An Amphiphilic Polymer-Supported Strategy Enables Chemical Transformations under Anhydrous Conditions for DNA-Encoded Library Synthesis
An Amphiphilic Polymer-Supported Strategy Enables Chemical Transformations under Anhydrous Conditions for DNA-Encoded Library Synthesis
复制标题
DOI：
10.1021/acscombsci.9b00164
复制
发表时间：
2020-03-01
影响因子：
--
通讯作者：
Berst, Frederic
中科院分区：
文献类型：
--
作者：
Ruff, Yves;Martinez, Roberto;Berst, Frederic
DNA编码库的使用已经成为一种强大的命中生成技术。结合组合化学的力量，以枚举大型化合物集合与池中的亲和选择的效率，该方法使得有可能针对药物相关性的生物靶标询问巨大的化学空间。因此，用于合成编码文库的化学转化在鉴定多样性和药物样起始点中起着至关重要的作用。目前建立的转化大多限于水相容性反应，以适应不断增长的寡核苷酸标签。在此，我们描述了一个实用的捕捉和释放方法的发展，利用阳离子，两亲性PEG为基础的聚合物，在无水条件下进行化学转化固定的DNA共轭物。我们证明了我们的APTAC的实用性通过在纯有机溶剂中对DNA缀合的小分子进行几种具有挑战性的转化（在无水条件下两亲聚合物促进的转化）方法：在四氢呋喃中加入与DNA共轭酮相当的碳负离子，在二氯甲烷中使用锡（Sn）胺方案（SnAP）合成饱和杂环，和双催化（Ir/Ni）金属光氧化还原脱羧交叉偶联的羧酸DNA共轭芳基卤化物在DMSO中。此外，我们证明了后者在多滴定板格式的可行性。
The use of DNA-encoded libraries has emerged as a powerful hit generation technology. Combining the power of combinatorial chemistry to enumerate large compound collections with the efficiency of affinity selection in pools, the methodology makes it possible to interrogate vast chemical space against biological targets of pharmaceutical relevance. Thus, the chemical transformations employed for the synthesis of encoded libraries play a crucial role in the identification of diverse and drug-like starting points. Currently established transformations have mostly been limited to water-compatible reactions to accommodate the growing oligonucleotide tag. Herein, we describe the development of a practical catch-and-release methodology utilizing a cationic, amphiphilic PEG-based polymer to perform chemical transformations on immobilized DNA conjugates under anhydrous conditions. We demonstrate the usefulness of our APTAC (amphiphilic polymer-facilitated transformations under anhydrous conditions) approach by performing several challenging transformations on DNA-conjugated small molecules in pure organic solvents: the addition of a carbanion equivalent to a DNA-conjugated ketone in tetrahydrofuran, the synthesis of saturated heterocycles using the tin (Sn) amine protocol (SnAP) in dichloromethane, and the dual-catalytic (Ir/Ni) metallaphotoredox decarboxylative crosscoupling of carboxylic acids to DNA-conjugated aryl halides in DMSO. In addition, we demonstrate the feasibility of the latter in multititer-plate format.