Probing a Novel Mechanism of Cholinesterase Inactivation by Phosphorothiolates

9808372 Eppson本研究的长期目标是了解硫代磷酸酯（带有P-S-R基团的有机磷化合物）中存在的不对称性如何调节胆碱酯酶失活和再活化的速率、程度和机制。 异马拉硫磷是马拉硫磷中发现的一种硫代磷酸酯杂质，在碳和磷上都具有不对称中心，是研究与各种胆碱酯酶相互作用的绝佳起点。 一个共同的目标是制备能够探测胆碱酯酶功能的新型手性硫代磷酸酯结构。 虽然知识的三维结构的胆碱酯酶近年来取得了迅速的进展，立体化学精确的活性位点探针和灭活剂的需要的发展已经落后。 对这些新化合物的开发和需求可以大大增加我们对溶液反应性、立体异构对机制的影响以及胆碱酯酶结构和功能的认识。 在这项研究中，将进行两个具体的目标：（1）确定胆碱酯酶的机制，由异马拉硫磷，和（2）使用特定的化学设计特点，结合异马拉硫磷的结构-反应性关系，设计和制备P-手性硫代磷酸酯为基础的抗胆碱酯酶剂，以测试双阶段抑制机制的范围。一个严重的化学品问题仍然是公众关注的焦点;“有机磷（OP）杀虫剂（例如，马拉硫磷、二嗪农等）安全的，如果不是，什么关键的相互作用是负责或与有毒行动有关，他们可以很容易地确定？“为了解决和回答这个问题，需要对有机磷酸盐作用模式的化学和生物化学机制有基本的了解。 虽然OP的作用机制被广泛理解，但很少有人知道OP分子中的“左手性”或“右手性”或对称性如何改变其性质。 本研究旨在寻求这样一种理解。

9808372ThompsonThe long-range objective of this research is to understand how asymmetry present in phosphorothiolates (organophosphorus compounds bearing a P-S-R group) regulates the rate, extent and mechanism of cholinesterase inactivation and reactivation. Isomalathion, a phosphorothiolate impurity found in malathion, bears centers of asymmetry at both carbon and phosphorus and is an excellent starting point for studying interactions with various cholinesterases. A co-objective is to prepare novel chiral phosphorothiolate structures capable of probing cholinesterase function. Although knowledge of the three-dimensional structure of cholinesterase has advanced rapidly in recent years, the needed development of stereochemically precise active site probes and inactivators has lagged behind. The development and demand for these novel compounds could add significantly to our knowledge of solution reactivity, effects of stereoisomerism on mechanism, and cholinesterase structure and function. In this study, two specific aims will be undertaken; (1) to determine the mechanism of cholinesterase inactivation by isomalathion, and (2) to use specific chemical design features inherent to isomalathion in combination with structure-reactivity relationships to design and prepare P-chiral phosphorothiolate-based anticholinesterase agents to test the scope of dual-stage inhibition mechanisms. A serious chemical problem has remained at the forefront of public concern; "Are organophosphorus (OP) insecticides (e.g., malathion, diazinon, etc.) safe, and if not, what key interactions are responsible or correlate with toxic action and can they be readily identified?" In order to address and answer this question, a basic understanding of the chemical and biochemical mechanisms underlying organophosphate mode of action is required. Although OP mechanism of action is widely understood, very little is known about how "left-" or "right-handedness" or symmetry in OP molecules alters their properties. This research is directed toward pursuing such an understanding.