DNA-encoded library (DEL) technology enables rapid, economical synthesis, and exploration of novel chemical space. Reaction development for DEL synthesis has recently accelerated in pace with a specific emphasis on ensuring that the reaction does not compromise the integrity of the encoding DNA. However, the factors that contribute to a reaction’s “DNA compatibility” remain relatively unknown. We investigated several solid-phase reactions and encoding conditions and determined their impact on DNA compatibility. Conditions that minimized the accessibility of reactive groups on the DNA encoding tag (switching solvent, low temperature, double-stranded encoding tag) significantly improved compatibility. We showcased this approach in the multistep synthesis of an acyldepsipeptide (ADEP1) fragment, which preserved 73% of DNA for a >100-fold improvement over canonical conditions. These results are particularly encouraging in the context of multistep reaction sequences to access natural product-like scaffolds and more broadly underscore the importance of reconciling the biophysical properties and reactivity of DNA with chemistry development to yield high-quality libraries of those scaffolds.

中文翻译：

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在固相 DNA 编码文库合成中实现最大 DNA 回收率的考虑因素。

DNA 编码文库 (DEL) 技术能够快速、经济地合成和探索新的化学空间。DEL 合成的反应开发最近加快了步伐，特别强调确保反应不会损害编码 DNA 的完整性。然而，影响反应“DNA 兼容性”的因素仍然相对未知。我们研究了几种固相反应和编码条件，并确定了它们对 DNA 兼容性的影响。最大限度地减少 DNA 编码标签上反应基团可及性的条件（转换溶剂、低温、双链编码标签）显着提高了兼容性。我们在酰基缩肽 (ADEP1) 片段的多步合成中展示了这种方法，该片段保留了 73% 的 DNA > 比规范条件提高 100 倍。这些结果在获得天然产物样支架的多步反应序列的背景下尤其令人鼓舞，并且更广泛地强调了协调 DNA 的生物物理特性和反应性与化学发展以产生这些支架的高质量文库的重要性。