Structural Elucidation, Synthesis and Study of the Chlorosulfolipids

氯磺脂的结构解析、合成与研究

• 批准号: 8011218
• 负责人: Christopher D Vanderwal
• 金额: $ 28.42万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 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/8011218
• 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; 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; research study; scaffold; small molecule; solid state nuclear magnetic resonance; stereochemistry; success; three dimensional structure

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）：自然界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强大和多样的生物活性，但从自然来源中只能获得极少量。至于氯原子的存在给这些化合物带来了什么好处，这个重要的问题还有待回答。回答这个问题的能力取决于氯化化合物合成的有效策略，而目前这一领域的复杂程度很低。氯磺胺类化合物是一类具有大量含氯立体中心的立体结构的复杂烷烃，是一类特别有趣的多氯化分子。当人们食用受污染的贻贝时，某些氯磺胺类已被确定为腹泻性贝类中毒的病原体，而其他氯磺胺类是许多淡水藻类的细胞和鞭毛膜中的唯一极性脂。这些化合物在烷烃链的两端具有两个极性硫酸盐基团，是稳定膜的主要组成部分，这确实很有趣。据认为，这些化合物可能比最初预期的要广泛得多，并且可能在藻类物种中普遍存在。目前只建立了贻贝源性脂质的相对和绝对立体化学。迄今为止，对这些具有挑战性的靶点的合成，或对其构象行为，或其体积或膜性质的研究很少有报道。丹尼藻的细胞膜和鞭毛膜主要由氯脂肪酸组成，基本上不含磷脂；在许多淡水藻类物种中发现了这些多氯天然产物。本文拟采用核磁共振方法对牛蒡主要氯磺酸脂的相对立体化学和绝对立体化学进行研究。然后我们将通过合成来验证立体化学配位。这些努力已经取得了巨大的成功。对这种脂质靶点的对映选择性途径将被开发出来，它也将适应于首次合成对映富集氯磺胺类贻贝毒素。我们将重新研究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性质，并通过合成证实这些结果。我们还将重新分离和确定几个氯化程度较低的蛇麻脂质的结构，并合成具有代表性的成员。利用核磁共振波谱和计算模型对合成的氯磺酸脂的溶液构象进行了研究。这部分研究的目的是进一步了解多氯烷烃的构象，并根据烷烃链上氯残基的数量和立体化学性质，获得控制分子形状（构象）的预测能力。最后，我们将研究利用目前在UCI的Martin实验室开发的尖端固态核磁共振方法合成的氯磺酸脂。我们将使用可变角度纺丝（VAS）和开关角度纺丝（SAS）等实验来了解这些脂质分子在生理相关（散装）条件下的动力学。本提案中研究的长期影响将包括为立体选择性合成多氯天然产物提供更有效的策略，以及对多氯烷烃的反应性有更深入的了解。我们还将受益于强有力的控制分子形状的新策略，这与功能密切相关。最后，这项研究可以开始揭示膜设计的进化转向，导致许多淡水藻类的氯亚砜基细胞膜。