Dykstra Kevin D, Streckfuss Eric, Liu Min, Liu Jian, Yu Younong, Wang Ming, Kozlowski Joseph A, Myers Robert W, Buevich Alexei V, Maletic Milana M, Vachal Petr, Krska Shane W
Chemical Capabilities for Accelerating Therapeutics, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.
Discovery Chemistry, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
ACS Med Chem Lett. 2021 Feb 8;12(3):337-342. doi: 10.1021/acsmedchemlett.0c00596. eCollection 2021 Mar 11.
An integrated workflow has been established that enables the synthesis, purification, and subsequent biological testing of compound libraries on a microgram scale. This approach utilizes mass directed preparative HPLC in conjunction with charged aerosol detection (CAD) to generate solutions of investigational compounds at high purity and standardized concentrations, facilitating high fidelity biological testing. This new workflow successfully delivered libraries of histone deacetylase (HDAC) inhibitors that afforded biological data consistent with that obtained from standard scale parallel medicinal chemistry techniques. The advantages of this new approach to library synthesis include greatly reduced material requirements and amenability to high-throughput experimentation.
已经建立了一种集成工作流程，能够在微克规模上进行化合物库的合成、纯化及后续生物学测试。该方法利用质量导向的制备型高效液相色谱结合带电气溶胶检测（CAD），以生成高纯度和标准化浓度的研究化合物溶液，便于进行高保真生物学测试。这种新的工作流程成功交付了组蛋白脱乙酰酶（HDAC）抑制剂库，所提供的生物学数据与从标准规模平行药物化学技术获得的数据一致。这种新的库合成方法的优点包括大大降低了材料需求以及适用于高通量实验。
