Synthesis of a Bridged Bicyclic Natural Product Using Allenyl Esters

在此更新申请中，我们建议继续开发新的有机反应，以促进 合成天然产物启发双环化合物（resveramorphs），我们最近已经证明， 保护神经细胞免受氧化应激。具体来说，我们的几种resveramorphs保护突触 在果蝇模型中（在幼虫神经肌肉接头处）， 低至100 pM。据我们所知，这种水平的神经保护活性对于小分子来说是前所未有的。 展望未来，我们寻求继续专注于独特的结构单元（等位基因）的化学， 他们准备这些神经保护化合物作为工具，以表征潜在的新细胞靶点， 对氧化应激的神经保护。我们的化学合成路线将使化合物 需要缩小和识别生物靶点，并表征小分子相互作用 与这个目标。更具体地说，我们最近发现了一种新的碳亲核试剂加成反应 到在不存在过渡金属的情况下发生的未活化的碳-碳三键。我们建议 探索该反应的合成潜力，阐明其机理，并利用其更有效地制备 resveramorphs。在另一个目标中，我们通过利用以下方法寻求制备resveramorph类似物的不对称途径： 我们的联烯基积木的轴向手性特性。最终，这种有机反应的发展是 预计将提高resveramorphs的可及性，根据我们目前的研究， 具有结构/活性关系（SAR）。随着额外的合成工具被提议作为这一部分， 更新申请，我们建议扩大这一SAR研究，以确定这些元素在分子中的重要 用于结合（药效团），并最终确定用于生物学研究的甚至更有效的"工具化合物"。 在这方面，我们的初步数据表明，resveramorphs的作用，稳定休息膜 潜力和延长突触传递。从这个和其他数据，我们假设resveramorphs 可能直接调节钾离子通道。通过与我们的生物学成员的合作， 部门（和coPI），将检查resveramorphs的神经保护活性。在这个阶段， 项目，针对两种无脊椎动物模型中钾通道的遗传操作，果蝇 melanogaster和秀丽隐杆线虫（Caesophylhabditis elegans），被提议用于鉴定我们的活性类似物的生物靶标。 最终，这些研究有望为未来的药物化学研究提供坚实的基础， 鉴定新的药物来对抗帕金森氏症和阿尔茨海默氏症。

In this renewal application we propose to continue the development of new organic reactions for the facilitated synthesis of natural product inspired bicyclic compounds (resveramorphs) that we have recently shown to protect neuronal cells from oxidative stress. Specifically, several of our resveramorphs protect synaptic transmission from acute oxidative stress in a fruit fly model (at the larval neuromuscular junction) at doses as low as 100 pM. To our knowledge, this level of neuroprotective activity is unprecedented for a small molecule. Moving forward, we seek to continue our focus on the chemistry of unique building blocks (allenoates), using them to prepare these neuroprotective compounds as tools to characterize a potentially new cellular target for neuroprotection against oxidative stress. Our chemical synthesis routes will make possible the compounds needed to narrow down and identify the biological target, as well as to characterize small-molecule interactions with that target. More specifically, we have recently discovered a new addition reaction of carbon nucleophiles to unactivated carbon-carbon triple bonds that takes place in the absence of transition metals. We propose to explore the synthetic potential of this reaction, elucidate its mechanism, and use it to more efficiently prepare resveramorphs. In another aim, we seek an asymmetric route to resveramorph analogs by taking advantage of the axial chirality properties of our allenoate building blocks. Ultimately, this organic reaction development is expected to enhance accessibility to resveramorphs, which, based on our current studies, are beginning to exhibit a structure/activity relationship (SAR). With the additional synthetic tools being proposed as part of this renewal application, we propose to expand this SAR study to define those elements in the molecule important for binding (pharmacophore) and ultimately identify an even more potent “tool compound” for biological study. In this regard, our preliminary data indicate that resveramorphs act by stabilizing the resting membrane potential and prolonging synaptic transmission. From this and other data, we hypothesize that resveramorphs may be modulating potassium channels directly. Through a collaboration with a member of our Biology Department (and coPI), the neuroprotective activity of resveramorphs will be examined. In this phase of the project, genetic manipulations targeting potassium channels in two invertebrate models, Drosophila melanogaster and Caenorhabditis elegans, are proposed to identify the biological target of our active analogs. Ultimately, these studies are expected to provide a firm footing for future medicinal chemistry investigations to identify novel agents against diseases such as Parkinson’s and Alzheimer’s.