Polypyrrole-based Anion-Binding Agents

描述(由申请人提供)：这个正在进行的项目涉及使用吡咯NH氢键相互作用来结合、运输和检测具有生物相关性的阴离子。它建立在一种阴离子识别方法的基础上，这种方法最早是由P.I.和他的同事在近十年前提出的，现在已经发展到现在被世界各地越来越多的学术实验室采用。同时，基于吡咯的阴离子识别事件最近被用来解释灵芝菌素的作用模式，灵芝菌素是一种天然存在的三吡咯类物质，具有良好的免疫抑制和抗癌活性。类似的NH-阴离子相互作用也涉及到L-吡咯赖氨酸促进的途径，这是今年早些时候发现的一种新的遗传编码氨基酸。因此，制造和研究基于吡咯的阴离子受体的动力比以往任何时候都要大。无论是在探索阴离子结合的基本决定因素方面，还是在能够针对具有医疗和公共卫生重要性的问题的产生系统方面，都是如此。后者表现为各种挑战，如阴离子代谢物检测、化学战剂检测、肾衰竭患者磷酸盐和草酸盐浓度的控制，以及药物开发的多重机会。到目前为止的工作已经证实，i)基于吡咯的受体可以结合和感知极性介质中的磷、氯、草酸盐以及氟等生理上重要的阴离子，ii)结合过程的强度和选择性可以通过结构修饰来微调，以及iii)可以制造含有吡咯受体的聚合物。S实验室开发的几个聚吡咯系统显示的细胞毒性达到或超过灵芝菌素。因此，拟议的研究将集中于使用新的和现有的基于吡咯的受体来i)更全面地探索阴离子识别的动力学和热力学，ii)产生用于治疗终末期肾脏疾病的磷酸盐和草酸盐结合材料，iii)创建用于检测有机磷神经气体的水解产物的支撑式传感器，以及iv)开发可作为潜在的新型抗癌药物和免疫抑制剂的先导化合物。

DESCRIPTION (provided by applicant): This ongoing project involves the use of pyrrole NH hydrogen bonding interactions to bind, transport, and sense anions of biological relevance. It builds on an approach to anion recognition that was first put forward by the P.I. and his coworkers almost a decade ago and which has evolved to the point where it is now being adopted by an increasing number of academic laboratories world-wide. Meanwhile, pyrrole-based anion recognition events have been invoked recently to explain the mode of action of prodigiosin, a naturally occurring tripyrrolic entity with promising immunosuppressive and anticancer activity. Similar NH-anion interactions are implicated in pathways promoted by L-pyrrolysine, a new genetically encoded amino acid discovered earlier this year. Thus, the incentive to make and study pyrrole-based anion receptors is greater than ever. This is true both with regard to probing the basic determinants of anion binding and in terms of generating systems capable of targeting problems of medical and public health importance. These latter are represented by such diverse challenges as anionic metabolite sensing, chemical warfare agent detection, control of phosphate and oxalate concentrations in patients suffering from kidney failure, and multiple opportunities in drug development. Work to date has established that i) pyrrole-based receptors can bind and sense such physiologically important anions as phosphate, chloride, and oxalate, as well as fluoride, in polar media, ii) the strength and selectivity of the binding process can be fine-tuned through structural modifications, and iii) polymers containing pyrrolic receptors can be made. It has also led to the finding that several polypyrrole systems developed in the P.l.'s laboratory display cytotoxicities that meet or exceed those of prodigiosin. The proposed research will thus focus on using new and extant pyrrole-based receptors to i) probe more fully the kinetics and thermodynamics of anion recognition, ii) generate phosphate and oxalate binding materials for treating end-stage renal disease, iii) create supported sensors for detecting the hydrolysis products of organophosphate nerve gases, and iv) develop lead compounds that can be taken forward as potential new anti-cancer drugs and immunosuppressive agents.