Expanding the scope of DNA encoded library chemistry using micelles.

DNA编码的化学文库（DEL）正在成为整个制药行业现代命中发现的重要能力。事实上，DEL是一种用于在筛选活动期间识别命中分子的策略，该分子可以导致潜在的候选药物。DEL的合成依赖于在DNA缀合的底物上进行多次转化。因此，每个步骤所采用的条件必须与DNA标签相容。换句话说，反应必须在高稀释度的水性条件下进行，并且必须在广泛的底物范围内取得成功。胶束反应条件的使用正日益成为促进水中具有挑战性的转化的一种手段。特别地，现代胶束形成表面活性剂如TPGS和Nok促进一系列金属催化的转化，如Suzuki偶联、Buchwald- Hartwig胺化和烯烃复分解，并且可以以低成本的简便方式使用。胶束转化的效率来自于在胶束内形成的笼内的有机试剂和底物的局部化，导致在所谓的“纳米反应器”内反应物质的异常高的局部浓度。我们相信，这种方法在进行DEL合成中可能具有很大的实用性，因为胶束可以在基质的有机基质部分周围形成，将反应物质定位到反应位点并保护DNA标签，其将保留在外部水环境中。因此，该项目将扩大可用于使用胶束“纳米反应器”生成DEL的化学范围，这将增加多样性产生反应的效率并保护DNA免于降解。这一概念是基于越来越多的证据表明，胶束条件下提高DEL合成的效率，建立在我们的第一个结果与铃木宫浦交叉耦合。该小组进行的工作表明，使用TPGS-750-M表面活性剂进行DNA偶联导致以前所未有的效率（平均>98%）干净地转化为所需的联芳基产物，而没有可检测到的DNA损伤。我们将在这些结果的基础上扩展可应用于胶束条件的转化范围，重点关注在传统DEL条件下不成功的过程。最初，我们将专注于胶束转化在亲核芳香取代反应（SNAr）中的应用。SNAr程序广泛应用于化合物库合成中，常用于将胺加成到杂环亲电试剂上以产生具有所需性质的产物。据报道，SNAr是药物化学研究和放大过程中引用次数第三多的反应。因此，该项目将产生重大影响，以产生可靠的文库来识别铅样分子。尽管在DEL合成中使用，但SNAr的使用在很大程度上限于高度活化的亲电试剂，如带有吸电子基团的卤代三嗪和嘧啶。活化程度较低的亲电试剂不具有足够的反应性，不能与宽范围的亲核试剂有效地联合收割机结合以在DEL条件下产生大的文库。最近已经表明，胶束条件显着促进一系列的一般SNAr反应在降低的温度下脱DNA。在DNA上开发的方法将被应用于产生用于筛选的文库，并可能识别铅样分子。主题：医疗技术

DNA-encoded chemical libraries (DELs) are becoming established as an important capability in modern hit finding across the pharmaceutical industry. Indeed, a DEL is a strategy used to identify a hit molecule during screening campaigns that can lead to potential drug candidates. Synthesis of DELs relies on carrying out multiple transformations on DNA conjugated substrates. The conditions employed for each step must, therefore, be compatible with the DNA tag. In other words, reactions have to be carried out in aqueous conditions at high dilution and be successful across a wide range of substrates.The use of micellar reaction conditions is increasingly becoming established as a means of promoting challenging transformations in water. In particular, modern micelle-forming surfactants such as TPGS and Nok promote a range of metal catalysed transformations, such as Suzuki couplings, Buchwald- Hartwig aminations and olefin metathesis and can be employed in a facile manner with low cost. The efficiency of micellar transformations arises from the localisation of organic reagents and substrates within the cages formed within the micelles resulting in exceptionally high local concentrations of reacting species within so-called "nanoreactors". We believe that this methodology could be of great utility in carrying out DEL synthesis as micelles could form around the organic substrate portion of the substrate, localising the reactive species to the site of reaction and protecting the DNA tag, which would remain in the external aqueous environment.This project will thus expand the range of chemistry available for generating DELs using micellar "nanoreactors", which will increase the efficiency of diversity generating reactions and protect the DNA from degradation. The concept is based on increasing evidence that micellar conditions enhance the efficiency of DEL synthesis, building on our first results with Suzuki-Miyaura cross couplings. Work conducted within the group has revealed that use of TPGS-750-M surfactant for couplings on DNA led to clean conversions to the desired biaryl products with unprecedented efficiency (>98% on average) with no detectable DNA damage. We will expand on these results to extend the range of transformations that can be applied to micellar conditions, focusing on processes that are unsuccessful under traditional DEL conditions.Initially, we will focus on the application of micellar transformations to Nucleophilic Aromatic Substitution reactions (SNAr). SNAr procedure is used extensively in library synthesis frequently for the addition of amines to heterocyclic electrophiles to produce products with desirable properties. SNAr is reported to be the third most cited reaction both in medicinal chemistry research and scale-up processes. This project will therefore have a significant impact in order to produce reliable libraries to identify lead-like molecules. Despite being employed in DEL synthesis, SNAr use has been largely restricted to highly activated electrophiles such as halotriazines and pyrimidines bearing an electron withdrawing group. Less activated electrophiles are not sufficiently reactive to combine efficiently with the broad range of nucleophiles to produce large libraries under DEL conditions. It has recently been shown that micellar conditions significantly promote a range of general SNAr reactions at reduced temperatures off-DNA. The methodology developed on-DNA will be applied to generate libraries for screening and potentially identify lead-like molecules.Theme: Healthcare Technologies