Syntheses and Peptide-binding Properties of C2-symmetric Metallomacrocycles

Abstract

Over the last decade, much effort in supramolecular chemistry has been devoted to developing efficient synthetic receptors for peptides. Peptides as a substrate are interesting for their biological significance. There are many biochemical or medicinal processes, for examples enzymatic activity, antibody action and bacterial infections, in which a selective molecular interaction of peptide plays a decisive role. Thus study of synthetic receptors capable of selective binding to a specific peptide are not only useful for better understanding of biological processes, but also facilitate the design of sensors, catalysts and new medicinal therapeutics. Recently, metallomacrocycles which are self-assembled from a flexible ligand by exploiting metal-ligand coordinate bond are recognized as the emerging class of new synthetic receptors for peptide substrates. In metallo-macrocylic receptors, metal acts to maintain macrocyclic structure and thus makes the receptor preorganized for the effective complexation with the corresponding substrates. Besides, certain metals can act chromogenic and catalytic center and thus have the potential applicability for chemical sensors and catalysts. Here, we describe syntheses and peptide binding properties of novel metallomacrocyclic receptors (1 and 2). Syntheses of receptor 1 and 2 began with the preparation of the flexible ligands (4 and 6), as shown on Scheme 1. Compounds 3 was prepared by following the standard amide coupling procedures through pentafluorophenyl activated esters from 5. Amide coupling reaction between bispentafluorophenyl ester of 3 and 5-aminomethyl-2,2':6',2''terpyridine provided the bis-terpyridine ligand of 4. Metallomacrocycle 1 was prepared as dark red solids with 70.0% yield by mixing FeCl2 and ligand 4 in ethanol, stirring for 12 hrs under reflux condition, then adding the saturated NH4PF6 aq. solution. Amide coupling reaction between 5 3 and (L)-phenylalanine 5-aminomethyl-2,2': 6',2''-terpyridine amide provided the bis-terpyridine ligand of 6. Metallomacrocycle 2 was prepared as dark red solids with 80.0% yield by following the similar synthetic procedures using ligand 6. Metallomacrocycles (1 and 2) have the well-defined, potential substrate binding cavities having the convergent hydrogen bonding donor/acceptors and the hydrophobic surfaces. To examine the peptide-binding properties of receptors, 1 and 2 were screened against a tripeptide library on hydrophobic polystyrene in CHCl3. 3 The library was prepared by encoded split synthesis and has the general structure AcAA3-AA2-AA1-NH(CH2)6-C(O)NH-Polystyrene. 4 Decoding the tripeptides on the colored beads by using electron capture gas chromatography revealed selective peptidesbinding properties of macrocyclic compounds (1 and 2). The most tightly binding substrates with macrocyclic compounds (1 and 2) are shown in Table 1. The binding data in Table 1 reveal a number of notable trends. For example, receptor 1 was found to bind strongly with the substrate with Gly (8/15) at AA1 position, while there are no significant selectivities for the residues at AA2 and AA3 positions. However, receptor 2 shows different selectivity for the residue at each position of tripeptide