An Automated Synthesis Platform to Support Drug Discovery and Reaction Development

快速平行合成，特别是与化学片段的筛选（基于片段的药物发现）结合，是现代药物化学的支柱，并且允许在平行反应中快速产生先导或命中结构的多种类似物。一个化学家，利用验证的片段或中间体和自动化合成平台在这个RTI应用程序中要求，可以在几天内制备几十个甚至几百个化合物，大大加快了命中到铅的过程。此外，该技术非常适合对反应发现和开发至关重要的许多参数进行快速和可重现的优化。本提案中描述的研究将通过发现和优化生物活性小分子作为药物先导或用于聚合物合成的单体，以及平行筛选反应条件以优化目的，利用这两种独特的能力。重要的是，这些努力将补充我们在位于SFU科学学院的高通量化学生物学中心的高通量筛选方面的现有优势，为合成结构多样的化学库，快速铅优化和天然产物多样化创造新的机会。目前，我们只能使用标准实验室设备一次一个地进行小规模的化合物收集，这大大限制了我们利用新发现的主要候选物、经验证的治疗靶点和新聚合物材料的能力。所要求的设备将使HQP能够同时合成多达96种化合物的库，进行反应后处理，并以最少的用户输入进行粗纯化。SFU没有类似或相关的设备，进一步延迟获取自动化合成平台将严重影响我们将化学筛选和合成方面的专业知识转化为医学和材料实际进步的能力。

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.