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

描述（由申请人提供）：分子探针、成像剂、生物材料和治疗性先导化合物的合成总是涉及迭代、多步化学合成。因此，从事小分子发现的研究机构每年制备数千至数万种化合物。化合物纯化的速度几乎总是决定了在生物学背景下评价目标化合物的总体速度。为了解决西北大学（NU）的这一严重瓶颈，我们要求资金购买最先进的高通量（HT）液相色谱（LC）系统。有了这个独特的仪器，我们将提供一个工作人员支持的开放式HT系统，广泛用于有机，医药，生物有机和生物材料纯化。该集成系统将分析-制备（A2 Prep）色谱组件与弹性光散射、二极管阵列紫外-可见光和质谱检测器相结合。相关的机器人提供样品制备/重新格式化、自动取样和馏分收集。安捷伦科技公司将提供整个系统，与一个重要的硬件组件的机器人正在提供给他们的LEAP技术。该系统将被安置在新的理查德和芭芭拉西尔弗曼大厅，在合成和分子医学中心（CESAMM），在NU的生命过程化学研究所（CLPI）。该仪器将提供给埃文斯顿和芝加哥市中心医学院的用户，并将由内部咨询委员会监督，该委员会由研究者和三名主要合作研究者、生物学院和未成年人用户的代表、CLPI和NU药物发现和化学生物学中心的主任组成。当然，还将参与负责A2 Prep系统的技术和日常监督的人员，CESAMM，NU发展HT化学中心和NU综合分子结构教育和研究中心（IMSERC）的主任，在那里进行相关的分析实验，包括广泛的LC-MS。该仪器将为一系列重大NU项目提供新的方向，例如与癫痫和中风有关的药物发现，基于金属的成像造影剂和治疗方法的设计，基于新型化学转化的复杂新型抗癌天然产物的合成，以及阿尔茨海默病和相关神经退行性疾病的新治疗方法。这些和其他重要研究领域的进展都受到当前化合物纯化速度的严重限制。对A2 Prep仪器系统的资助将使研究人员能够将注意力集中在他们生物医学研究工作的真正目标上：更好的分子概念和设计，因为我们寻求在分子医学中制备越来越有效的诊断和治疗药物。 公共卫生相关性：用于测试生物驱动的假说以诊断和治疗疾病的分子的制备涉及化学合成的多步路线。这个过程很像一条装配线：每个中间化合物必须在进入下一个操作之前进行纯化，最终产生用于测试的目标分子。由于西北大学每年生产数千种中间化合物，因此纯化步骤是一项关键且劳动密集型的研究任务。化合物纯化带来的挑战包括大量的研究时间投资，从而严重限制了新发现的速度。为西北大学生物医学研究界收购专门的纯化系统将大大增强现有NIH资助项目的影响，并为需要大量纯化化合物的新分子重点项目提供燃料。最重要的是，它将使研究人员能够减少繁琐的纯化，更多地关注日益有效的诊断和治疗药物的设计。

DESCRIPTION (provided by applicant): 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.