Synthesis of a Bridged Bicyclic Natural Product Using Allenyl Esters

使用烯丙酯合成桥联双环天然产物

基本信息

批准号：
10046244
负责人：
SALVATORE D LEPORE
金额：
$ 44.84万
依托单位：
FLORIDA ATLANTIC UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10046244
关键词：
Acute Alkynes Alzheimer&apos s Disease Area Bicyclo Compounds Binding Biological Biology Caenorhabditis elegans Carbon Cells Chemistry Collaborations Cyclization Data Development Disease Doctor&apos s Degree Dose Drosophila genus Drosophila melanogaster Electrophysiology (science)Elements Eligibility Determination Esters Exhibits Future Grant Invertebrates Investigation Legal patent Libraries Membrane Potentials Methods Modeling Natural Products Neuromuscular Junction Neurons Neuroprotective Agents Organic Chemistry Oxidative Stress Parkinson Disease Periodicity Pharmaceutical Chemistry Phase Positioning Attribute Potassium Channel Preparation Production Progress Reports Property Reaction Recording of previous events Research Rest Route Stress Structure-Activity Relationship Synapses Synaptic Transmission System Transition Elements Work analog base biophysical chemistry cellular targeting chemical synthesis design foot genetic manipulation improved member neuroprotection novel novel strategies oxidative damage pharmacophore programs propadiene scaffold small molecule tool undergraduate research undergraduate student

项目摘要

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.

在此续签应用中，我们建议继续开发新的有机反应我们最近显示的自然产物的合成启发的双环化合物（白环植物）。保护神经元细胞免受氧化应激。果蝇模型中急性氧化应激的传播据我们所知，低于100 pm。向前迈进，我们看到，我们继续专注于独特的建筑块（Allenoates）的化学反应它们准备这些神经保护化合物，以表征对氧化应激的神经保护作用。需要缩小和识别生物学靶标，并表征小分子相互作用更具体地，我们发现了新的碳接核器在没有过渡金属的情况下进行的未激活的碳三键探索该反应的合成潜力，阐明其机制，并使用它来提高效率在另一个目标中，我们寻求一种不对称的途径我们的烯酸酯构建块的轴向手性特性。有望增强对陶瓷的可访问性，根据我们当前的研究，展示结构/活动关系（SAR）。续订应用，我们建议扩展SAR研究，以定义分子中重要的元素用于结合（药理），并最终确定生物学研究更有效的“工具化合物”。在这方面，我们的预预制作数据表明，静态膜通过稳定来起作用。潜在的和延长的突触传播。可以通过与我们的生物学成员的合作来调节钾通道。部门（和COPI），将在此阶段检查纪念物的神经保护活动。项目，针对两个无脊椎动物模型中钾通道的遗传操作 Melanogaster和Caenorhabditis秀丽隐杆线虫被支撑以识别我们活跃类似物的生物学靶标。最终，这些研究有望为未来的药物化学投资提供坚定的基础识别反对埃里森和帕金森氏症和阿尔茨海默氏症的新颖特工。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Allenoate Prenucleophiles: A Triply Diastereoselective Approach to β-Hydroxy Esters Containing All-Carbon α-Quaternary Centers.

联烯酸亲核体：含有全碳α-四元中心的β-羟基酯的三重非对映选择性方法。

DOI：
10.1021/acs.orglett.9b02930
发表时间：
2019
期刊：
Organic letters
影响因子：
5.2
作者：
Maki,SamanthaL;Maity,Pradip;Dougherty,Shannon;Johns,Jennifer;Lepore,SalvatoreD
通讯作者：
Lepore,SalvatoreD

Diversification reactions of γ-silyl allenyl esters: selective conversion to all-carbon quaternary centers and γ-allene dicarbinols.

γ-甲硅烷基联烯基酯的多样化反应：选择性转化为全碳季中心和γ-丙二烯二甲醇。