Selective Recognition of Amino Acids and Peptides by Small Supramolecular Receptors

To this day, the recognition and high affinity binding of biomolecules in water by synthetic receptors remains challenging, while the necessity for systems for their sensing, transport and modulation persists. This problematic is prevalent for the recognition of peptides, which not only have key roles in many biochemical pathways, as well as having pharmacological and biotechnological applications, but also frequently serve as models for the study of proteins. Taking inspiration in nature and on the interactions that occur between several receptors and peptide sequences, many researchers have developed and applied a variety of different synthetic receptors, as is the case of macrocyclic compounds, molecular imprinted polymers, organometallic cages, among others, to bind amino acids, small peptides and proteins. In this critical review, we present and discuss selected examples of synthetic receptors for amino acids and peptides, with a greater focus on supramolecular receptors, which show great promise for the selective recognition of these biomolecules in physiological conditions. We decided to focus preferentially on small synthetic receptors (leaving out of this review high molecular weight polymeric systems) for which more detailed and accurate molecular level information regarding the main structural and thermodynamic features of the receptor biomolecule assemblies is available.     

Molecular Recognition by Zn(II)-Capped Dynamic Foldamers

Two α-aminoisobutyric acid (Aib) foldamers bearing Zn(II)-chelating N-termini have been synthesized and compared with a reported Aib foldamer that has a bis(quinolinyl)/mono(pyridyl) cap (BQPA group). Replacement of the quinolinyl arms of the BQPA-capped foldamer with pyridyl gave a BPPA-capped foldamer, then further replacement of the linking pyridyl with a 1,2,3-triazole gave a BPTA-capped foldamer. Their ability to relay chiral information from carboxylate bound to Zn(II) at the N-terminus to a glycinamide-based NMR reporter of conformational preference at the C-terminus was measured. The importance of the quinolinyl arms became readily apparent, as the foldamers with pyridyl arms were unable to report on the presence of chiral carboxylate in acetonitrile. Low solubility, X-ray crystallography and ¹H NMR spectroscopy suggested that interfoldamer interactions inhibited carboxylate binding. However changing solvent to methanol revealed that the end-to-end relay of chiral information could be observed for the Zn(II) complex of the BPTA-capped foldamer at low temperature.     

Recognition of Chiral Carboxylates by Synthetic Receptors

Recognition of anionic species plays a fundamental role in many essential chemical, biological, and environmental processes. Numerous monographs and review papers on molecular recognition of anions by synthetic receptors reflect the continuing and growing interest in this area of supramolecular chemistry. However, despite the enormous progress made over the last 20 years in the design of these molecules, the design of receptors for chiral anions is much less developed. Chiral recognition is one of the most subtle types of selectivity, and it requires very precise spatial organization of the receptor framework. At the same time, this phenomenon commonly occurs in many processes present in nature, often being their fundamental step. For these reasons, research directed toward understanding the chiral anion recognition phenomenon may lead to the identification of structural patterns that enable increasingly efficient receptor design. In this review, we present the recent progress made in the area of synthetic receptors for biologically relevant chiral carboxylates.     

Utilizing a pH‐Sensitive Dye in the Selective Fluorescent Recognition of Sulfate

A receptor containing amidopyrrole binding subunits and free amino groups, conjugated to a naphthalimide dye, has been designed and synthesized. The intrinsic selectivity of the binding motif for phosphate present in DMSO completely disappears in 10 % DMSO aqueous buffer at pH 3.6, at which the receptor is protonated. The electrostatic interactions between the receptor and an anion start to dominate, thus leading to selectivity for sulfate. The ability of the HSO₄^? anion to transfer the proton to the amino group during the recognition event suppresses the photoinduced electron transfer (PET) on the dye, resulting in a selective turn‐on fluorescent response. The choice of pH of the solution for sensing is dictated by the pK_a value of the dye.     

High‐Affinity Anion Binding by Steroidal Squaramide Receptors

Exceptionally powerful anion receptors have been constructed by placing squaramide groups in axial positions on a steroidal framework. The steroid preorganizes the squaramide NH groups such that they can act cooperatively on a bound anion, while maintaining solubility in nonpolar media. The acidic NH groups confer higher affinities than previously‐used ureas or thioureas. Binding constants exceeding 10¹⁴ M ^?1 have been measured for tetraethylammonium salts in chloroform by employing a variation of Cram’s extraction procedure. The receptors have also been studied as transmembrane anion carriers in unilamellar vesicles. Unusually their activities do not correlate with anion affinities, thus suggesting an upper limit for binding strength in the design of anion carriers.     

Molecular Recognition of Zwitterions with Artificial Receptors

Many biomolecules exist as internal ion pairs or zwitterions within a biologically relevant pH range. Despite their importance, the molecular recognition of this type of systems is specially challenging due to their strong solvation in aqueous media, and their trend to form folded or self‐assembled structures by pairing of charges of different sign. In this Minireview, we will discuss the molecular recognition of zwitterions using non‐natural, synthetic receptors. This contribution does not intend to make a full in‐depth revision of the existing research in the field, but a personal overview with selected representative examples from the recent literature.     

