Diverse Properties of Guanidiniocarbonyl Pyrrole-Based Molecules: Artificial Analogues of Arginine

Abstract

The guanidinium moiety, which is present in active sites of many enzymes, plays an important role in the binding of anionic substrates. In addition, it was also found to be an excellent binding motif for supramolecular chemistry. Inspired by Nature, scientists have developed artificial receptors containing guanidinium scaffolds that bind to a variety of oxoanions through hydrogen bonding and charge pairing interactions. However, the majority of binding studies is restricted to organic solvents. Polyguanidinium based molecules can form efficient complexes in aqueous solvents due to strong electrostatic interactions. However, they only have moderate association constants, which are significantly decreased in the presence of competing anions and salts. Hence, to improve the binding affinity of the guanidinium moiety, our group developed the cationic guanidiniocarbonyl pyrrole (GCP) moiety. This rigid planar analogue binds efficiently to oxoanions, like carboxylates even in aqueous solvents. The lower p K_a value (7-8) of GCP compared to guanidinium derivatives (p K_a 13) favors the formation of strong, hydrogen bonded ion pairs. In addition, carboxylate binding is further enhanced by additional amide hydrogen bond donors located at the five position of the pyrrole core. Moreover, the design has allowed for introducing secondary interactions between receptor side chains and guest molecules, which allows for optimizing binding specificity and selectivity. The spectroscopic data confirmed stabilization of guanidiniocarbonyl pyrrole/oxoanion complexes through a combination of ion pairing and multiple hydrogen bonding interactions. The key role of the ionic interaction in a polar solvent, is demonstrated by a zwitterion derivative of the guanidiniocarbonyl pyrrole, which self-assembles in both dimethyl sulfoxide and pure water with association constants of K > 10¹⁰ M^-1 and K = 170 M^-1, respectively. In this Account, we discuss strategies for making GCP functionalized compounds, in order to boost their ability to bind oxoanions. Then we explore how these building blocks have been incorporated into different synthetic molecules and peptide sequences, highlighting examples that demonstrated the versatility of this binding scaffold. For instance, the high oxoanion binding property of GCP-based compounds was exploited to generate a detectable signal for sensing applications, thus improving selectivity and sensitivity in aqueous solution. Moreover, peptides and molecules containing GCP have shown excellent gene transfections properties. Furthermore, the self-assembly and zwitterionic behavior of zwitterionic GCP analogues was used to develop variety of supramolecular architectures such as stable supramolecular β-helix structure, linear supramolecular oligomers, one-dimensional rods or two-dimension sheets, fibers, vesicles, soft nanospheres, as well as stimuli responsive supramolecular gels.