Partially fluorinated alkyl motifs for pharmaceuticals and agrochemicals research

拟议的研究旨在探索几种小的部分氟化基序的制备，用于附加在小有机分子上，用于生物活性发现。这项工作还将扩展到性能有机材料，特别是用于显示的液晶。在开发过程中，经常将氟引入分子以调整分子的物理特性，或者在药物的情况下，以改善体内特性（药代动力学）。这导致在药品和农用化学品领域进入市场的所有生物活性产品中，约有20-30%被引入了氟。氟有一个有趣的特性，它是高度极化的（它是电负性最强的元素），它通过西格玛键吸引电子密度（被称为感应效应），这有改变分子整体极性的效果，或者改变邻近原子的性质，例如使氢比平时更具电正性。然而氟原子本身与相邻分子的相互作用很差（弱分子间相互作用）。它也相对较小，是仅次于氢的最小的原子，可以以稳定的形式与碳结合（碳- f键是有机化学中最强的键）。这些特性的结合使氟成为取代分子上的氢原子以调整其性质的绝佳工具（通过将电子密度拉向氟），而不会过多地改变分子的形状，也不会改变分子间相互作用的性质。当引入一个以上的氟时，这可能会成为问题。通常情况下，行业可能会引入CF3小组。现在它变得相当大了。它是疏水的，它排斥水，它赋予分子增加的亲脂性。这可以很好地结合到一个特定的蛋白质目标上，但是这种分子不太溶于水，更容易溶于脂质膜，现在它很难穿过膜，进入血液，直到它到达目标。因此，一个好的组合是增加对蛋白质靶上疏水位点的亲和力，但保持合理的水溶性。理想情况下，如果有机取代基可以稍微大一点，但不增加亲脂性（logp），相对于Et或CH3，那么这样的有机取代基将是有吸引力的。在这个建议中，我们已经确定了四个新颖的基序，并且具有这些极性疏水特性。基元1和基元2是氧和硫二氟乙醚。我们已经设计了制备它们的方法，并希望探索化学方法，将它们引入一系列建筑材料和药用产品中。我们还将系统地探索它们的极性（Log p）和它们的新陈代谢（如果有的话，身体可能如何修改它们）。基序3和4是带有3个氟的环丙烷。它们是极化的，因为它们有两个氢（亚甲基）和三个电负性氟原子相邻。在基序4中有一个额外的氧原子（也是电负性的），使这个基序进一步极化。这些图案非常新颖，但我们已经证明它们可以很容易地制备出来。该计划将探索它们的潜在效用和特性，重点是生物活性发现计划，通过该计划，我们的目标是使它们引起国际工业界和学术界的注意。Motif 5设想了三个氟原子，每个在环丙烷环的三个碳上，并且在立体化学中所有的氟原子都指向上面。据计算，这是正在研究的基序中最具极性的，并且将是生物活性研究之外的广泛科学家（包括材料化学家和物理学家）感兴趣的特殊结构，因为它具有非常不寻常的极性特性。

The proposed research aims to explore the preparation of several small partially fluorinated motifs for appending to small organic molecules for use in bioactives discovery. The work will also extend to performance organic materials, specifically liquid crystals for displays.Fluorine is often introduced into molecules during development to tune the physical properties of the molecule, or in the case of drugs, to improve in-vivo properties (pharmacokinetics). This has resulted in fluorine being introduced into about 20-30% of all bioactive products coming onto the market in the pharmaceuticals and agrochemicals sectors. Fluorine has the interesting property of being highly polarised (it is the most electronegative element) and it pulls electron density through sigma bonds (known as the inductive effect), and this has the effect of changing the overall polarity of the molecule, or changing the nature of neighbouring atoms eg making hydrogens more electropositive than usual. However the fluorine atom itself is very poor at interacting with adjacent molecules (weak intermolecular interactions). It is also relatively small and the next smallest atom after hydrogen that can be bound to carbon in a stable form (C-F bond is the strongest bond in organic chemistry). This combination of features makes fluorine an excellent tool for replacing hydrogen atoms on a molecule to tune its properties (by tugging electron density towards the fluorine), without changing the shape of the molecule too much, and without changing the nature of intermolecular interactions. When more than one fluorine is introduced, this can become problematic. Typically industry might introduce a CF3 group. This now is getting quite large. It is hydrophobic and it repels water, and it confers increased lipophilicity on the molecule. This can be good for binding to a particular protein target, but the molecule is less soluble in water and more soluble in lipid membranes, and it now has difficulty passing through membranes and being carried in the blood, until it gets to its target. So a good combination is to increase affinity for hydrophobic sites on a protein target, but to retain reasonable water solubility. Ideally if organic substituents can be introduced that are a little larger, but that do not increase lipophilicity (Log P), relative to Et or CH3, then such organic substituents would be attractive. In this proposal we have identified four motifs that are novel, and posess these polar hydrophobic characteristics. Motifs 1 and 2 are oxygen and sulfur difluoroethyl ethers. We have devised methods to prepare them, and want to explore chemistry for introducing them into a range of building bocks, and medicinal like products. We will also systematically explore their polarity (Log Ps) and their metabolism (how the body may modify them, if at all).Motifs 3 and 4 are cyclopropanes carrying three fluorines. They are polarised as they have two hydrogens (methylene group) with three electronegative fluorine atoms adjacent. In motif 4 there is an additional oxygen atom (also electronegative), polarising this motif further. These motifs are highly novel, but we have demonstrated that they can be readily prepared. The programme will explore their potential utility and properties with a focus on bioactive discovery programmes, and through this programme we would aim to bring them to the attention of the international community in industry and academia. Motif 5 envisages three fluorines, one each on the three carbons of a cyclopropane ring, and with a stereochemistry that has all of the fluorines pointing up. This is claculated to be the most polar of the Motifs under investigation, and would be a special structure of interest to a wide range of scientists beyond bioactives research, including materials chemists and physicists, as it would have highly unusual polar properties.