Structural Elucidation, Synthesis and Study of the Chlorosulfolipids

氯磺脂的结构解析、合成与研究

• 批准号: 7788733
• 负责人: Christopher D Vanderwal
• 金额: $ 28.52万
• 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/7788733
• 关键词: 6-bromo-3-(bromomethyl)-7-methyl-2,3,7-trichloro-1-octene; 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; 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; barbamide; base; chlorination; computerized tools; design; drug discovery; flexibility; improved; inhibitor/antagonist; interest; meetings; member; molecular shape; public health relevance; 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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because of the importance of organohalogen chemistry to drug discovery. Though the current halogen of choice for pharmaceutical development is fluorine, the use of chlorine in drug compounds has been increasing. The strategies for stereoselective chlorination and the improved understanding of the properties of chlorinated molecules advanced in this proposal will therefore benefit pharmaceutical research. The chlorosulfolipids, which are the targets of the described synthesis efforts, are the causative agents of Diarrhetic Shellfish Poisoning (DSP) when humans ingest mussels containing these natural products. Access to enantioenriched synthetic mussel toxin might aid in the discovery of the original source and biosynthesis of these compounds; this knowledge could aid in the prevention of DSP outbreaks. Finally, the chlorosulfolipids derived from algae might be a truly important evolutionary diversion in membrane design; although the direct link to public health is not completely clear, this important research area will likely have implications much beyond our current proposal.

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，已确定了2000多种氯化天然产物。这些氯化次级代谢物中有许多都显示出强大而多样的生物活性，但从自然来源获得的数量极少。至于氯原子的存在赋予这些化合物什么好处，这个重要问题还有待回答。回答这一问题的能力取决于合成氯化化合物的有效战略，目前这一领域的复杂程度较低。 chlorosulfolipids，一个家庭的立体化学复杂的烷烃，显示许多含氯立体中心，代表了一个特别有趣的一类多氯分子。当人们食用受污染的贻贝时，某些氯硫脂已被确定为腹泻性贝类中毒的病原体，其他的是许多淡水藻类的细胞和鞭毛膜中的唯一极性脂质。这些化合物在烷烃链的两端带有两个极性硫酸根基团，是稳定膜的主要成分，这确实很有趣。据认为，这些化合物可能比最初预期的更广泛，并且可能在藻类物种中普遍存在。相对和绝对的立体化学只建立了贻贝衍生的脂质。迄今为止，很少有研究对这些具有挑战性的目标，或调查到他们的构象行为，或他们的散装或膜性能的合成，已被报道。 丹麦嗜铬单胞菌的细胞膜和鞭毛膜主要由氯硫脂组成，基本上不含磷脂;这些多氯天然产物已在许多淡水藻类物种中发现。我们建议阐明的相对和绝对立体化学的主要氯硫脂从O。Danica的NMR方法。然后我们将通过合成来验证立体化学归属。这些努力已经取得了巨大成功。一个对映体选择性的路线，这个脂质目标将被开发，它也将适应于第一个对映体富集的氯磺脂贻贝毒素的合成。 我们将重新审视相关的多氯天然产物malhamensilipin A，并通过光谱方法确定其立体化学，并通过合成来证实这些结果。 我们还将重新分离和确定几个氯代较少的O的结构。Danica脂质和合成的代表成员。将使用NMR光谱和计算建模研究合成的chlorosulfolipids的溶液构象。这部分研究的目的是进一步了解多氯代烷烃的构象，并获得预测能力，控制分子的形状（构象），根据氯残留物的数量和立体化学沿着烷烃链。 最后，我们将研究合成所产生的chlorosulfolipids使用最先进的固态核磁共振方法目前正在开发中的马丁实验室在UCI。我们将使用可变角旋转（VAS）和开关角旋转（SAS）实验，除其他外，了解这些脂质分子在生理相关（散装）条件下的动力学。该提案中研究的长期影响将包括提供更有效的多氯天然产物立体选择性合成策略，以及更好地了解多氯烷烃的反应性。我们还将受益于控制分子形状的强大新策略，这与功能密切相关。最后，这项研究可以开始阐明膜设计的进化转向，导致许多淡水藻类的氯硫脂细胞膜。 公共卫生相关性：由于有机卤素化学对药物发现的重要性，拟议的研究与公共卫生相关。虽然目前用于药物开发的卤素选择是氟，但氯在药物化合物中的使用一直在增加。因此，立体选择性氯化的策略和对氯化分子性质的进一步理解将有利于药物研究。作为所述合成努力的目标的氯硫脂是当人类摄入含有这些天然产物的贻贝时腹泻性贝类中毒（DSP）的病原体。获得对映体富集的合成贻贝毒素可能有助于发现这些化合物的原始来源和生物合成，这方面的知识可以帮助预防DSP的爆发。最后，来自藻类的氯硫脂可能是膜设计中真正重要的进化转向;尽管与公共健康的直接联系尚不完全清楚，但这一重要研究领域的影响可能远远超出我们目前的建议。