Chiral Ion Mobility Spectrometry for Rapid Separation of Enantiomeric Compounds

描述（由申请人提供）：蛋白质组装、药物相互作用和底物识别是依赖于分子手性方向的几种重要生理相互作用。初步结果清楚地表明，通过用手性分子修饰漂移气体，离子迁移谱可以提供一种新颖的和快速的手性化合物分离技术。与手性色谱和毛细管电泳类似，手性离子迁移谱检测对映体混合物的能力是基于分析物与中性手性改性剂的相互作用。本研究的最终目标是开发和商业化快速手性分离和表征仪器：电喷雾电离-手性离子迁移谱-质谱仪（ESI-CIMS-MS）。所提出的系统不仅可以在毫秒内分离手性分子，而且可以将方法开发时间缩短到几分钟。ESI-CIMS-MS的快速分离和简单的方法开发使其成为许多应用的首选方法分析时间是一个关键的考虑因素。所提出的系统可用于直接测量药物产品中的手性成分的对映体过量，可用于增加药物发现中的手性测量的吞吐量，当数百种药物化合物被筛选为候选药物时，可用于监测制备性手性分离过程的性能，或可用作色谱系统的手性选择性检测器。第一阶段的研究重点是生物活性的手性化合物与拟议的系统的表征。广泛的挥发性手性分子将作为CIMS的手性改性剂进行测试。本研究旨在探索最佳的仪器条件，以实现最大的手性分离，以证明不同类别的生物活性的手性化合物与有效的手性修饰剂的分离，探索利用手性修饰剂与对映体离子之间的多种气相相互作用力来提高手性拆分的可能性，分析和比较CIMS和色谱系统的手性分离特性，并探索定量测定对映体过量的可能性。作为一个长期的目标，使用已知的手性修饰剂确定分析物手性的可能性也将被检查。在第一阶段研究中学到的CIMS的基本知识将用于设计和制造第二阶段的ESI-CIMS-MS系统，该系统将被商业化以支持广泛的生物医学研究。 提出的手性离子迁移谱仪-质谱仪，在几秒钟内分离和鉴定手性化合物，可以潜在地取代手性色谱，因为手性分析时间是一个关键的考虑因素。快速对映体过量测量在药物发现过程和药品的QA/QC中至关重要，因为全球用于药物制剂的单一对映体化合物的销售额达到1500亿美元/年。该系统还可用于生物医学研究中生物标志物、代谢物和其他生物活性化合物的定量和检测。

DESCRIPTION (provided by applicant): Assembly of proteins, drug interactions, and substrate recognition are a few of the vital physiological interactions that depend on the chiral orientation of molecules. Preliminary results clearly demonstrate that by modifying the drift gas with chiral molecules, ion mobility spectrometry can provide a novel and rapid separation technique for chiral compounds. Similar to chiral chromatography and capillary electrophoresis, the ability of chiral ion mobility spectrometry to examine enantiomeric mixtures is based upon the interaction of analytes with neutral chiral modifiers. The ultimate goal of the research proposed is to develop and commercialize the rapid chiral separation and characterization instrument: electrospray ionization - chiral ion mobility spectrometer - mass spectrometer (ESI-CIMS-MS). The proposed system can not only separate chiral molecules in milliseconds, but also reduce method development time to minutes. Great separation speed and easy method development of ESI-CIMS-MS make it the method of choice for many applications analysis time is a critical consideration. The proposed system can be used to directly measure enantiomeric excess of chiral ingredients in pharmaceutical products, may serve to increase throughput for chirality measurements in drug discovery when hundreds of drug compounds are being screened as drug candidates, can be used to monitor the performance of preparative chiral separation processes, or can be used as a chiral selective detector for chromatographic systems. The Phase I research focuses on the characterization of bioactive chiral compounds with the proposed system. A broad range of volatile chiral molecules will be tested as chiral modifier for the CIMS. The research seeks to explore optimal instrumental conditions where maximum chiral separation can be achieve, to demonstrate the separation of different classes of biologically active chiral compounds with effective chiral modifiers, to explore the possibility of enhancing chiral resolution using multiple gas phase interaction forces between chiral modifier and enantiomeric ions, to analyze and compare chiral separation characteristics of CIMS and chromatographic systems, and to explore the potential of quantitative determination of enantiomeric excess. As a longer term goal, the possibility of determining analytes chirality of using known chiral modifier will also be examined. The fundamental knowledge of the CIMS learned in the Phase I research will be used to design and fabricate an ESI-CIMS-MS system in Phase II, which will be commercialized to support a wide range of biomedical research. Proposed chiral ion mobility spectrometer - mass spectrometer, separating and identifying chiral compounds in seconds, can potentially replace chiral chromatography for chiral analysis time is a critical consideration. Rapid enantiomeric excess measurement is essential in drug discovery process and QA/QC of pharmaceutical products as worldwide sales of single-enantiomer compounds made into the pharmaceutical formulations reaches $150 billion/year. The proposed system can also be used for the analysis of chiral compounds in complex mixture for quantification and detection of biomarkers, metabolites and other bioactive compounds in biomedical research.