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、运输和感知生物相关的阴离子。它建立在一种阴离子识别方法的基础上，这种方法最初是由私家侦探和他的同事们在大约十年前提出的，现在已经发展到被世界上越来越多的学术实验室所采用的地步。同时，基于吡咯的阴离子识别事件最近被用来解释子紫素的作用模式，子紫素是一种天然存在的三吡咯类实体，具有良好的免疫抑制和抗癌活性。类似的nh阴离子相互作用与l - pyrlysine促进的途径有关，l - pyrlysine是今年早些时候发现的一种新的遗传编码氨基酸。因此，制造和研究吡咯基阴离子受体的动机比以往任何时候都大。无论是在探索阴离子结合的基本决定因素方面，还是在产生能够针对医疗和公共卫生重要性问题的系统方面，都是如此。这些挑战包括阴离子代谢物感测、化学战剂检测、肾衰竭患者体内磷酸盐和草酸盐浓度的控制以及药物开发中的多种机会。迄今为止的工作已经确定：1)吡罗受体可以在极性介质中结合和感知诸如磷酸盐、氯化物和草酸盐以及氟化物等生理上重要的阴离子；2)结合过程的强度和选择性可以通过结构修饰进行微调；3)可以制造含有吡罗受体的聚合物。它还导致发现在p.l.发展了几种聚吡咯系统。在实验室中显示的细胞毒性达到或超过了稗子素。因此，拟议的研究将侧重于利用新的和现有的吡罗基受体来i)更充分地探测阴离子识别的动力学和热力学，ii)产生磷酸盐和草酸盐结合材料以治疗终末期肾脏疾病，iii)创建支持传感器以检测有机磷酸盐神经气体的水解产物，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.