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Structural Elucidation, Synthesis and Study of the Chlorosulfolipids

氯磺脂的结构解析、合成与研究

基本信息

批准号：
8600291
负责人：
Christopher D Vanderwal
金额：
$ 28.14万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8600291
关键词：
Address Algae Alkanes Anabolism Area Behavior Biological Biological Factors Calmodulin Cell membrane Cells Chemistry Chlorine Collaborations Complex Computer Simulation Coupled Cytotoxic Antibiotics Databases Development Disease Outbreaks Drug Compounding Esters Family Fluorine Fresh Water Funding Generations Goals Halogens Health Human Inorganic Sulfates Institution Investigation Knowledge Learning Light Link Lipids Membrane Membrane Lipids Methods Molecular Conformation Mussels NMR Spectroscopy Nature Oceanography Ochromonas Organic Synthesis Outcome Pharmacologic Substance Phase Phospholipids Poisoning Positioning Attribute Prevention Principal Investigator Property Protein Phosphatase Inhibitor Public Health Relative (related person)Reporting Research Role Route Sampling Shellfish Site Solutions Source Spectrum Analysis Steroids Structure Technology Terpenes Toxin Unspecified or Sulfate Ion Sulfates Ursidae Family analog base chlorination computerized tools design drug discovery flexibility improved inhibitor/antagonist interest meetings member molecular shape programs research study scaffold small molecule solid state nuclear magnetic resonance stereochemistry success

项目摘要

DESCRIPTION (provided by applicant): Nature makes extensive use of chlorine in biosynthesis; to date, over 2000 chlorinated natural products have been identified. Many of these chlorinated secondary metabolites display potent and varied biological activities, but are available from natural sources in only minute quantities. The significant question as to what advantage is conferred upon these compounds by the presence of the chlorine atom remains to be answered. The ability to answer this question is dependent upon effective strategies for the synthesis of chlorinated compounds, and the current level of sophistication in this field is low. The chlorosulfolipids, a family of stereochemically complex alkanes that display numerous chlorine-bearing stereogenic centers, represent one particularly intriguing class of polychlorinated molecules. Certain chlorosulfolipids have been established as causative agents of Diarrhetic Shellfish Poisoning when people have consumed tainted mussels, and others are the exclusive polar lipids in the cell and flagellar membranes of many species of freshwater algae. That these compounds, which bear two polar sulfate groups at opposite ends of the alkane chain, are major components of stable membranes is truly intriguing. It is thought that these compounds could be much more widespread than originally expected, and might be pervasive among algal species. The relative and absolute stereochemistry has only been established for the mussel-derived lipids. To date, few studies toward the synthesis of these challenging targets, or investigations into their conformational behavior, or their bulk or membrane properties, have been reported. The cell and flagellar membranes of the alga Ochromonas danica are largely composed of chlorosulfolipids and contain essentially no phospholipids; these polychlorinated natural products have been found in numerous freshwater algae species. We propose to elucidate the relative and absolute stereochemistry of the major chlorosulfolipid from O. danica by NMR methods. We will then verify the stereochemical assignment by synthesis. These endeavors have already met with substantial success. An enantioselective route to this lipid target will be developed, and it will also be adapted to the first synthesis of enantioenriched chlorosulfolipid mussel toxin. We will revisit the related polychlorinated natural product malhamensilipin A, and determine its stereochemistry by spectroscopic methods, and confirm these results by synthesis. We will also reisolate and determine the structure of several of the less chlorinated O. danica lipids and synthesize representative members. The solution conformations of the chlorosulfolipids synthesized will be studied using NMR spectroscopy and with computational modeling. The goal of this portion of the research is to further our understanding of the conformations of polychlorinated alkanes, and to garner a predictive ability to control molecular shape (conformation) according to the number and stereochemistry of chlorine residues along an alkane chain. Finally, we will study the chlorosulfolipids generated by synthesis using cutting edge solid-state NMR methods currently in development in the Martin lab at UCI. We will use variable angle spinning (VAS) and switched angle spinning (SAS) experiments, among others, to learn about the dynamics of these lipid molecules in physiologically relevant (bulk) conditions. The long-term impact of the research in this proposal will include the availability of more effective strategies for the stereoselective synthesis of polychlorinated natural products, and a greater understanding of the reactivity of polychlorinated alkanes. We will also benefit from powerful new strategies for the control of molecular shape, which is intimately tied to function. Finally, this research could begin to shed light on an evolutionary diversion in membrane design that resulted in the chlorosulfolipid-based cell membranes of many freshwater algae.

