Total Synthesis of Highly Oxygenated Icetexane Diterpenoids

高含氧Icetexane二萜的全合成

• 批准号: 8014946
• 负责人: Felipe de Jesus Cortez
• 金额: $ 1.57万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2011-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8014946
• 关键词: Accounting; Alkynes; Biological; Biological Factors; Biological Testing; CCR5 gene; Chagas Disease; Complex; Development; Disease; Diterpenes; Exhibits; Family; Family member; Gallium; HIV; HIV Infections; Indenes; Infection; Lactones; Lead; Malignant Neoplasms; Medicine; Metals; Methodology; Methods; Molecular; Nitriles; Play; Property; Public Health; Reaction; Research; Role; Salts; Salvia; Testing; Trypanosoma cruzi; analog; catalyst; chemokine receptor; effective therapy; functional group; improved; insight; interest; member

DESCRIPTION (provided by applicant): The development of new strategies and methods for the total synthesis of biologically active natural products and medicinally important compounds are important for the study of general medicine. By building complex molecules, we gain access to significant quantities of natural products with biological activity for further testing. In addition, we gain the ability to access analogs of these compounds in an attempt to improve bioactivity. The focus of the research is the development and utilization of a new cycloisomerization reaction or the synthesis of seven-membered rings and its application to the total synthesis of a biologically important family of natural products. Specifically, this project focuses on A) the use of gallium salts, which are cheaper and less toxic than other commonly used cycloisomerization metal catalysts, to activate alkynes in the isomerization of indene intermediates to form seven-membered rings as well as, B) the utilization of this methodology in the total synthesis of natural products with biological activity. This methodology can be applied to the total synthesis of the icetexane natural products, isolated from various members belonging to the Salvia genus. The members of this family have been shown to exhibit interesting biological activities. For example, komaroviquinone, isolated from Dracocephalum komarovi, shows trypanocidal activity against the infectious form of Trypanosoma cruzi, the causative agent for Chagas' disease. Another important bioactivity displayed by komaroviquinone is inhibition of the chemokine receptor CCR5, which plays a vital role in HIV infection. Inhibition of CCR5 could lead to a general method for curbing infection. Icetexone, anastomosine, and dihydroanastomosine are three compounds in this family that have yet to be synthesized. They differ from other members in the family through the inclusion of an additional 5- membered lactone ring. The bioactivity of these compounds has not been fully studied; however, preliminary accounts suggest that the C5 epimer of icetexone displays trypanocidal activity comparable to that found in komaroviquinone. The study of methodology and total synthesis benefits public health by allowing for the synthesis of molecules that can lead to more effective treatments for common diseases, such as Chagas' disease. These studies can also lead to the synthesis of analogs of molecules that may improve on current treatments of disease.

描述（由申请人提供）：生物活性天然产物和药用重要化合物的全合成新策略和方法的开发对于普通药物的研究非常重要。通过构建复杂的分子，我们获得了大量具有生物活性的天然产物，以进行进一步的测试。此外，我们获得了获得这些化合物的类似物的能力，试图提高生物活性。研究的重点是开发和利用一种新的环异构化反应或七元环的合成及其在生物学上重要的天然产物家族的全合成中的应用。具体而言，该项目的重点是A）使用镓盐，其比其他常用的环异构化金属催化剂更便宜且毒性更小，以在茚中间体的异构化中活化炔以形成七元环，以及B）在具有生物活性的天然产物的全合成中利用该方法。该方法可应用于从鼠尾草属植物中分离得到的icetexane天然产物的全合成。该家族的成员已被证明表现出有趣的生物活性。例如，从科马罗维青兰（Dracocephalum komarovi）中分离的科马罗维醌（komaroviquinone）显示出针对克氏锥虫（Trypanosoma cruzi）的感染形式（恰加斯病的病原体）的杀锥虫活性。komaroviquinone显示的另一个重要的生物活性是抑制趋化因子受体CCR5，其在HIV感染中起着至关重要的作用。CCR5的抑制可能导致抑制感染的一般方法。冰酮、曲马新和二氢曲马新是这个家族中尚未合成的三种化合物。它们与家族中其他成员的不同之处在于包含一个额外的5元内酯环。这些化合物的生物活性尚未得到充分研究，然而，初步的帐户表明，C5差向异构体的icetexone显示锥虫杀活性中发现的komaroviquinone。方法学和全合成的研究通过允许合成可以导致对常见疾病（例如恰加斯病）更有效的治疗的分子而有益于公共卫生。这些研究还可以导致分子类似物的合成，这些类似物可能会改善目前的疾病治疗。