Recognition of Anions by Synthetic Receptors in Aqueous Solution

Natural anion binding systems achieve high substrate affinity and selectivity most often by arranging converging binding sites inside a cavity or cleft that is well shielded from surrounding solvent molecules by the folded peptide chain. Types of interactions employed for anion recognition are electrostatic interactions, hydrogen-bonding, and coordination to a Lewis-acidic metal center. In this review, successful strategies aimed at the development of synthetic receptors active in water or aqueous solvent mixtures are described. It is shown that considerable progress has been made during recent years in the development of potent anion receptors and that for every type of interaction used in nature for anion binding, corresponding synthetic models exist today. Representative examples of these systems are presented with a special emphasis on synthetic receptors whose characterization involved a detailed thermodynamic analysis of complex formation to demonstrate the important interplay between enthalpy and entropy for anion recognition in water.This revised version was published online in July 2005 with a corrected issue number.     

Affinity Enhancement by Dendritic Side Chains in Synthetic Carbohydrate Receptors

Dendritic side chains have been used to modify the binding environment in anthracene‐based synthetic carbohydrate receptors. Control of length, charge, and branching enabled the positioning of side‐chain carboxylate groups in such a way that they assisted in binding substrates rather than blocking the cavity. Conformational degeneracy in the dendrimers resulted in effective preorganization despite the flexibility of the system. Strong binding was observed to glucosammonium ions in water, with K_a values up to 7000 M ^?1. Affinities for uncharged substrates (glucose and N‐acetylglucosamine) were also enhanced, despite competition from solvent and the absence of electrostatic interactions.     

Synthetic Receptors for the High‐Affinity Recognition of O‐GlcNAc Derivatives

The combination of a pyrenyl tetraamine with an isophthaloyl spacer has led to two new water‐soluble carbohydrate receptors (“synthetic lectins”). Both systems show outstanding affinities for derivatives of N‐acetylglucosamine (GlcNAc) in aqueous solution. One receptor binds the methyl glycoside GlcNAc‐β‐OMe with K_a≈20 000 m ^?1, whereas the other one binds an O‐GlcNAcylated peptide with K_a≈70 000 m ^?1. These values substantially exceed those usually measured for GlcNAc‐binding lectins. Slow exchange on the NMR timescale enabled structural determinations for several complexes. As expected, the carbohydrate units are sandwiched between the pyrenes, with the alkoxy and NHAc groups emerging at the sides. The high affinity of the GlcNAcyl–peptide complex can be explained by extra‐cavity interactions, raising the possibility of a family of complementary receptors for O‐GlcNAc in different contexts.     

Exploration of the Chiral Recognition of Sugar‐Based Diindolylmethane Receptors: Anion and Receptor Structures

In this study, we have conducted a systematic investigation of the chiral recognition of carboxylic anions by D ‐glucuronic acid/diindolylmethane receptors. We investigate the influence of the anion structure on chiral recognition in the diindolylmethane/glucuronic acid‐based receptor 1 a . We found that presence of an additional hydrogen‐bond donor at the α position to the carboxylic function is essential for effective chiral differentiation in these systems. Furthermore, we present a synthetic procedure that allows for the synthesis of sugar‐decorated receptors that possess a modified substituent at the anomeric position. Four new receptors 1 b – e have been synthesized, and their chiral‐discrimination ability toward model carboxylates is studied. The obtained results show that the chiral recognition of these receptors can be fine‐tuned by incorporation of a proper substituent into the receptor structure.     

Tight and Selective Caging of Chloride Ions by a Pseudopeptidic Host

The selective molecular recognition of chloride versus similar anions is a continuous challenge in supramolecular chemistry. We have designed and prepared a simple pseudopeptidic cage ( 1 a ) that defines a cavity suitable for the tight encapsulation of chloride. The interaction of the protonated form of 1 a with different inorganic anions was studied in solution by ¹H NMR spectroscopy and ESI‐MS, and in the solid state by X‐ray diffraction. The solution binding data showed that the association constants of 1 a to chloride are more than two orders of magnitude higher than to any other tested inorganic anion. Remarkably, 1 a displayed a high selectivity for chloride over other closely related halides such as bromide (selectivity=111), iodide (selectivity=719), and fluoride (selectivity >1000). Binding experiments (¹H NMR spectroscopy and ESI‐MS) suggested that 1 a has a high‐affinity (inner) binding site and an additional low‐affinity (external) binding site. The supramolecular complexes with F^?, Cl^?, and Br^? have been also characterized by the X‐ray diffraction of the corresponding [ 1 a? nHX] crystalline salts. The structural data show that the chloride anion is tightly encapsulated within the host, in a binding site defined by a very symmetric array of electrostatic H‐bonds. For the fluoride salt, the size of the cage cavity is too large and is occupied by a water molecule, which fits inside the cage efficiently competing with F^?. In the case of the bigger bromide, the mismatch of the anion inside the cage caused a geometrical distortion of the host and thus a large energetic penalty for the interaction. This minimalistic pseudopeptidic host represents a unique example of the construction of a simple well‐defined binding pocket that allows the highly selective molecular recognition of a challenging substrate.     

