Chemical Biology and Therapeutics Science Program, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States.
Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
J Am Chem Soc. 2020 Apr 29;142(17):7776-7782. doi: 10.1021/jacs.9b13186. Epub 2020 Apr 16.
DNA-encoded libraries of small molecules are being explored extensively for the identification of binders in early drug-discovery efforts. Combinatorial syntheses of such libraries require water- and DNA-compatible reactions, and the paucity of these reactions currently limit the chemical features of resulting barcoded products. The present work introduces strain-promoted cycloadditions of cyclic allenes under mild conditions to DNA-encoded library synthesis. Owing to distinct cycloaddition modes of these reactive intermediates with activated olefins, 1,3-dipoles, and dienes, the process generates diverse molecular architectures from a single precursor. The resulting DNA-barcoded compounds exhibit unprecedented ring and topographic features, related to elements found to be powerful in phenotypic screening.
小分子 DNA 编码文库正在被广泛探索，以鉴定早期药物发现工作中的配体。这些文库的组合合成需要水相和 DNA 相容的反应，而目前这些反应的缺乏限制了编码产物的化学特征。本工作在温和条件下引入环状丙二烯的应变促进环加成反应，用于 DNA 编码文库的合成。由于这些反应中间体与活化烯烃、1,3-偶极子和二烯具有独特的环加成模式，该过程可以从单个前体生成多种分子结构。得到的 DNA 编码化合物具有前所未有的环和地形特征，与表型筛选中发现的有力元素有关。
