Chiroptical Induced CPL-Based Tool as a Probe of Biological Substrates

描述（由申请人提供）：本研究项目的长期目标是发展圆偏振发光（CPL）作为生物分子对映选择性识别和研究含金属生物分子体系中的手性结构的工具。分子手性——一个分子的两个镜像不能相互叠加的特性——对现代药物研究至关重要。虽然手性结构之间的差异可能看起来微不足道，但化合物三维结构的微小变化却会深刻地改变给定化合物与周围环境的相互作用。例如，在20世纪60年代，外消旋沙利度胺被广泛用于治疗孕吐。其中一种对映体能有效减少晨吐，但不幸的是，该药的另一种对映体会导致出生缺陷。因此，很容易理解为什么单对映体药物很有吸引力，研究人员正在研究它们作为癌症、心血管疾病和中枢神经系统（CNS）缺陷的可能治疗方法。据估计，2009年对映不纯药物将产生150亿美元的收入。本提案的中心假设是，CPL是一种先进的普通圆二色（CD）方法，由于其在灵敏度、可靠性、易用性和最小的样品制备方面的优势。特别重要的是，我们对直接和选择性激发镧系（III）离子（Ln(III) = Eu, Tb）的方法改进将增加发光位点之间的区分，使解释更容易（即CPL将反映Ln（III）离子周围的时间平均局域螺旋度）。特别感兴趣的是使用CPL选择性地研究只存在于感兴趣的系统中的发光发色团的重要性；相反，CD受大多数发色团和/或平衡混合物以加性方式影响。更具体地说，该研究将(1)研究CPL光谱作为对映体选择性识别生物分子（如氨基酸）的分析工具的灵敏度和选择性，(2)检验CPL光谱作为手性镧系元素结构存在的探针和作为手性结构变化指标的有效性。(3)证明了使用铕（III） CPL光谱来理解蛋白质的手性结构与其结合金属离子(即Ca（II), Mg(II)）的能力之间的关系的重要性，这些金属离子被Eu（III）离子取代。

DESCRIPTION (provided by applicant): The long-term objective of this research project is to develop circularly polarized luminescence (CPL) as a tool for enantioselective recognition of biomolecules and for investigating chiral structures in metal-containing biomolecular systems. Molecular chirality-the property whereby two mirror images of a molecule cannot be superimposed on each other-is crucial to modern drug research. While the difference between chiral structures may seem trivially small, the slight change in the compounds' three-dimensional structure profoundly alters the given compound's interaction with its surroundings. For example, in the 1960s, racemic thalidomide was widely used to treat morning sickness. One of the enantiomers was effective at reducing morning sickness, but unfortunately the drug's other enantiomer caused birth defects. For this reason, it is easy to understand why single-enantiomer drugs are attractive, and researchers are looking at them as possible treatments for cancer, cardiovascular disease, and central nervous system (CNS) defects. In 2009, estimates suggest that enantiopure drugs will produce $15 billion in revenue. The central hypothesis of this proposal is that CPL is an advancement over the common circular dichroism (CD) method due to its superiority in sensitivity, reliability, ease of use, and minimal sample preparation. Of special importance is that our methodological refinement of directly and selectively exciting the lanthanide(III) ion (Ln(III) = Eu, Tb) will increase discrimination between luminescent sites, making interpretation easier (i.e. CPL will reflect the time- averaged local helicity around the Ln(III) ion). Of special interest is the importance of using CPL for selectively studying only luminescent chromophores present in the systems of interest; CD, in contrast, is affected by most chromophores and/or equilibrium mixtures in an additive manner. More specifically, the study will (1) investigate the sensitivity and selectively of CPL spectroscopy used as an analytical tool for enantioselective recognition of biomolecules such as amino acids, (2) examine the effectiveness of CPL spectroscopy as a probe into the existence of chiral lanthanide structures and as an indicator of changes in the chiral structures, and (3) demonstrate the importance of using europium(III) CPL spectroscopy to understand the relationships between the chiral structures of proteins and their ability to bind metal ions (i.e. Ca(II), Mg(II)) where these metal ions are substituted by Eu(III) ions.