Sensing A Paradigm Shift in the Field of Molecular Recognition: From Selective to Differential Receptors

Molecular recognition has evolved from a science designed to understand biological systems into a much more diverse area of research. While work continues to elucidate “nature's tricks” with respect to intermolecular interactions, much attention has turned to the perspective that molecular recognition, by design, can lead to new technologies. Applications ranging from molecular sensing to information storage and even working molecular machines have been envisioned. This review will highlight a few historical hallmarks of molecular recognition oriented at studying the basic science of intermolecular interactions, but then detail recent advances in molecular recognition aimed towards applications in the field of molecular sensing. Rational design can be used to create synthetic receptors with a good deal of predictability and selectivity, and many signal transduction mechanisms exist for converting these receptors into sensors. This is the first topic discussed. The concept of “differential” or “generalized” sensing is then presented, where one uses an array of sensors that do not necessarily conform to the “lock and key” principle. This approach to sensing is inspired by the mammalian senses of taste and smell, which we briefly describe. To mimic senses of taste and smell, one is naturally led to the use of combinatorial libraries, a direction of research that has seen continued growth over the past few years. We summarize the current state of the art in synthetic combinatorial receptors/sensors, and then predict a future direction that the field of molecular recognition will possibly take. The review is not meant for the specialist, but instead for a general audience. It does not present a highly detailed analysis of each individual topic: synthetic receptors, sensors, olfaction/gustation, and combinatorial receptors/sensors. Instead, this review shows how all these fields complement each other and fit together to create sensing devices. Our conclusion is that specific analyte sensing, differential sensing, and combinatorial chemistry can and will be combined to create sensor arrays, and give the subfield of molecular recognition that uses synthetic systems a bright future in this type of sensing scenario.     

Nitrate Anion Recognition in Organic–Aqueous Solvent Mixtures by a Bis(triazolium)acridine‐Containing [2]Rotaxane

The synthesis of a novel [2]rotaxane host system containing a bis(triazolium)acridine‐based axle component is reported. ¹H NMR anion‐binding titrations reveal that the rotaxane is able to recognise selectively the NO₃^? anion over a range of more basic oxoanions (AcO^?, HCO₃^? and H₂PO₄^?) in a competitive organic–aqueous solvent mixture.     

A Carbohydrate–Anion Recognition System in Aprotic Solvents

A carbohydrate–anion recognition system in nonpolar solvents is reported, in which complexes form at the B‐faces of β‐D ‐pyranosides with H1‐, H3‐, and H5‐cis patterns similar to carbohydrate–π interactions. The complexation effect was evaluated for a range of carbohydrate structures; it resulted in either 1:1 carbohydrate–anion complexes, or 1:2 complex formation depending on the protection pattern of the carbohydrate. The interaction was also evaluated with different anions and solvents. In both cases it resulted in significant binding differences. The results indicate that complexation originates from van der Waals interactions or weak CH ??? A^? hydrogen bonds between the binding partners and is related to electron‐withdrawing groups of the carbohydrates as well as increased hydrogen‐bond‐accepting capability of the anions.     

Molecular Receptors for Recognition and Sensing of Nucleotides

Nucleotides are constituents of nucleic acids and they have a variety of functions in cellular metabolism. Synthetic receptors and sensors are required to reveal the role of nucleotides in living organisms and mechanisms of signal transduction events. In recent years, a large number of nucleotide-selective synthetic receptors have been devised, which utilize different molecular designs and sensing mechanisms. This Minireview presents recent progress in the design of synthetic molecular receptors for selective recognition of nucleotides in aqueous solution. The binding properties of receptors and the origins of their selectivity for a particular nucleotide are discussed.     

Molecular Recognition of Nucleotides in Water by Scorpiand‐Type Receptors Based on Nucleobase Discrimination

The detection of nucleotides is of crucial importance because they are the basic building blocks of nucleic acids. Scorpiand‐based polyamine receptors functionalized with pyridine or anthracene units are able to form stable complexes with nucleotides in water, based on coulombic, π–π stacking, and hydrogen‐bonding interactions. This behavior has been rationalized by means of an exploration with NMR spectroscopy and DFT calculations. Binding constants were determined by potentiometry. Fluorescence spectroscopy studies have revealed the potential of these receptors as sensors to effectively and selectively distinguish guanosine‐5′‐triphosphate (GTP) from adenosine‐5′‐triphosphate (ATP).