描述（由申请人提供）：大自然在生物合成中广泛使用氯；迄今为止，已鉴定出2000多种氯化天然产物。许多这些氯化次生代谢物显示出有效且多样的生物活性，但从天然来源中只能获得微量。关于氯原子的存在赋予这些化合物什么优点的重要问题仍有待回答。回答这个问题的能力取决于氯化化合物合成的有效策略，而目前该领域的复杂程度较低。氯磺脂是一类立体化学复杂的烷烃，具有许多含氯立体中心，代表了一类特别有趣的多氯化分子。当人们食用受污染的贻贝时，某些氯磺脂已被确定为腹泻性贝类中毒的病原体，而其他氯磺脂是许多淡水藻类的细胞和鞭毛膜中独有的极性脂质。这些在烷链两端带有两个极性硫酸基团的化合物是稳定膜的主要成分，这确实很有趣。人们认为这些化合物的分布范围可能比最初预期的要广泛得多，并且可能普遍存在于藻类物种中。仅针对贻贝来源的脂质建立了相对和绝对立体化学。迄今为止，关于这些具有挑战性的靶标的合成或对其构象行为或其体积或膜特性的研究很少有报道。 Ochromonas danica 藻类的细胞膜和鞭毛膜主要由氯磺脂组成，基本上不含磷脂；这些多氯天然产物已在多种淡水藻类中发现。我们建议通过 NMR 方法阐明来自 O.danica 的主要氯磺脂的相对和绝对立体化学。然后我们将通过合成验证立体化学分配。这些努力已经取得了巨大成功。将开发针对该脂质靶点的对映选择性途径，并且该途径还将适用于对映体富集的氯磺脂贻贝毒素的首次合成。我们将重新审视相关的多氯天然产物malhamensilipin A，并通过光谱方法测定其立体化学，并通过合成来确认这些结果。我们还将重新分离并确定几种氯化程度较低的 O. danica 脂质的结构，并合成代表性成员。将使用核磁共振波谱和计算模型来研究合成的氯磺脂的溶液构象。这部分研究的目标是进一步了解多氯烷烃的构象，并获得根据烷烃链上氯残基的数量和立体化学来控制分子形状（构象）的预测能力。最后，我们将研究使用 UCI 马丁实验室目前正在开发的尖端固态 NMR 方法合成产生的氯磺脂。我们将使用变角旋转 (VAS) 和变角旋转 (SAS) 实验等来了解这些脂质分子在生理相关（整体）条件下的动力学。该提案中研究的长期影响将包括为多氯天然产物的立体选择性合成提供更有效的策略，以及对多氯烷烃的反应性有更深入的了解。我们还将受益于控制分子形状的强大新策略，分子形状与功能密切相关。最后，这项研究可以开始揭示膜设计的进化转移，这种进化转移导致了许多淡水藻类基于氯磺脂的细胞膜。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Approaches to the chemical synthesis of the chlorosulfolipids.

DOI：
10.1021/ar400246w
发表时间：
2014-02-18
期刊：
ACCOUNTS OF CHEMICAL RESEARCH
影响因子：
18.3
作者：
Chung, Won-Jin;Vanderwal, Christopher D.
通讯作者：
Vanderwal, Christopher D.

General approach to the synthesis of the chlorosulfolipids danicalipin A, mytilipin A, and malhamensilipin A in enantioenriched form.

DOI：
10.1021/jo5000829
发表时间：
2014-03-07
期刊：
The Journal of organic chemistry
影响因子：
0
作者：
Chung WJ;Carlson JS;Vanderwal CD
通讯作者：
Vanderwal CD

Enantioselective divergent syntheses of several polyhalogenated Plocamium monoterpenes and evaluation of their selectivity for solid tumors.

几种多卤化 Plocamium 单萜的对映选择性发散合成及其对实体瘤选择性的评估。

DOI：
10.1002/anie.201407726
发表时间：
2014
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
0
作者：
Vogel,CarlV;Pietraszkiewicz,Halina;Sabry,OmarM;Gerwick,WilliamH;Valeriote,FrederickA;Vanderwal,ChristopherD
通讯作者：
Vanderwal,ChristopherD

Stereoselective Halogenation in Natural Product Synthesis.