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.

在此更新申请中，我们建议继续开发新的有机反应，以促进我们最近展示了受天然产物启发的双环化合物（resveramorphs）的合成具体来说，我们的几种白藜芦醇可以保护神经元细胞免受氧化应激。果蝇模型（幼虫神经肌肉接头处）急性氧化应激的传播剂量为据我们所知，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，我们寻求继续关注独特结构单元（联烯化合物）的化学，使用他们准备这些神经保护化合物作为工具来表征潜在的新细胞靶标我们的化学合成路线将使这些化合物成为可能。需要缩小和识别生物靶标，以及表征小分子相互作用更具体地说，我们最近发现了一种新的碳亲核试剂加成反应。我们建议在没有过渡金属的情况下发生未活化的碳-碳三键。探索该反应的合成潜力，阐明其机理，并利用它更有效地制备在另一个目标中，我们通过利用 resveramorph 类似物寻求一种不对称途径。最终，这种有机反应的发展是我们的联烯酸酯结构单元的轴向手性特性。预计将提高白藜芦醇的可及性，根据我们目前的研究，白藜芦醇正开始展示结构/活性关系（SAR），其中提出了额外的合成工具。更新应用程序，我们建议扩展此 SAR 研究，以定义分子中重要的那些元素结合（药效团）并最终确定一种更有效的“工具化合物”用于生物学研究。在这方面，我们的初步数据表明，resveramorphs 通过稳定静息膜发挥作用从这个数据和其他数据中，我们得出了resveramorphs。可能通过与我们的生物学成员合作直接调节钾通道。部门（和coPI），将在这个阶段检查resveramorphs的神经保护活性。项目，两种无脊椎动物模型果蝇中钾靶向通道的基因操作建议使用黑腹果蝇和秀丽隐杆线虫来鉴定我们的活性类似物的生物靶标。最终，这些研究预计将为未来的药物化学研究提供坚实的基础确定针对帕金森氏症和阿尔茨海默氏症等疾病的新药。

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）

Carbon-Carbon Bond Formation Facilitated by π-Complexed Organometallic Auxiliaries: An Overview.

α-络合有机金属助剂促进碳-碳键形成：概述。

DOI：
发表时间：
2019
期刊：
影响因子：
0.8
作者：
Roy, Animesh;Bhat, Bilal A;Lepore, Salvatore D
通讯作者：
Lepore, Salvatore D

Asymmetric Protonation of Cumulenolates: Synthesis of Allenyl Aldehydes Facilitated by an Organomanganese Auxiliary.

积聚烯醇盐的不对称质子化：有机锰助剂促进烯醛的合成。

DOI：
10.1021/acs.orglett.5b03681
发表时间：
2016-03-18
期刊：
Organic letters
影响因子：
5.2
作者：
Roy A;Bhat BA;Lepore SD
通讯作者：
Lepore SD

Resveratrol-Inspired Bridged Bicyclic Compounds: A New Compound Class for the Protection of Synaptic Function from Acute Oxidative Stress.

白藜芦醇启发的桥联双环化合物：一种新的化合物类别，用于保护突触功能免受急性氧化应激。

DOI：
10.1021/acschemneuro.8b00577
发表时间：
2018-11-21
期刊：
ACS chemical neuroscience
影响因子：
5
作者：
Wesley L. Bollinger;Elijah J St Germain;S. Maki;Nadia Sial;Salvatore D. Lepore;K. Dawson
通讯作者：
K. Dawson

Alkyne Cycloadditions Mediated by Tetrabutylammonium Fluoride: A Unified and Diversifiable Route to Isoxazolines and Pyrazolines.

四丁基氟化铵介导的炔环加成：异恶唑啉和吡唑啉的统一且多样化的路线。