Chiral separation and analysis by molecular propeller effect

利用分子螺旋桨效应进行手性分离与分析

• 批准号: 9135760
• 负责人: MIRIANAS CHACHISVILIS
• 金额: $ 29.64万
• 依托单位: SOLVEXA, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2018-03-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9135760
• 关键词: Academia; Agriculture; Algorithmic Software; Algorithms; Biotechnology; Chemicals; Chemistry; Chromatography; Computer software; Crystallization; Crystallography; Data; Development; Devices; Drug Industry; Food; Goals; Hand; Handedness; High Pressure Liquid Chromatography; Hour; Industry; Institution; Lead; Left; Methods; Molecular; Molecular Analysis; Motion; Nature; Nutraceutical; Performance; Pharmacologic Substance; Phase; Preparation; Publishing; Research; Research Personnel; Resolution; Rotation; Running; Sampling; Savings; Small Business Innovation Research Grant; Solvents; Staging; System; Techniques; Technology; Temperature; Testing; Theoretical model; Time; TimeLine; Vibrational Circular Dichroism; Viscosity; Work; base; chiral molecule; commercial application; commercialization; cost; design; dipole moment; drug development; drug discovery; electric field; enantiomer; innovation; instrument; method development; molecular dynamics; novel; novel therapeutics; prediction algorithm; prototype; public health relevance; residence; screening; small molecule; stereochemistry; theories; tool

 DESCRIPTION (provided by applicant): In this SBIR Phase I proposal we propose to test a novel chiral separation technology for rapid separation, purity analysis and identification of absolute stereochemistry. The technology will enable significant cost and time savings for chiral chemistry research and industry - (1) by eliminating the need for expensive chiral stationary phases, (2) by significantly shortening separation method development and (3) through the use of predictive software for performance prediction and stereochemistry determination. Current techniques for chiral resolution and analysis such as high-performance liquid chromatography, x-ray crystallography and vibrational circular dichroism are time consuming, expensive or low fidelity. Recently we have experimentally validated the existence of a molecular propeller effect using rotating electric fields and demonstrated both chiral separation and absolute configuration determination. In this project we propose to investigate alternative means of imposing rotation on the molecules using shear flows which offers multiple advantages such as no requirements for high dipole moment of the molecule, low polarity of the solvent and strong electric fields. Briefly, when exposed to shear flow the left and right-handed chiral molecules rotate and act as molecular propellers, propelling along the direction perpendicular to shear plane but into opposite directions due to their opposite handedness. The propeller effect, as a hydrodynamic phenomenon does not rely on specific interactions with a chemical matrix, therefore the direction and velocity of translational motion for any new chiral molecule can be reliably determined using theoretical modeling, thus providing a priori information about expected performance, as well as enabling the assignment of absolute configuration. The proposed method, relying on the molecular propeller effect will enable the development of an inexpensive and easy-to-use benchtop instrument for chiral separation and analysis. The FDA, due to the generally proven advantages of single enantiomer compounds, mandates that for most new drugs each enantiomer needs to be evaluated separately thereby increasing the need for new chiral separation and analysis techniques. The rate of drug discovery and commercialization will be positively impacted if more researchers, both in academia and industry are able to afford chiral separation and analysis at earlier stages of lead discovery. The Specific Aims are: (1) design and build a shear flow-based proof-of-principle device; and (2) demonstrate enantiomeric enrichment and absolute stereochemistry determination of at least five chiral molecules; investigate design parameter tradeoffs such as shear rate, type of the solvent, viscosity and temperature; and investigate optimal algorithms for predictive software for high fidelity absolute configuration determination. The long-term goal of the project is to develop a simple-to-use and low-cost method and device that will both accelerate the rate of drug discovery and development by pharmaceutical industry and also find applications in other industries using chiral compounds such as agricultural, food and nutraceuticals.

 描述（由申请人提供）：在本SBIR I期提案中，我们提议测试一种用于快速分离、纯度分析和绝对立体化学鉴定的新型手性分离技术。该技术将为手性化学研究和工业节省大量成本和时间-（1）消除对昂贵手性固定相的需求，（2）显著缩短分离方法的开发，（3）通过使用预测软件进行性能预测和立体化学测定。 目前的手性拆分和分析技术，如高效液相色谱法，X射线晶体学和振动圆二色谱法是耗时，昂贵或低保真度。最近，我们已经实验验证了存在的分子螺旋桨效应，使用旋转电场，并证明了手性分离和绝对构型确定。在这个项目中，我们建议研究使用剪切流对分子施加旋转的替代方法，该方法具有多种优点，例如不需要分子的高偶极矩，溶剂的低极性和强电场。简而言之，当暴露于剪切流时，左手和右手手性分子旋转并充当分子推进器，沿沿着垂直于剪切平面的方向推进，但由于其相反的手性而进入相反的方向。螺旋桨效应作为一种流体动力学现象，不依赖于与化学基质的特定相互作用，因此任何新手性分子的平移运动的方向和速度可以使用理论建模可靠地确定，从而提供有关预期性能的先验信息，以及能够分配绝对构型。所提出的方法，依赖于分子螺旋桨效应，将使开发一个廉价和易于使用的台式仪器手性分离和分析。由于单一对映异构体化合物的普遍证明的优点，FDA要求对于大多数新药，每种对映异构体需要单独评估，从而增加了对新的手性分离和分析技术的需求。如果学术界和工业界有更多的研究人员能够在先导化合物发现的早期阶段进行手性分离和分析，药物发现和商业化的速度将受到积极影响。具体目标是：（1）设计和构建基于剪切流的原理验证装置;和（2）展示至少五种手性分子的对映体富集和绝对立体化学测定;研究设计参数权衡，例如剪切速率、溶剂类型、粘度和温度;和研究用于高保真绝对构型测定的预测软件的最佳算法。 该项目的长期目标是开发一种简单易用、低成本的方法和设备，既能加快制药行业的药物发现和开发速度，又能在农业、食品和营养保健品等使用手性化合物的其他行业中找到应用。