Controlling Cavitand Conformations for Drug Delivery Studies

描述（由申请人提供）：本提案的一般原理是使用外部刺激（光，小分子和电化学）释放结合在容器分子（空腔）内部的客体分子。本提案的长期目标是发展受管制的药物输送系统。具有精确药物递送调节的系统将保护反应性药物，并允许它们在特定的时间间隔（时间控制）进行管理，从而提高药物治疗的有效性。确定哪些外部刺激源是最有效的，并理解控制结合客体分子释放的规则将是本研究的重中之重。本文介绍了三种含功能的空腔体的合成和设计，这些空腔体在外部刺激的存在下执行明确的结构变化。核磁共振、紫外可见光谱、循环伏安法、质谱法和等温量热法都将被用来确定这些系统的结构和动力学。本课题的具体目标如下：1)可控分子空间——设计并合成三种对外部刺激（光、小分子和电化学）敏感的空腔体。2)改变形态-探索外部刺激对空腔和构象的影响。3)控制功能-确定哪种形式的外部刺激适合控制客体分子从空腔中释放。是否可以利用外部刺激来控制空腔和分子的功能？提出了一种调节空腔体催化功能的策略。开发能够控制药物释放的分子所需的基本知识将从这项研究中获得。本文提出的空腔体是乙酰胆碱等重要生物相关分子的良好宿主。控制这些分子的捕获和释放将帮助我们治疗阿尔茨海默氏症等与大脑中乙酰胆碱缺乏有关的疾病。拟议的研究培训计划将包括实验室合成、分析化学、在国内和国际会议上的演讲（Gordon、ACS和ISMSC）、生物相关领域的课程（生物有机化学和分子生物学）和伦理学、拨款写作研讨会和在同行评审期刊上发表文章。

DESCRIPTION (provided by applicant): The general principle of this proposal is to use external stimuli (light, small molecules and electrochemistry) to release guest molecules bound inside of container molecules (cavitands). The long term objective of this proposal is to develop controlled drug delivery systems. Systems with exact regulation of drug delivery will protect reactive drugs and allow them to be administered at specific time intervals (temporal control) resulting in improved effectiveness of drug therapy. Determining which sources of external stimuli are most affective and understanding the rules that govern the release of bound guest molecules will be paramount to this study. The synthesis and design of three classes of cavitands containing functionality that executes a well-defined structural change in the presence of external stimulus is presented. NMR, UV-Vis spectroscopy, cyclic voltammetry, mass spectrometry and isothermal calorimetry will all be exploited to ascertain the structures and dynamics of these systems. The specific aims of this proposal are as follows: 1) Controlled Molecular Space - design and synthesize three classes of cavitands that are sensitive to external stimuli (light, small molecules and electrochemistry). 2) Altering Form - explore the effects that external stimuli have on cavitand conformations. 3) Controlling Function - determine which forms of external stimuli are suitable to control the release of guest molecules from cavitands. Can external stimulus be used to control the function of cavitand molecules? A strategy is proposed to regulate the catalytic function of a cavitand. The fundamental knowledge required to develop molecules capable of controlled drug release will be gained from this research. The cavitands proposed herein are excellent hosts for important bio-relevant molecules like acetylcholine. The controlled capture and release of these molecules will help us treat diseases such as Alzheimer's that are associated with acetylcholine deficiencies in the brain. The proposed research training program will include laboratory synthesis, analytical chemistry, presentations at national and international conferences (Gordon, ACS and ISMSC), courses in bio-related fields (Bioorganic Chemistry and Molecular Biology) and ethics, grant writing workshops and publication in peer reviewed journals.