A Tweezer-like Peptide-binding Receptor

Abstract

In recent years, significant progress has been made in the construction of synthetic molecules that selectively bind peptide substrates and other small molecules. Some such molecules have the complex, cage-like structures, but a different and simple structural motif such as molecular tweezer with two substrate binding arms has emerged as having selective peptide-binding properties. Among those are two-armed receptors based on cyclic oligomers of 1,2diamine and isophthalic acid. Although such receptors showed remarkable binding properties, to have further possible applications its binding properties had to be improved. Here, a novel two-armed tweezer-like peptidebinding receptor is described. Receptor (1) consist of two different parts: A linker to which the tweezer arms are attached; and two substrate binding arms based on cyclic tetramer of two isophthalic acids and two 1,2-diaminocyclohexane. Particularly, linker in receptor (1) has transition metal ion (Ru). In this receptor-like molecule, metal ion acts to make potential substrate-binding sites to be preorganized for the effective complexation with suitable substrates. Furthermore, metal ion such as Ru can act as the sensitive probes for binding with substrates and provide the additional interactions between linkers and peptide substrates. Synthesis of 1 began with the preparation of monocyclic intermediates of 1,2-diaminocyclohexanes and isophthalic acid derivatives by the known procedures for the related molecules. Ester bond formation reaction between bis(pentafluorophenyl)ester (2) and 4,4'-hydroxymethyl-2,2'dipyridine (3), and the subsequent reaction with Ru(bpy)2Cl2 in refluxing EtOH provided 1 with 48.2% yield. Recently, combinatorial chemistry has become a major tool in the elucidation of the binding properties of receptors. By using such methods it has become possible to find the binding properties of receptors efficiently, and furthermore to detect subtle differences in receptor-substrate binding that could not have been studied by conventional experiments. Receptor 1 has the distinct red color due to transition metal ion (Ru), and thus ideal for solid phase color binding assay using encoded combinatorial library of peptide substrates. Receptor 1 was screened against a tripeptide library on Scheme 1. Two-armed Tweezerlike Receptor (1).