DNA Compatible Multistep Synthesis and Applications to DNA Encoded Libraries
DNA Compatible Multistep Synthesis and Applications to DNA Encoded Libraries
复制标题
DOI：
10.1021/acs.bioconjchem.5b00239
复制
发表时间：
2015-08-01
影响因子：
4.7
通讯作者：
Strebel, Quentin
中科院分区：
文献类型：
--
作者：
Satz, Alexander Lee;Cai, Jianping;Strebel, Quentin
DNA 编码的小分子的复杂混合物可以通过高通量测序轻松分析。这些 DNA 编码文库 (DEL) 通常用于发现与药物相关蛋白质相互作用的分子。该文库所展示的化学多样性是成功发现有效、新颖和类药物化学物质的关键。 DEL 的小分子部分通常通过多步骤过程合成，并且每个化学步骤都是在它同时附着到编码 DNA 寡聚物上的同时完成的。因此，文库化学多样性通常仅限于 DNA 兼容的合成反应。本文提供了 24 个反应的方案，这些方案已针对 DEL 的高通量生产进行了优化。这些方案详细介绍了苯并咪唑、咪唑啉酮、喹唑啉酮、异吲哚啉酮、噻唑和咪唑并吡啶的多步合成。此外，还提供了各种有用的化学反应的方案，包括 BOC 脱保护（在 pH 中性条件下）、氨甲酰化和 Sonogashira 偶联。最后，详细介绍了从三氯硝基嘧啶和三氯嘧啶支架合成功能化 DEL 的分步方案。
Complex mixtures of DNA encoded small molecules may be readily interrogated via high-throughput sequencing. These DNA encoded libraries (DELs) are commonly used to discover molecules that interact with pharmaceutically relevant proteins. The chemical diversity displayed by the library is key to successful discovery of potent, novel, and drug-like chemical matter. The small molecule moieties of DELs are generally synthesized though a multistep process, and each chemical step is accomplished while it is simultaneously attached to an encoding DNA oligomer. Hence, library chemical diversity is often limited to DNA compatible synthetic reactions. Herein, protocols for 24 reactions are provided that have been optimized for high-throughput production of DELs. These protocols detail the multistep synthesis of benzimidazoles, imidazolidinones, quinazolinones, isoindolinones, thiazoles, and imidazopyridines. Additionally, protocols are provided for a diverse range of useful chemical reactions including BOC deprotection (under pH neutral conditions), carbamylation, and Sonogashira coupling. Last, step-by-step protocols for synthesizing functionalized DELs from trichloronitropyrimidine and trichloropyrimidine scaffolds are detailed.