Liquid Chromatography System with Mass-Based Analysis and Purification to Support Departmental Reaction Optimization and Medicinal Chemistry Programs

随着药物、杀虫剂、聚合物和食品添加剂等的发现，有机化学是一门强大的科学，在过去的一个世纪里，它帮助我们现代社会的预期寿命和生活水平大幅提高。新药和商品化学品的发现依赖于新反应和新化合物的持续输入，以测试所需的应用。在药物发现领域，必须反复设计、合成、纯化和测试许多化合物，直到确定具有所有所需有益特性的最佳分子。两个共同申请者的研究实验室都与医学院的合作者积极参与了一些重点药物发现项目，以及其他早期项目，旨在开发新的化学型和生产具有药用价值的小分子的新方法。高效液相色谱联用质谱检测（LCMS）的质量基纯化技术在这些项目的各个阶段都是必不可少的，例如纯化用于生物测试的少量化合物，进行分析前或分析后的质量控制，甚至评估铅化合物在不同介质和储存条件下的稳定性。我们目前的部门LCMS仪器是一个主要系统，于2004年购买，经常昼夜使用（带有程序注射），平均每周使用30小时。该系统比当前的模型落后好几代，并且不再被供应商支持。它正在迅速恶化，危及依赖这一宝贵技术的许多药物发现项目和其他活动的进展。因此，本RTI申请描述了一项建议，以获得配备质量分析和半制备纯化的现代HPLC-ESMS系统，以支持共同申请人实验室的日常有机合成活动及其众多药物化学合作，特别是在肿瘤学研究中。该系统将成为部门分析和仪器实验室中化合物净化和分析服务设施的关键组成部分，该实验室也支持美国大学化学系的其他项目。它将在反应优化、分析和纯化的各个方面支持应用药物化学项目和其他合成方法学开发项目。对所要求的仪器的迫切需求是由最近在当前过时的仪器上的自动进样器的故障清楚地说明的，该故障被原供应商认为无法使用。一个新的工具将立即支持和改善超过25名HQP在共同申请人和其他研究小组的培训环境。此外，它将由一名经验丰富的全职技术人员在专门的部门设施内管理和维护。

With discoveries like drugs, insecticides, polymers, and food additives, organic chemistry is a powerful science that has helped our modern society enjoy a dramatic increase in life expectancy and standard of living in the past century. The discovery of new drugs and commodity chemicals rely on a continuous input of new reactions and new compounds to be tested for the desired applications. In the field of drug discovery, numerous compounds must be designed, synthesized, purified and tested iteratively until an optimal molecules is identified that possesses all of the desired beneficial properties. Research laboratories of both co-applicants are actively involved in a number of focused drug discovery projects with collaborators in the Faculty of Medicine, as well as other early-stage projects aimed at developing new chemotypes and new methods to produce small molecules of medicinal interest. The technology of high-performance liquid chromatography coupled with mass spectrometric detection (LCMS) with mass-based purification is essential in various stages of these projects, for example to purify small amounts of compounds for biological testing, to perform pre- or post-assay quality control, or even to assess the stability of lead compounds under different media and storage conditions. Our current departmental LCMS instrument is a workhorse system, purchased in 2004, that is often utilized day and night (with programmed injections) for an average of 30 hours/week. This system is several generations behind current models, and is no longer supported by the vendor. It is deteriorating rapidly, which jeopardizes the progress of numerous drug discovery projects and other activities that rely on this invaluable technology. Thus, this RTI application describes a proposal to acquire a modern HPLC-ESMS system equipped with mass-based analysis and semi-preparative purification to support the daily organic synthesis activities of the co-applicants' laboratories and their numerous medicinal chemistry collaborations, particularly in oncology research. The system will be a key component of a compound purification and analysis service facility within a departmental Analytical and Instrumentation Laboratory, which also supports other programs in the U of A Department of Chemistry. It will support applied medicinal chemistry projects and other synthetic methodology development projects in all aspects of reaction optimization, analysis, and purification. The urgent need for the requested instrument is acutely illustrated by the very recent failure of the autosampler on the current obsolete instrument, which was deemed unserviceable by the original vendor. A new instrument would immediately support and enhance the training environment of over 25 HQP in the research groups of the co-applicants and others. Moreover, it would be managed and maintained, by a full-time, highly experience technologist within a dedicated departmental facility.