Synthesis of HDAC Inhibitor Libraries via Microscale Workflow
Kevin D. Dykstra, Eric Streckfuss, Min Liu, Jian Liu, Younong Yu, Ming Wang, Joseph A. Kozlowski, Robert W. Myers, Alexei V. Buevich, Milana Maletic, Petr Váchal, Shane W. Krska
Abstract
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.