Differential Optical Rotation for Chiral Analysis

用于手性分析的微分旋光度

• 批准号: 6791142
• 负责人: Phillip Ray Gibbs
• 金额: $ 10万
• 依托单位: STHENO CORPORATION
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6791142
• 关键词: biomedical equipment development; biotechnology; drug screening /evaluation; high throughput technology; optical rotation; pharmacokinetics; polarimetry; racemization; stereoisomer

DESCRIPTION (provided by applicant): Many diseases are still without an effective treatment today, and others have evolved resistances requiring new therapeutic agents to be developed. In the effort to develop discovery candidates for medical applications, an important observation is that the vast majority of useful drugs contain one or several chiral centers. Since the wrong enantiomer can cause harmful side effects, very high enantiomeric purity of therapeutics is essential for safe and effective treatment. Thus, both producing enantiomerically pure formulations and testing for enantiomeric purity are critical. Unfortunately, both of these activities remain significant challenges, even with the current "state of the art" analytical instrumentation. The proposed work intends to develop a next-generation chiral analysis technique that is suitable for non-contact, rapid, accurate, and highly sensitive screening of chiral samples. This approach utilizes several experimentally simple, but scientifically sophisticated techniques from "state of the art" optics research first developed for nonlinear-optical spectroscopy, but which we now apply to simple polarimetry. The method transforms the detection of optical rotation into a dual-beam technique that utilizes the advantages of differential signal detection. In addition, advances in components such as digital lock-in detection, wavelength tunable sources, polarization modulation, and polarizing optics are utilized to extend the utility of the technique into the UV region. A prototype device will be constructed and tested with several chiral substrates, products, and mixtures of pharmaceutical interest to establish limits of detection (LOD), limits of quantitation (LOQ), and demonstrate superior determination of enantiomeric excess (ee%) as compared to current chiral detectors. Chiral enzymatic reactions will also be investigated to demonstrate examples of real-time kinetic analysis. Particular emphasis will be placed on demonstrating utility for analyzing multiple chiral species present in mixtures, which is particularly difficult for current methods to analyze directly.

描述（由申请人提供）：许多疾病今天仍然没有有效的治疗方法，其他疾病已经发展出耐药性，需要开发新的治疗剂。在开发用于医学应用的发现候选物的努力中，一个重要的观察结果是绝大多数有用的药物含有一个或多个手性中心。由于错误的对映体可能导致有害的副作用，因此非常高的对映体纯度的治疗剂对于安全有效的治疗是必不可少的。因此，制备对映体纯的制剂和测试对映体纯度都是至关重要的。不幸的是，这两项活动仍然是重大的挑战，即使与当前的“最先进的”分析仪器。本研究旨在开发新一代手性分析技术，适用于非接触、快速、准确和高灵敏度的手性样品筛选。这种方法利用了几个实验简单，但科学上复杂的技术，从“国家的最先进的”光学研究首先开发的非线性光学光谱，但我们现在适用于简单的偏振。该方法将旋光度的检测转化为利用差分信号检测的优点的双光束技术。此外，先进的组件，如数字锁定检测，波长可调光源，偏振调制和偏振光学器件被用来扩展到紫外线区域的技术的效用。将使用几种手性底物、产物和药物感兴趣的混合物构建和测试原型装置，以建立检测限（LOD）、定量限（LOQ），并证明与当前手性检测器相比，对映体过量（ee%）的测定具有上级优势。手性酶反应也将进行研究，以证明实时动力学分析的例子。特别强调的是，将被放置在演示分析混合物中存在的多个手性物种，这是特别困难的，目前的方法直接分析的实用程序。