Activation of Electrophilic Reagents and Intermediates

描述(申请人提供)：在拟议的研究中，将研究阳离子亲电化学体系。许多强效药物是亲电物种，与蛋白质(即酶抑制剂)和核酸(即化疗烷化剂)上的亲核部位发生反应。这项拟议的工作与这些类型药物的结构-活性关系有关，因为它将揭示亲电体变得更具活性的机制。具体地说，这项工作应通过确定哪些类型的化学结构容易形成反应性、阳离子亲电性来确定阳离子化学的范围。机理研究也将确定阳离子亲电体倾向于如何反应。这一阶段的工作将包括研究一种新型的无金属脱氢酶系统。这些研究目标将通过对凝聚相酸催化反应中适当设计的模型系统的研究来实现。利用理论和光谱方法，还将研究这些亲电体系的结构和能量。 由于阳离子亲电剂通常表现出很高的反应活性，因此建议在有机合成中利用这些物种。利用与阳离子亲电体有关的酸催化反应，合成靶点将包括各种神经药物(抗抑郁药、抗惊厥药和抗痉挛药)，以及可能用于治疗囊性纤维化的产品。一些合成化学也可能能够制备对治疗药物成瘾有用的物质。许多临床上重要的药物都是用缺乏电子的芳基功能化的。这项拟议的工作将证明，通过利用阳离子亲电剂的反应性，这些基团可以很容易地结合到反应产物中。这些结果可能使药物化学家能够制备更有效的药物，并降低这些药物的生产成本。

DESCRIPTION (provided by applicant): In the proposed research, dicationic electrophilic chemical systems will be studied. Many potent drugs are electrophilic species that react with nucleophilic sites on proteins (i.e., enzyme inhibitors) and nucleic acids (i.e., chemotherapy alkylating agents). The proposed work is relevant to the structure-activity relationships of these types of drugs, as it will reveal the mechanisms by which electrophiles are made more reactive. Specifically, the work shall establish the scope of dicationic chemistry by determining what types of chemical structures are prone to form reactive, dicationic electrophiles. Mechanistic studies will also determine how dicationic electrophiles tend to react. Included in this phase of the work will be the study of a novel metal free, dehydrogenase enzyme system. These research goals will be accomplished by the study of appropriately designed model systems in condensed phase, acid-catalyzed reactions. Using theoretical and spectroscopic methods, the structures and energies of these electrophilic systems will also be studied. Since dicationic electrophiles often exhibit high reactivities, it is proposed that these species can be exploited in organic synthesis. Using acid-catalyzed reactions involving dicationic electrophiles, synthetic targets will include various neuropharmaceuticals (anti-depressants, anti-convulsants, and anti-spasmodics), as well as products which could be useful in the treatment of cystic fibrosis. Some the synthetic chemistry may also be capable of preparing substances useful in the treatment of drug addiction. A number of clinically important drugs are functionalized with electron-deficient aryl groups. The proposed work will demonstrate that these groups can be readily incorporated into the reaction products by exploiting the reactivity of dicationic electrophiles. These results may enable medicinal chemists to prepare more effective pharmaceuticals and lower the cost of production for these drugs.