The chlorosulfolipids are amphiphilic natural products with stereochemically complex patterns of chlorination and sulfation. Despite their role in toxic shellfish poisoning, potential pharmacological activities, and unknown biological roles, they remain understudied due to the difficulties in purifying them from natural sources. The structure of these molecules, with a charged sulfate group in the middle of the hydrophobic chain, appears incompatible with the conventional lipid bilayer structure. Questions about chlorosulfolipids remain unanswered partly due to the unavailability of structural analogues with which to conduct structure–function studies. We approach this problem by combining enantioselective total synthesis and membrane biophysics. Using a combination of Langmuir pressure–area isotherms of lipid monolayers, fluorescence imaging of vesicles, mass spectrometry imaging, natural product isolation, small-angle X-ray scattering, and cryogenic electron microscopy, we show that danicalipin A (1) likely inserts into lipid bilayers in the headgroup region and alters their structure and phase behavior. Specifically, danicalipin A (1) thins the bilayer and fluidizes it, allowing even saturated lipid to form fluid bilayers. Lipid monolayers show similar fluidizing upon insertion of danicalipin A (1). Furthermore, we show that the halogenation of the molecule is critical for its membrane activity, likely due to sterically controlled conformational changes. Synthetic unchlorinated and monochlorinated analogues do not thin and fluidize lipid bilayers to the same extent as the natural product. Overall, this study sheds light on how amphiphilic small molecules interact with lipid bilayers and the importance of stereochemistry and halogenation for this interaction.

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Ochromonas danica 的氯硫脂对脂质双层的卤化依赖性影响

氯硫脂是两亲性天然产物，具有立体化学复杂的氯化和硫酸化模式。尽管它们在有毒贝类中毒、潜在的药理活性和未知的生物学作用中起作用，但由于难以从天然来源纯化它们，因此它们的研究仍然不足。这些分子的结构，在疏水链的中间带有一个带电荷的硫酸基团，似乎与传统的脂质双层结构不相容。关于氯硫脂的问题仍未得到解答，部分原因是无法进行结构-功能研究的结构类似物。我们通过结合对映选择性全合成和膜生物物理学来解决这个问题。使用脂质单层的朗缪尔压力-面积等温线的组合，1 ) 可能插入头组区域的脂质双层并改变它们的结构和相行为。具体而言，丹尼脂素 A ( 1 ) 使双层变薄并使其流化，甚至允许饱和脂质形成流体双层。脂质单层在插入 danicalipin A ( 1 )时表现出类似的流化。此外，我们表明分子的卤化对其膜活性至关重要，这可能是由于空间控制的构象变化。合成的未氯化和单氯化类似物不会像天然产物那样使脂质双层变薄和流化。总的来说，这项研究阐明了两亲性小分子如何与脂质双层相互作用以及立体化学和卤化对这种相互作用的重要性。