Highly efficient on-DNA amide couplings promoted by micelle forming surfactants for the synthesis of DNA encoded libraries.
Highly efficient on-DNA amide couplings promoted by micelle forming surfactants for the synthesis of DNA encoded libraries.
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DOI：
10.1039/d1sc03007h
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发表时间：
2021-07-14
期刊：
影响因子：
8.4
通讯作者：
Waring MJ
中科院分区：
文献类型：
--
作者：
Hunter JH;Anderson MJ;Castan IFSF;Graham JS;Salvini CLA;Stanway-Gordon HA;Crawford JJ;Madin A;Pairaudeau G;Waring MJ
DNA 编码文库 (DEL) 代表了寻找蛋白质小分子配体的强大新技术，并且越来越多地应用于药物化学中的命中发现。合成高质量 DEL 的关键是识别其组装的化学反应，在与 DNA 标记底物兼容的条件下，在一系列不同的底物上进行非常高的转化。当前 DEL 合成中使用的许多化学物质不满足这一要求，导致文库保真度低。酰胺偶联是筛选文库合成和 DEL 中最常用的反应。因此，非常需要在 DEL 合成中进行高效、广泛适用的酰胺偶联的能力。我们报告了一种使用胶束形成表面活性剂进行酰胺偶联的方法，该方法由修饰的连接体促进，广泛适用于各种底物。最重要的是，这对于 DNA 缀合的羧酸（N-to-C）与溶液中的胺的偶联效果非常好，但目前这一过程效率非常低。描述了通过试剂筛选和统计驱动优化来优化 DNA 缀合酸和胺偶联的单独程序。通过对具有前所未有的转换水平的广泛示例的应用，说明了该方法的通用性。 DNA 缀合酸（N-to-C）偶联在 DEL 合成中的实用性通过完全 DNA 编码化合物的三循环合成（通过氨基酯偶联的两个循环、中间酯水解、然后用胺封端）来说明。该方法对于高保真 DEL 的合成非常有用。利用疏水性接头与胶束形成表面活性剂 TPGS-750M 相结合，开发了高效的正向和反向 DNA 酰胺偶联。该方法对于 DNA 编码文库合成中的多种底物都非常有效。
DNA encoded libraries (DELs) represent powerful new technology for finding small molecule ligands for proteins and are increasingly being applied to hit finding in medicinal chemistry. Crucial to the synthesis of high quality DELs is the identification of chemical reactions for their assembly that proceed with very high conversion across a range of different substrates, under conditions compatible with DNA-tagged substrates. Many current chemistries used in DEL synthesis do not meet this requirement, resulting in libraries of low fidelity. Amide couplings are the most commonly used reaction in synthesis of screening libraries and also in DELs. The ability to carry out highly efficient, widely applicable amide couplings in DEL synthesis would therefore be highly desirable. We report a method for amide coupling using micelle forming surfactants, promoted by a modified linker, that is broadly applicable across a wide range of substrates. Most significantly, this works exceptionally well for coupling of DNA-conjugated carboxylic acids (N-to-C) with amines in solution, a procedure that is currently very inefficient. The optimisation of separate procedures for coupling of DNA-conjugated acids and amines by reagent screening and statistically driven optimisation is described. The generality of the method is illustrated by the application to a wide range of examples with unprecedented levels of conversion. The utility of the (N-to-C) coupling of DNA-conjugated acids in DEL synthesis is illustrated by the three cycle synthesis of a fully DNA-encoded compound by two cycles of coupling of an aminoester, with intermediate ester hydrolysis, followed by capping with an amine. This methodology will be of great utility in the synthesis of high fidelity DELs. Highly efficient forward and reverse on-DNA amide couplings were developed exploiting hydrophobic linkers in combination with the micelle forming surfactant TPGS-750M. The method is highly effective for a wide range of substrates in the synthesis of DNA-encoded libraries.
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影响因子：
3.6
作者：
Lipshutz, Bruce H.;Ghorai, Subir;Abela, Alexander R.;Moser, Ralph;Nishikata, Takashi;Duplais, Christophe;Krasovskiy, Arkady;Gaston, Ricky D.;Gadwood, Robert C.
通讯作者：
Gadwood, Robert C.
影响因子：
3.2
作者：
Belyanskaya, Svetlana L.;Ding, Yun;Israel, David I.
通讯作者：
Israel, David I.
影响因子：
3.5
作者：
Favalli, Nicholas;Bassi, Gabriele;Neri, Dario
通讯作者：
Neri, Dario
影响因子：
7.3
作者：
Brow, Dean G.;Bostrom, Jonas
通讯作者：
Bostrom, Jonas
影响因子：
2.3
作者：
Lipshutz, Bruce H.
通讯作者：
Lipshutz, Bruce H.