activity studies. From such studies a better understanding of the transmission of impulses through excitable membranes will emerge. Azadirachtin is available from its natural source in greater quantities than TTX, and so chemical transformations have already shed light on some aspects of its structure/activity profile. But because of the complexity of the molecule, far more needs to be done. In addition to using it for its insecticidal properties, rural Indians use the neem tree for dental care. Thus they chew the soft branches of the tree, the juice acting as a dentifrice and the fibers as dental floss. A German toothpaste has recently appeared on the market which incorporates azadirachtin. The chemical basis for this dental care has yet to be clarified. Both molecules may be regarded as "densely-functionalized carbocycles", a category of natural products for which our laboratory has been developing methodology in the context of our carbohydrate-to-carbocycle transformations. For several years we have shown free radical methods to be ideal for carbohydrate manipulations in view of the fact that the multiple functional groups present in these substances are usually unaffected during these reactions. In view of the rich functionalization of TTX and azadirachtin, the application of free-radical procedures for their construction therefore resonates with our interests, and indeed in our approach to both molecules, free radical methodology features very prominently for several key transformations. Also of long standing interest is the Diels Alder reaction, ever since our laboratory showed that there are dramatic differences in rates and yield between carbohydrate alpha-enones and their carbocyclic counterparts. It is therefore very appropriate that our approach to azadirachtin combines both of these methodologies, free radical and Diels Alder.

河豚毒素（TTX）和印楝素有许多共同的特性。 两者都是传说中的民间传说，前者作为一个强大的毒素， 日本河豚，后者作为神秘成分的印楝 树，用于整个印度次大陆作为一个数千年来， 杀虫剂和杀菌剂。这两种化合物都无视几十年的努力 由几大洲的杰出化学家致力于结构解析， 这两种结构最终都是通过物理而不是化学方法来解决的 方法. TTX通过阻断可兴奋膜的离子通道发挥作用， 这种性质是非常有价值的，因为它允许生物化学家鉴定和 分离出这些鲜为人知的生物结构。在目前 河豚鱼是实验室使用的TTX的主要来源， 非常需要一种灵活的综合方法， 用于结构/活性研究的类似物的制备。从 这样的研究可以更好地理解脉冲的传输 通过可兴奋的膜将出现。 印楝素可从其天然来源大量获得 所以化学转化已经揭示了一些 其结构/活动概况的各个方面。但由于其复杂性 还有更多的工作要做除了用于 由于印度楝树具有杀虫特性，印度农村的印第安人用它来做牙科用牙。 在乎因此，他们咀嚼柔软的树枝，果汁作为一个 把纤维当作牙线。德国牙膏 最近出现在市场上，其中包含印楝素。的 这种牙齿护理的化学基础还有待澄清。 这两种分子都可以被认为是“密集官能化的碳环”， 我们实验室一直在开发的天然产品类别 在我们的碳水化合物到碳环的背景下， 转变 几年来，我们已经展示了自由基方法， 是理想的碳水化合物的操作，因为事实上， 这些物质中存在的多个官能团通常 在这些反应中不受影响。鉴于丰富的功能化 TTX和印楝素，自由基程序的应用， 因此，它们的建设符合我们的利益， 我们对这两种分子的方法，自由基方法学的特点非常 突出几个关键的转变。也是由来已久 自从我们的实验室发现了Diels桤木反应以来， 在利率和收益率上， 碳水化合物α-烯酮和它们的碳环对应物。是 因此，我们对印楝素的研究方法结合了 在这些方法中，自由基和狄尔斯桤木。