Investigating lipophilicity and hydrogen bonding properties of functionalised aliphatic compounds

研究功能化脂肪族化合物的亲脂性和氢键特性

• 批准号: EP/P019943/1
• 负责人: Bruno Linclau
• 金额: $ 50.81万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FP019943%2F1
• 关键词: Investigating; lipophilicity; hydrogen; bonding; properties

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.

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、超分子水平或宏观水平)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氟化一直是化学家最喜欢的工具之一，以防止不良性质/事件(如降解)，或微调所需的性质/事件(如酸/碱、构象)。这是因为氟原子的高度电负性和非极化性，以及由此产生的高度极化和强烈的碳-氟键。这一非常活跃的研究领域导致了人们对如何从这些特殊特征中获利的理解不断加深。我们过去的研究导致了新的工具和新的见解，这启发了我们进行新的、令人兴奋的和创新的研究。我们将研究的主要性质是氢键和亲脂性(这是细胞膜通透性的衡量标准)。氢键是分子与其局部环境之间最重要的非共价(非固定的、暂时的)特定相互作用，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极大的相关性。化合物的效力描述了分子达到目标后的效力。但是，化合物的亲油性是决定其达到目标的有效性的主要因素。因此，效力和亲脂性是生物活性化合物(探针、诊断和药物)最重要的性质。我们小组之前由EPSRC资助的研究导致了一种新的方法来测量含氟化合物的亲脂性(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、更直接，而且另一个主要好处是不需要紫外线活性。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(不含芳环，具有紫外线活性)。这些脂族化合物正越来越多地被用于药物开发，但使用标准的工业方法来测量它们的亲脂性并不容易。此外，虽然分配系数是膜通透性评估的事实标准，但关于化合物实际分配到脂质双层的数据更为稀少。使用一种新形式的19F固体核磁共振，我们将能够评估分配系数与分配到天然双层中的关系，包括氟化的影响。我们还想将我们的研究从氟氢化合物扩展到至关重要的脂肪胺(这些在大多数药物中都能找到)，以便研究氟化对其亲脂性和酰胺类化合物的pH依赖的影响，在这些方面，我们的技术允许我们研究全新的方面，如异构体的亲脂性(分子在空间中的不同取向)。这将扩展到糖类异构体(不同的糖类形式)。我们还将扩大方法学范围，扩大亲脂性范围，并将其用于测试非氟化合物。在此之前，我们还考察了脂肪醇的氢键给予能力。鉴于这一成功，我们打算将我们的研究扩展到胺和酰胺。我们还想研究涉及氟的分子内氢键对亲脂性的影响。我们的技术意味着我们处于独特的位置来做这件事。我们拟议的研究将大大增加我们对氟化对一类化合物中两种非常重要的性质的影响的理解，这类化合物在生命科学、化学和材料化学中具有越来越重要的作用。它将通过扩大亲脂性方法的应用范围和数量，进一步加强其重要性。

项目成果

Lipophilicity Modulations by Fluorination Correlate with Membrane Partitioning.

氟化的亲脂性调节与膜分配相关。

• DOI: 10.1002/anie.202301077
• 发表时间: 2023
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Wang Z

Relating Conformational Equilibria to Conformer-Specific Lipophilicities: New Opportunities in Drug Discovery.

• DOI: 10.1002/anie.202114862
• 发表时间: 2022-02-07
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Linclau, Bruno;Wang, Zhong;Jeffries, Benjamin;Graton, Jerome;Carbajo, Rodrigo J.;Sinnaeve, Davy;Le Questel, Jean-Yves;Scott, James S.;Chiarparin, Elisabetta
• 通讯作者: Chiarparin, Elisabetta

Lipophilicity Modulations by Fluorination Correlate with Membrane Partitioning

氟化的亲脂性调节与膜分配相关

• DOI: 10.1002/ange.202301077
• 发表时间: 2023
• 期刊: Angewandte Chemie
• 作者: Wang Z

A New Straightforward Method for Lipophilicity (log<em>P</em>) Measurement using ¹⁹F NMR Spectroscopy

使用¹⁹F NMR 光谱测量亲脂性 (log<em>P</em>) 的新直接方法

• DOI: 10.3791/58567
• 发表时间: 2019
• 期刊: Journal of Visualized Experiments
• 作者: Linclau B

Relating Conformational Equilibria to Conformer-Specific Lipophilicities: New Opportunities in Drug Discovery

将构象平衡与构象体特异性亲脂性联系起来：药物发现的新机遇

• DOI: 10.1002/ange.202114862
• 发表时间: 2021
• 期刊: Angewandte Chemie
• 作者: Linclau B