An Automated Synthesis Platform to Support Drug Discovery and Reaction Development

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Rapid parallel synthesis, especially in conjunction with screening of chemical fragments (fragment-based drug discovery), is a mainstay of modern medicinal chemistry and allows for rapid production of multiple analogs of a lead or hit structure, in parallel reactions. A single chemist, utilizing validated fragments or intermediates and the automated synthesis platform requested in this RTI application, can prepare dozens or even hundreds of compounds in a matter of days, greatly accelerating the hit-to-lead process. In addition, this technology is ideally suited for the rapid and reproducible optimization of many parameters that are critical to both reaction discovery and development. The research described in this proposal will take advantage of both of these unique capabilities through the discovery and optimization of biologically active small molecules as drug leads or monomers to be used in polymer synthesis, and parallel screening of reaction conditions for optimization purposes. Importantly, these efforts will complement our existing strengths in high-throughput screening in the Center for High-Throughput Chemical Biology located in the Faculty of Science at SFU by creating new opportunities for the synthesis of structurally diverse chemical libraries, rapid lead optimization and natural product diversification. Presently, we only have the capacity to make small compound collections one-at-a-time using standard laboratory equipment, which has significantly limited our ability to capitalize on new discoveries of lead candidates, validated therapeutic targets, and new polymeric materials. The requested equipment would allow HQP to synthesize, in parallel, libraries of up to 96 compounds at a time, perform reaction work up, and crude purifications with minimal user input. There is no similar or related equipment at SFU, and a further delay in acquiring the automated synthesis platform would significantly impact our ability to translate expertise in chemical screening and synthesis into practical advances in medicine and materials.