SELECTIVE METAL ORGANIZED SYNTHETIC RECEPTORS

描述：(逐字摘自申请人的摘要)大多数药物是小分子，结合在大分子靶点的凹陷上。充当捆绑口袋的药物(例如万古霉素)的稀缺并不表明它们缺乏效用：例如，抗体非常有用。然而，化学在设计有用的更小、更简单的捆绑口袋方面落后于人。靶向酶或受体上的小分子或任意位置的能力将增加可用于药物开发的策略。我研究的长期目标是设计和制备具有预定特异性的合成抗体样结合部位和酶样催化剂。我们在这里提出了一类主体分子，每个主体分子都由金属组装或组织，以结合多功能有机客体。金属为快速构建复杂结构、控制其形状和官能团的呈现以及对结构进行微小扰动提供了有效的方法。选择性的一个关键是多个结合作用的协同作用。根据有效摩尔值(EM)衡量，我们的受体是杰出的。我们计划探索这些大的EM值的普遍性。这将导致有趣和有用的受体，以及增加对这些因素在自然系统中的重要性的认识。具体目标：1.进一步概括和表征我们所展示的自组装金属络合物将以双拓扑方式束缚宾客。当我们修饰金属和配体时，我们将评估对这些EM值的影响，这将有助于我们设计特定的结合部位。2.展示用于立体化学控制定义良好的主体分子的结构的分子模板。我们的目标是展示对空腔形状的控制，以及对结合基团和附件的取向的控制。

DESCRIPTION: (Verbatim from the Applicant's Abstract) Most pharmaceuticals are small molecules that bind to concavities in large molecular target sites. The scarcity of drugs that act like binding pockets (e.g., Vancomycin) is not an indication of their lack of utility: antibodies, for example, are very useful. However, chemistry lags in its ability to design useful smaller, simpler binding pockets. The ability to target a small molecule or arbitrary location on an enzyme or receptor would increase the strategies available for pharmaceutical development. Long term objectives of my research are to design and prepare synthetic antibody-like binding sites and enzyme-like catalysts with predetermined specificity. We propose here a family of host molecules, each assembled or organized by a metal, to bind polyfunctional organic guests. The metals provide effective methods for building complex structures rapidly, controlling their shapes and presentation of functional groups, and making small perturbations to the structures. A key to selectivity is the cooperation of multiple binding interactions. As measured by effective molarity (EM) values, our receptors are outstanding. We plan to probe the generality of these large EM values. This will lead to interesting and useful receptors, as well as to an increased appreciation of the significance of these factors in natural systems. Specific aims: 1. To generalize and characterize further the self- assembled metal complexes that we have shown will ditopically bind guests. As we modify metals and ligands, we will evaluate the effect on these EM values, which will assist our ability to design a specific binding site. 2. To demonstrate molecular templating for stereochemical control of the construction of well defined host molecules. We aim to demonstrate control of cavity shape, as well as of orientation of binding groups and appendages.