Biomimetic Synthesis of Fused Polycyclic Ethers

本项目探讨了在有毒“赤潮”现象中产生的熔融多环醚的仿生合成。虽然这些结构复杂的化合物的生物合成途径尚未完全阐明，但推测融合多环醚结构是由相对简单的无环多烯前体产生的聚环氧化合物的区域选择性和立体特异性串联氧酰基化引起的。本项目将专注于模拟这些生物合成的氧环化反应，以合成半brevetoxin B和一种新发现的五环天然产物brevenal。Brevenal特别令人感兴趣，因为它是一种无毒的竞争性抑制剂，可以抑制其他融合多环醚（如Brevenal毒素b）的神经毒性活性。同位素标记的多烯也将被合成，与这两种天然产物可能的生物遗传前体相对应。在合作工作中，这些多烯和衍生的聚氧化物将在短卡雷氏菌培养物的饲养实验中进行研究。短卡雷氏菌是导致赤潮和相关的融合多环醚天然产物毒素生产的生物。通过这个奖项，有机和大分子化学项目支持了埃默里大学化学系Frank E. McDonald博士的研究。麦克唐纳教授和他的学生正在探索“赤潮”现象中产生的毒素的合成，这种现象造成美国东南部大西洋和墨西哥湾沿岸地区的鱼类死亡，并在人类摄入受污染的鱼类时产生神经毒性症状。他们的合成旨在模仿自然界使用的合成路线，并包括对一种新发现的天然产物brevenal的研究，brevenal是一种无毒的竞争性抑制剂，可以抑制其他红潮毒素的神经毒性活性。麦克唐纳教授的研究将揭示复杂毒素生物合成的基本过程。此外，它们有望对红潮毒性的潜在治疗方法的发展产生影响，在由自然波浪作用形成的气溶胶以及红潮毒素故意输送引起的毒性的情况下具有价值。

This project addresses the biomimetic syntheses of fused polycyclic ethers produced in toxic "red tide" phenomena. Although biosynthetic pathways for these structurally complex compounds have not been completely elucidated, fused polycyclic ether structures are presumed to arise from regioselective and stereospecific tandem oxacyclizations of polyepoxide compounds arising from relatively simple acyclic polyene precursors. This project will focus on mimicking these biosynthetic oxacyclizations in the synthesis of hemibrevetoxin B and a newly discovered pentacyclic natural product, brevenal. Brevenal is of particular interest, as it is a nontoxic, competitive inhibitor for the neurotoxic activity of other fused polycyclic ethers such as brevetoxin B. Isotopically labelled polyenes corresponding to the possible biogenetic precursors of both natural products will also be synthesized. In collaborative work, these polyenes and derived polyepoxides will be studied in feeding experiments with cultures of Karenia brevis, the organism responsible for the red tide and associated production of fused polycyclic ether natural product toxins.With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Dr. Frank E. McDonald of the Department of Chemistry at Emory University. Professor McDonald and his students are exploring the synthesis of toxins produced in "red tide" phenomena, responsible for fish kills along the Atlantic and Gulf Coast areas of the southeastern United States and producing neurotoxic symptoms in humans when contaminated fish are ingested. Their syntheses are designed to mimic the synthetic routes used by Nature, and include studies of a newly discovered natural product, brevenal, which serves as a nontoxic, competitive inhibitor for the neurotoxic activity of other red tide toxins. Professor McDonald's studies will shed light on the fundamental processes responsible for the biological synthesis of complex toxins. In addition, they promise impacts in the development of potential treatments for red tide toxicity, of value in the case of toxicity due to aerosol formation by natural wave action as well as intentional delivery of red tide toxins.