Hunter James H, Anderson Matthew J, Castan Isaline F S F, Graham Jessica S, Salvini Catherine L A, Stanway-Gordon Harriet A, Crawford James J, Madin Andrew, Pairaudeau Garry, Waring Michael J
Cancer Research UK Newcastle Drug Discovery Unit, Chemistry, School of Natural and Environmental Sciences, Newcastle University Bedson Building Newcastle upon Tyne NE1 7RU UK
Department of Discovery Chemistry, Genentech Inc. 1 DNA Way South San Francisco CA 94080 USA.
Chem Sci. 2021 Jun 22;12(27):9475-9484. doi: 10.1039/d1sc03007h. eCollection 2021 Jul 14.
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.
DNA编码文库（DELs）是寻找蛋白质小分子配体的强大新技术，越来越多地应用于药物化学中的先导化合物发现。高质量DELs合成的关键在于确定其组装的化学反应，该反应在与DNA标记底物兼容的条件下，能在一系列不同底物上以非常高的转化率进行。目前DEL合成中使用的许多化学方法都不符合这一要求，导致文库的保真度较低。酰胺偶联是筛选文库合成以及DELs合成中最常用的反应。因此，在DEL合成中能够进行高效、广泛适用的酰胺偶联将是非常理想的。我们报道了一种使用胶束形成表面活性剂的酰胺偶联方法，该方法由一种修饰的连接子促进，广泛适用于各种底物。最重要的是，这对于溶液中DNA共轭羧酸（N到C）与胺的偶联非常有效，而目前该过程效率很低。描述了通过试剂筛选和统计驱动优化对DNA共轭酸和胺偶联的单独程序进行优化。该方法的通用性通过应用于大量具有前所未有的转化率的实例得到了说明。通过氨基酯的两个偶联循环、中间酯水解，然后用胺封端，对一种完全DNA编码的化合物进行三个循环合成，说明了DNA共轭酸在DEL合成中（N到C）偶联的实用性。这种方法在高保真DELs的合成中将具有很大的实用性。
