Biochemical Model Reactions

描述(申请人提供)：该项目旨在发明和研究能够模仿天然酶的新型分子。在项目的第一部分，我们将研究模拟属于细胞色素P-450类别的酶的新型催化剂。在我们的酶模拟物中，底物与催化剂结合，然后在仅由催化剂/底物复合体的几何形状确定的位置进行羟基化或环氧化。这与化学合成中的正常情况形成对比，在化学合成中，底物的内在反应性在决定反应发生的位置方面发挥着主要作用--通常它们起着唯一的作用。我们建议1)改进底物与酶模拟物结合的方式，特别是使用包括金属离子配位的“点和环”计划来结合常用的底物；2)将工作扩展到新的底物，包括那些本身灵活的底物；以及3)开发用于氧化的实用试剂。我们期望这种仿生合成反应可以应用于制药行业中有用的药物的合成和制造。 该项目的第二部分涉及人造酶--酶模拟物--基于包括树枝状大分子在内的合成聚合物。在这里，我们在水中进行反应，并利用聚合物内部是非水的这一事实，这在酶中也是如此。因此，我们得到了基材的疏水结合，但在聚合物内部的反应非常迅速。我们将与各种聚合物合作，并用疏水单元对其进行修饰。我们提出了由辅酶结合或可逆结合的酶模拟物催化的反应，目的是开发仿生方法来合成胺，如氨基酸以及硫胺素和其他噻唑离子产生的特殊催化产物。我们将专注于生产高对映体过量的产品，部分方法是使用多肽还原产生的手性多胺。在这里，与健康相关的也是开发新的合成方法，这些方法可能在药物化合物的制造中有用。此外，该项目的两个部分都将帮助我们了解天然酶。

DESCRIPTION (provided by applicant): This project is aimed at inventing and studying novel molecules that can imitate natural enzymes. In the first part of the project we will study novel catalysts that imitate the enzymes belonging to the class called cytochrome P-450. In our enzyme mimics substrates are bound to the catalyst and then hydroxylations or epoxidations are performed at sites determined only by the geometry of the catalyst/substrate complex. This is in contrast to the normal situation in chemical syntheses in which the intrinsic reactivities of the substrates play a major role in determining where reactions occur--frequently they play the only role. We propose to 1) improve the way in which substrates are bound to the enzyme mimics, in particular using a "point and ring" plan including metal ion coordination for binding commonly available substrates; 2) extend the work to novel substrates, including those that are themselves flexible; and 3) develop practical reagents for the oxidations. We expect that such biomimetic synthetic reactions could be applied to the synthesis and manufacturing of useful medicinal compounds in the pharmaceutical industry. The second part of the project deals with artificial enzymes -- enzyme mimics -- that are based on synthetic polymers, including dendrimers. Here we perform the reactions in water and take advantage of the fact that the interior of the polymer is non-aqueous, as is true in enzymes as well. Thus we obtain hydrophobic binding of substrates but very rapid reactions in the polymer interiors. We will be working with various polymers, and modifying them with hydrophobic units. We propose reactions catalyzed by enzyme mimics that have coenzymes either attached or reversibly bound, with the aim of developing biomimetic methods to synthesize amines such as amino acids as well as products from the special catalysis that thiamine and other thiazolium ions produce. We will be focusing on producing products with high enantiomeric excesses, in part by using chiral polyamines produced by the reduction of polypeptides. Here too the health relevance is the development of novel synthetic methods that could be useful in the manufacture of medicinal compounds. In addition, both parts of the project will help us understand natural enzymes.