Diversified strategy for the synthesis of DNA-encoded oxindole libraries.
Diversified strategy for the synthesis of DNA-encoded oxindole libraries.
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DNA编码的羟吲哚文库合成的多样化策略
DOI：
10.1039/d0sc06696f
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发表时间：
2021-01-04
期刊：
影响因子：
8.4
通讯作者：
Lu X
中科院分区：
文献类型：
--
作者：
Wang X;Liu J;Yan Z;Liu X;Liu S;Suo Y;Lu W;Yue J;Chen K;Jiang H;Zhao Y;Zheng M;Dai D;Lu X
DNA编码文库技术(DELT)使用DNA作为条形码来跟踪化学反应的顺序，并通过组合扩展来设计和合成具有数十亿个小分子的文库。这一强大的技术平台已成功用于多种疾病的命中识别和靶标验证。作为一个高度集成的技术平台，DEL能够通过使用DNA上兼容的反应或DNA外支架合成来加速合成化学的翻译。在这里，我们报道了一系列基于氧化吲哚支架的新型DNA转化的开发，用于设计和合成面向多样性的DNA编码库，用于筛选。具体地说，我们开发了1，3-偶极环化、环丙化、氮杂环丙烷开环反应和Claisen-Schmidt缩合反应，以合成不同的氧化吲哚衍生物。这些转化中的大多数能够以多样性为导向合成DNA编码的氧化吲哚文库，该文库已用于三个蛋白质靶标的成功鉴定。我们已经证明，多元化的DEL合成策略可以加速合成化学在药物发现中的应用。采用多元化策略构建DNA编码的氧化吲哚文库。
DNA-encoded library technology (DELT) employs DNA as a barcode to track the sequence of chemical reactions and enables the design and synthesis of libraries with billions of small molecules through combinatorial expansion. This powerful technology platform has been successfully demonstrated for hit identification and target validation for many types of diseases. As a highly integrated technology platform, DEL is capable of accelerating the translation of synthetic chemistry by using on-DNA compatible reactions or off-DNA scaffold synthesis. Herein, we report the development of a series of novel on-DNA transformations based on oxindole scaffolds for the design and synthesis of diversity-oriented DNA-encoded libraries for screening. Specifically, we have developed 1,3-dipolar cyclizations, cyclopropanations, ring-opening of reactions of aziridines and Claisen–Schmidt condensations to construct diverse oxindole derivatives. The majority of these transformations enable a diversity-oriented synthesis of DNA-encoded oxindole libraries which have been used in the successful hit identification for three protein targets. We have demonstrated that a diversified strategy for DEL synthesis could accelerate the application of synthetic chemistry for drug discovery. Constructing DNA-encoded oxindole libraries by a diversified strategy.
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