An Integrated Open-Access HT Preparative Chromatography System for Molecular Medi

Scheidt, Karl

Abstract

The synthesis of molecular probes, imaging agents, biomaterials, and therapeutic lead compounds always involves iterative, multi-step chemical synthesis. Consequently, research institutions engaged in small molecule discovery prepare thousands to tens of thousands of compounds each year. The pace of compound purification almost always determines the overall pace at which target compounds are evaluated in biological contexts. To address this serious bottleneck at Northwestern University (NU), we request funds to purchase a state-of-the-art high throughput (HT) liquid chromatography (LC) system. With this unique instrument, we will provide a staff-supported open-access HT system broadly useful for organic, medicinal, bioorganic, and biomaterials purifications. The integrated system combines analytical-to-preparative (A2Prep) chromatography components with elastic light scattering, diode array ultraviolet-visible, and mass spectrometry detectors. Associated robotics provide for sample preparation/ reformatting, auto sampling, and fraction collection. Agilent Technologies will provide the overall system, with a significant hardware component for the robotics being supplied to them by LEAP Technologies. The Agilent-LEAP A2Prep system will be housed in the new Richard and Barbara Silverman Hall, in the Center for Synthesis and Molecular Medicine (CESAMM), in NU's Chemistry of Life Processes Institute (CLPI). The instrument will be available to users on both the Evanston and downtown Chicago medical campuses and will be overseen by a Internal Advisory Committee composed of the investigator and three major Co-Investigators, representatives of the biology faculty and of minor users, the Directors of the CLPI and of the NU Center for Drug Discovery and Chemical Biology. Also participating ex officio will be those responsible for the technical and daily oversight of the A2Prep system, the Directors of CESAMM, NU's developing HT chemistry center, and of NU's Integrated Molecular Structure Education and Research Center (IMSERC), where related analytical experiments, including extensive LC-MS, are performed. This instrument will fuel new directions with a wide array of major NU projects such as the drug discovery relating to epilepsy and stroke, the design of metal-based imaging contrast agents and therapeutics, the synthesis of complex new anticancer natural products based on novel chemical transformations, and new treatments for Alzheimer's disease and related neurodegenerative conditions. Progress is each of these and in other important research areas is seriously limited by the current pace of compound purification. Funding for the A2Prep instrument system will allow researchers to return their focus to the true goal of their biomedical research efforts: better concepts and designs for molecules, as we seek to prepare increasingly effective diagnostic and therapeutic agents in molecular medicine.

Public Health Relevance

The preparation of molecules to test biologically driven hypotheses to diagnose and treat diseases involves multi-step routes of chemical synthesis. This process is much like an assembly line: each intermediate compound must be purified before moving on to the next operation, eventually producing the target molecule for testing. With the many thousands of intermediate compounds produced each year at Northwestern, this purification step is a critical and labor-intensive research task. The challenges posed by compound purifications include a substantial investment of research time, thus critically curtailing the pace at which new discoveries can be made. The acquisition of a specialized purification system for the Northwestern University biomedical research community will greatly enhance the impact of existing NIH-funded projects, and fuel new molecule-focused programs that require large numbers of purified compounds. Most importantly, it will allow researchers to focus less on tedious purification and more on the design of increasingly effective diagnostic and therapeutic agents.