Karlsruhe Institute of Technology (KIT), Institute of Toxicology and Genetics, Hermann-von Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany.
Karlsruhe Institute of Technology (KIT), Institute of Functional Interfaces, Hermann-von Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany.
Small. 2020 Mar;16(10):e1905971. doi: 10.1002/smll.201905971. Epub 2020 Jan 27.
Miniaturization and parallelization of combinatorial organic synthesis is important to accelerate the process of drug discovery while reducing the consumption of reagents and solvents. This work presents a miniaturized platform for on-chip solid-phase combinatorial library synthesis with UV-triggered on-chip cell screening. The platform is based on a nanoporous polymer coating on a glass slide, which is modified via photolithography to yield arrays of hydrophilic (HL) spots surrounded by superhydrophobic (SH) surface. The combination of HL spots and SH background enables confinement of nanoliter droplets, functioning as miniaturized reactors for the solid-phase synthesis. The polymer serves as support for nanomolar solid-phase synthesis, while a photocleavable linker enables the release of the synthesized compounds into the droplets containing live cells. A 588 compound library of bisamides is synthesized via a four-component Ugi reaction on the chip and products are detected via stamping of the droplet array onto a conductive substrate and subsequent matrix-assisted laser desorption ionization mass spectrometry. The light-induced cleavage shows high flexibility in screening conditions by spatial, temporal, and quantitative control.
组合有机合成的小型化和并行化对于加速药物发现过程同时减少试剂和溶剂的消耗非常重要。本工作提出了一种用于芯片上固相组合文库合成的小型化平台，该平台采用 UV 触发的芯片细胞筛选。该平台基于玻璃载玻片上的纳米多孔聚合物涂层，通过光刻修饰得到亲水区（HL）斑点阵列，周围是超疏水（SH）表面。HL 斑点和 SH 背景的结合可以限制纳升级液滴，作为用于固相合成的微型反应器。聚合物用作纳米摩尔固相合成的支撑，而光裂解连接子可将合成的化合物释放到含有活细胞的液滴中。通过在芯片上进行四组分 Ugi 反应合成了 588 个双酰胺化合物库，并通过将液滴阵列冲压到导电衬底上并随后进行基质辅助激光解吸电离质谱法进行产物检测。光诱导裂解通过空间、时间和定量控制在筛选条件方面具有很高的灵活性。
