Investigating lipophilicity and hydrogen bonding properties of functionalised aliphatic compounds

设计分子以优化其性质的过程（无论是在官能团水平、分子水平、超分子或宏观水平）已经达到相当高的复杂程度。在这种情况下，有机化合物的选择性降解一直是化学家最喜欢的工具之一，以防止不期望的性质/事件（例如降解），或微调所需的性质/事件（例如酸碱性，构象）。这是因为氟原子的高电负性和非极化性以及由此产生的高度极化和强的碳-氟键。这一非常活跃的研究领域使人们越来越了解如何从这些特殊特性中获益。我们过去的研究产生了新的工具和新的见解，这激励我们进行新的令人兴奋的创新研究。我们将研究的主要性质是氢键和亲脂性（这是细胞膜渗透性的量度）。氢键是分子与其局部环境之间最重要的特异性非共价（非固定的，暂时的）相互作用，因此它在配体-蛋白质结合（化合物的效力），超分子化学和催化中具有最大的相关性。化合物的效力描述了分子一旦到达其目标时的有效性。但是，化合物的亲脂性是决定其达到目标的有效性的主要因素。因此，效能和亲脂性是生物活性化合物（探针、诊断和药物）的最重要性质。我们小组以前的EPSRC资助的研究导致了一种新的方法来测量氟化化合物的亲脂性（定义为化合物在辛醇/水两相混合物中的分配系数）。我们的新技术不仅比现有方法更准确和直接;另一个主要好处是不需要紫外线活性。现在，这给了我们一个令人兴奋的机会来研究脂肪族有机化合物（没有芳香环，这是紫外线活性）。这些脂肪族化合物越来越多地用于药物开发，但使用标准工业方法测量其亲脂性并不容易。此外，虽然分配系数是膜渗透性评估的事实上的标准，但关于化合物实际分配到脂质双层中的数据更少。使用一种新形式的19 F固态NMR，我们将能够评估分配系数如何与分配到天然双层中相关，包括二氢呋喃的影响。我们还希望将我们的研究从氟代醇扩展到至关重要的脂肪胺（这些存在于大多数药物中），为了研究β-内酰胺对其亲脂性的pH依赖性影响，以及酰胺，我们的技术使我们能够研究全新的方面，例如构象异构体的亲脂性（构象异构体是分子在空间中的不同取向）。这将扩展到糖端基异构体（这是不同的糖形式）。我们还将扩大方法范围，扩大亲脂性范围，并使用它来测试非氟化化合物。在此之前，我们也研究了脂肪醇的氢键供给能力。鉴于这一成功，我们打算将我们的研究扩展到胺和酰胺。我们还想研究分子内氢键对亲油性的影响。我们的技术意味着我们处于独特的位置来做到这一点。我们提出的研究将显着增加我们的理解，在生命科学，化学和材料化学中具有越来越重要的一类化合物的两个非常重要的特性的影响。它将通过扩大其应用范围和数量进一步巩固我们亲脂性方法的重要性。

The process of designing molecules in order to optimise their properties (whether at the functional group level, the molecular level, supramolecular or macroscopic level) has achieved considerable levels of sophistication. In this context, selective fluorination of organic compounds has been one of the chemist's favourite tools to prevent undesirable properties/events (eg degradation), or to fine-tune desired ones (eg acid/basicity, conformation). This is because of the high electronegativity and non-polarisability of the fluorine atom and of the resulting highly polarised and strong carbon-fluorine bond. This very active research area has resulted in an ever-increasing understanding of how to profit from these special characteristics.Our past research has led to novel instruments and novel insights, which inspired us to novel exciting and innovative research. The main properties we will investigate are hydrogen bonding and lipophilicity (which is a measure of cell membrane permeability). Hydrogen bonding is the most important specific non-covalent (non-fixed, temporary) interaction between a molecule and its local environment, and so it is of utmost relevance in ligand-protein binding (potency of a compound), supramolecular chemistry and catalysis. The potency of a compound describes how effective a molecule is once it reaches its target. But, the lipophilicity of a compound is a main factor that determines how effective a it is at reaching its target. Hence, potency and lipophilicity are the most important properties of bioactive compounds (probes, diagnostics and drugs). Previous EPSRC-funded research by our group led to a novel way to measure lipophilicity of fluorinated compounds (which is defined as the partition coefficient of a compound in an octanol/water biphasic mixture). Not only is our new technique more accurate and straightforward than existing methods; an additional major benefit is that no UV-activity is required. This now gives us an exciting opportunity to study aliphatic organic compounds (which do not have aromatic rings, which are UV active). These aliphatic compounds are being increasingly used in drug development, but it is not easily possible to measure their lipophilicity using standard industry methods. Furthermore, while the partition coefficient is the de facto standard for membrane permeability assessment, data regarding the actual partitioning of compounds into lipid bilayers is more scarce. Using a novel form of 19F solid state NMR we will be able to assess how the partition coefficient relates to partitioning into the native bilayer, including the influence of fluorination.We also want to expand our research from fluorohydrins to the vitally important aliphatic amines (these are found in most drugs), in order to study the pH-dependent influence of fluorination on their lipophilicity, and of amides, where our technique allows us to investigate completely novel aspects, such as lipophilicity of conformers (which are different orientations of a molecule in space). This will be extended to sugar anomers (which are different sugar forms). We will also extend the methodology scope, both widening the lipophilicity range, and using it to test non-fluorinated compounds. Previously, we have also investigated the hydrogen bond donating capacity of aliphatic alcohols. Given this success, we intend to expand our research to amines and amides. We also want to investigate the effect intramolecular hydrogen bonding involving fluorine has on lipophilicity. Our technique means we are uniquely placed to do this. Our proposed research will significantly increase our understanding of the impact that fluorination has on two very important properties in a class of compounds that have increasing importance in the life sciences, in chemistry, and in materials chemistry. It will further cement the importance of our lipophilicity methodology through expanding its scope and number of applications.