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High Fidelity Suzuki-Miyaura Coupling for the Synthesis of DNA Encoded Libraries Enabled by Micelle Forming Surfactants.
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-01-06 , DOI: 10.1021/acs.bioconjchem.9b00838
James H Hunter 1 , Lisa Prendergast 2 , Louis F Valente 3 , Andrew Madin 4 , Garry Pairaudeau 4 , Michael J Waring 1
Affiliation  

DNA encoded chemical libraries provide a highly efficient means of screening vast numbers of small molecules against an immobilized protein target. Their potential is currently restricted by the constraints of carrying out library synthesis in the presence of attached DNA tags, for which a limited number of reactions and substrates can be used. Even established reactions, such as Suzuki-Miyaura couplings, do not give efficient coupling reactions across a wide range of substrates and can lead to significant DNA degradation. We developed an efficient protocol for carrying out Suzuki-Miyaura couplings on DNA tagged substrates that proceeds with unprecedented efficiency to the desired biaryl products (>98% on average with no detectable DNA degradation) across a wide range of drug-like substrates using a micellar promoted process with commercial TPGS-750-M surfactant. We have demonstrated the applicability of this method in DEL synthesis by preparing a prototypical two-dimensional 36-member library employing the Suzuki-Miyaura coupling methodology as the final library synthesis step. This work shows, for the first time, that standard micellar surfactants can promote reactions for encoded library synthesis, leading to libraries of exceptional fidelity, and demonstrates the potential to expand the range of accessible DNA compatible chemistry.

中文翻译:


高保真 Suzuki-Miyaura 偶联用于合成由胶束形成表面活性剂实现的 DNA 编码文库。



DNA 编码的化学文库提供了一种针对固定蛋白靶标筛选大量小分子的高效方法。目前,它们的潜力受到在附加 DNA 标签存在的情况下进行文库合成的限制,为此可以使用有限数量的反应和底物。即使是已建立的反应,例如 Suzuki-Miyaura 偶联,也无法在多种底物上产生有效的偶联反应,并且可能导致显着的 DNA 降解。我们开发了一种有效的方案,用于在 DNA 标记的底物上进行 Suzuki-Miyaura 偶联,该方案使用胶束在各种药物样底物上以前所未有的效率获得所需的联芳产品(平均 >98%,没有可检测到的 DNA 降解)使用商业TPGS-750-M表面活性剂促进工艺。我们通过使用 Suzuki-Miyaura 耦合方法作为最终的库合成步骤制备原型二维 36 成员库,证明了该方法在 DEL 合成中的适用性。这项工作首次表明,标准胶束表面活性剂可以促进编码文库合成反应,从而产生具有极高保真度的文库,并展示了扩大可利用的 DNA 相容化学范围的潜力。
更新日期:2020-01-07
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