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首页> 外文期刊>Bioconjugate Chemistry >Systematic Evaluation and Optimization of Modification Reactions of Oligonucleotides with Amines and Carboxylic Acids for the Synthesis of DNA-Encoded Chemical Libraries
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Systematic Evaluation and Optimization of Modification Reactions of Oligonucleotides with Amines and Carboxylic Acids for the Synthesis of DNA-Encoded Chemical Libraries

机译：用于合成DNA编码化学文库的寡核苷酸与胺和羧酸的修饰反应的系统评价和优化

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摘要

DNA-encoded chemical libraries are collections of small molecules, attached to DNA fragments serving as identification barcodes, which can be screened against multiple protein targets, thus facilitating the drug discovery process. The preparation of large DNA-encoded chemical libraries crucially depends on the availability of robust synthetic methods, which enable the efficient conjugation to oligonucleotides of structurally diverse building blocks, sharing a common reactive group. Reactions of DNA derivatives with amines and/or carboxylic acids are particularly attractive for the synthesis of encoded libraries, in view of the very large number of building blocks that are commercially available. However, systematic studies on these reactions in the presence of DNA have not been reported so far. We first investigated conditions for the coupling of primary amines to oligonucleotides, using either a nucleophilic attack on chloroacetamide derivatives or a reductive animation on aldehyde-modified DNA. While both methods could be used for the production of secondary amines, the reductive animation approach was generally associated with higher yields and better purity. In a second endeavor, we optimized conditions for the coupling of a diverse set of 501 carboxylic acids to DNA derivatives, carrying primary and secondary amine functions. The coupling efficiency was generally higher for primary amines, compared to secondary amine substituents, but varied considerably depending on the structure of the acids and on the synthetic methods used. Optimal reaction conditions could be found for certain sets of compounds (with conversions >80%), but multiple reaction schemes are needed when assembling large libraries with highly diverse building blocks. The reactions and experimental conditions presented in this article should facilitate the synthesis of future DNA-encoded chemical libraries, while outlining the synthetic challenges that remain to be overcome.
机译：DNA编码的化学文库是小分子的集合，这些分子附着在用作识别条形码的DNA片段上，可以针对多种蛋白质靶点进行筛选，从而促进了药物发现过程。大型DNA编码的化学文库的制备至关重要地取决于可靠的合成方法的可用性，该方法能够与具有共同反应性基团的结构多样的构建基团的寡核苷酸有效缀合。考虑到市售的大量结构单元，DNA衍生物与胺和/或羧酸的反应对于合成编码的文库特别有吸引力。然而，迄今为止，尚未报道在DNA存在下对这些反应的系统研究。我们首先研究了对氯乙酰胺衍生物的亲核攻击或对醛修饰的DNA的还原反应，从而将伯胺与寡核苷酸偶联的条件。虽然两种方法都可用于生产仲胺，但还原动画方法通常具有更高的收率和更好的纯度。在第二个工作中，我们优化了将各种501羧酸与具有伯胺和仲胺功能的DNA衍生物偶联的条件。与仲胺取代基相比，伯胺的偶联效率通常更高，但取决于酸的结构和所用的合成方法而有很大不同。可以找到某些化合物的最佳反应条件（转化率> 80％），但是在组装具有高度不同结构模块的大型文库时，需要多种反应方案。本文介绍的反应和实验条件应有助于未来DNA编码化学文库的合成，同时概述了仍有待克服的合成难题。

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