Potowski Marco, Losch Florian, Wünnemann Elena, Dahmen Janina K, Chines Silvia, Brunschweiger Andreas
Department of Chemistry and Chemical Biology , TU Dortmund University , Otto-Hahn-Str. 6 , 44227 Dortmund , Germany . Email:
Chem Sci. 2019 Nov 1;10(45):10481-10492. doi: 10.1039/c9sc04708e. eCollection 2019 Dec 7.
DNA-encoded compound libraries are a widely used technology for target-based small molecule screening. Generally, these libraries are synthesized by solution phase combinatorial chemistry requiring aqueous solvent mixtures and reactions that are orthogonal to DNA reactivity. Initiating library synthesis with readily available controlled pore glass-coupled DNA barcodes benefits from enhanced DNA stability due to nucleobase protection and choice of dry organic solvents for encoded compound synthesis. We screened the compatibility of solid-phase coupled DNA sequences with 53 metal salts and organic reagents. This screening experiment suggests design of encoded library synthesis. Here, we show the reaction optimization and scope of three sp-bond containing heterocyclic scaffolds synthesized on controlled pore glass-connected DNA sequences. A ZnCl-promoted aza-Diels-Alder reaction with Danishefsky's diene furnished diverse substituted DNA-tagged pyridones, and a phosphoric acid organocatalyst allowed for synthesis of tetrahydroquinolines by the Povarov reaction and pyrimidinones by the Biginelli reaction, respectively. These three reactions caused low levels of DNA depurination and cover broad and only partially overlapping chemical space though using one set of DNA-coupled starting materials.
DNA编码化合物库是一种广泛应用于基于靶点的小分子筛选的技术。一般来说，这些文库是通过溶液相组合化学合成的，需要水相溶剂混合物以及与DNA反应性正交的反应。使用易于获得的可控孔径玻璃偶联DNA条形码启动文库合成，由于碱基保护和选择用于编码化合物合成的干燥有机溶剂，DNA稳定性增强。我们筛选了固相偶联DNA序列与53种金属盐和有机试剂的兼容性。该筛选实验为编码文库合成的设计提供了思路。在此，我们展示了在可控孔径玻璃连接的DNA序列上合成的三种含sp键的杂环支架的反应优化和范围。ZnCl促进的与达尼谢夫斯基二烯的氮杂狄尔斯-阿尔德反应生成了多种取代的DNA标记吡啶酮，磷酸有机催化剂分别通过Povarov反应合成了四氢喹啉，通过Biginelli反应合成了嘧啶酮。这三个反应导致的DNA脱嘌呤水平较低，并且尽管使用一组DNA偶联的起始原料，但覆盖了广泛且仅部分重叠的化学空间。
