Identification and isolation of a receptor for N-methyl alkylammonium salts:: Molecular amplification in a pseudo-peptide dynamic combinatorial library
Identification and isolation of a receptor for N-methyl alkylammonium salts:: Molecular amplification in a pseudo-peptide dynamic combinatorial library
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DOI：
10.1002/1521-3773(20010119)40:2
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发表时间：
2001-01-01
影响因子：
16.6
通讯作者：
Sanders, JKM
中科院分区：
文献类型：
--
作者：
Cousins, GRL;Furlan, RLE;Sanders, JKM
图1所示。均衡过程中库成员之间的相互转换以及随后由模板(T)施加的产品分布变化的示意图。字母大小代表产品浓度。我们报道了一种选择性结合乙酰胆碱和n -甲基喹啉盐的大环受体的伪肽的动态组合文库（DCL）的分子扩增。据我们所知，我们报告的产品分布的变化是迄今为止在共价动态组合系统中观察到的最大的变化，并作为动态组合化学（DCC）可用于通过非共价模板效应从大量候选分子中识别和分离新分子的概念的证明。dcl是通过金属±配体交换和氢键网络非共价生成的，[5]和共价部署一系列可逆反应[1]，如酯交换，[6]二硫交换，[7]烯基钯化学，[8]和传递然而，迄今为止报道的成功模板化共价dcl的例子非常有限。我们已经建立了基于腙的伪肽文库，这些伪肽通过在腙键[10]上的传递进行相互转换，并且最近报道了通过[18]冠-6与单体肼阳离子[11]的络合，在这样的文库中进行了显著的分子扩增这种效应是一般的肼离子，但我们现在报告了特定的分子放大的大环在一个动态组合混合物的基于腙的伪肽。由构建块mPro 1形成的DCL被设计成包含一个环状结构，可以模拟Kubik环状肽观察到的阳离子结合Kubik环肽5在氯仿中与乙酰胆碱（ACh）碘化物和n -甲基喹啉（NMQ）碘化物结合，稳定常数分别为11000mÀ1和42200mÀ1。[12a]将mPro三聚体2与受体5进行比较，发现它们的结构非常相似，除了我们的受体中有六个额外的键。预期ACh和NMQ将与mPro环三聚体2结合足够强，从而形成模板，从而导致分子扩增。
Figure 1. Schematic representation of the interconversion of library members by equilibrium processes and the subsequent product distribution change exerted by a template (T). Letter sizes are representative of product concentration. we report molecular amplification from a dynamic combinatorial library (DCL) of pseudo-peptides of a macrocyclic receptor that binds selectively to acetylcholine and N-methyl quinuclidinium salts. The shifts in product distribution we report are to our knowledge the largest yet observed for covalent dynamic combinatorial systems, and serve as proof of the concept that dynamic combinatorial chemistry (DCC) may be used to identify and isolate new molecules from large pools of candidates through noncovalent template effects. DCLs have been generated noncovalently through metal±ligand exchange [4] and hydrogen-bonding networks,[5] and covalently deploying a range of reversible reactions [1] such as transesterification,[6] disulfide exchange,[7] allylpalladium chemistry,[8] and transimination.[9] However, reported examples of successful templating of covalent DCLs are so far very limited. We have generated libraries of hydrazone-based pseudo-peptides which interconvert by transimination at the hydrazone bond,[10] and have recently reported significant molecular amplification in such a library by complexation of [18] crown-6 to the monomer hydrazinium cation.[11] This effect is general for hydrazinium cations, but we now report specific molecular amplification of a macrocycle in a dynamic combinatorial mixture of hydrazone-based pseudo-peptides. The DCL formed from building block mPro 1 was designed to contain a cyclic structure that would emulate cation binding observed with Kubik s cyclic peptides.[12] Kubik s cyclic peptide 5 binds acetylcholine (ACh) iodide and N-methyl quinuclidinium (NMQ) iodide in chloroform with stability constants of 11000mÀ1 and 42200mÀ1, respectively.[12a] Comparison of the mPro trimer 2 with receptor 5 reveals very similar structures, with the exception of six additional bonds in our receptor. The expectation was that ACh and NMQ would bind the mPro cyclic trimer 2 strongly enough to template its formation leading to molecular amplification.