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.     

Artificial ditopic Arg-Gly-Asp (RGD) receptors

Covalent fusion of two artificial recognition motifs for arginine and aspartate resulted in a new class of ditopic RGD receptor molecules, 1-4. The two binding sites for the oppositely charged amino acid residues are linked by either flexible linkers of different length (in 1-3) or a rigid aromatic spacer (in 4). These spacers are shown to be critical for the complexation efficiency of the artificial hosts. If the linkers are too flexible, as in 1-3, an undesired intramolecular self-association occurs within the host and competes with, and thereby weakens, substrate binding. The rigid aromatic linker in 4 prevents any intramolecular self-association and hence efficient RGD binding is observed, even in buffered water (association constant of K(a) approximately 3000 m(-1)). A further increase in hydrophobic contacts, as in host 16, can complement the specific Coulomb attractions, thereby leading to an even more stable complex (Ka=5000 m(-1)). The recognition events have been studied with NMR spectroscopy, UV/Vis spectroscopy, and fluorescence titrations.     

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.     

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.     

Synthetic Adrenaline Receptors Based on Bisphosphonates

Synthetic models of the natural adrenergic receptors are presented, and their binding properties to several biologically important amines and amino alcohols in dimethylsulfoxide and methanol are discussed. NMR titrations have been carried out to determine their binding constants.     

Recognition of Free Tryptophan in Water by Synthetic Pseudopeptides: Fluorescence and Thermodynamic Studies

Pseudopeptidic receptors containing an acridine unit have been prepared and their fluorescence response to a series of amino acids was measured in water. Free amino acids, not protected either at the C or the N terminus, were used for this purpose. The prepared receptors display a selective response to tryptophan (Trp) versus the other assayed amino acids under acidic conditions. The macrocyclic nature of the receptor is important as the fluorescence quenching is higher for the macrocyclic compound than for the related open‐chain receptor. Notably, under the experimental acidic conditions used, both the receptor and guest are fully protonated and positively charged; thus, the experimental results suggest the formation of supramolecular species that contain two positively charged organic molecular components in proximity stabilized through aromatic–aromatic interactions and a complex set of cation‐anion‐cation interactions. The selectivity towards Trp seems to be based on the existence of a strong association between the indole ring of the monocharged amino acid and the acridinium fragment of the triprotonated form of the receptor, which is established to be assisted by the interaction of the cationic moieties with hydrogen sulfate anions.     

Amino acid binding by 2-(guanidiniocarbonyl)pyridines in aqueous solvents: a comparative binding study correlating complex stability with stereoelectronic factors

A series of guanidiniocarbonylpyridine receptors has been synthesized, and these compounds bind amino acids (carboxylate forms) in aqueous DMSO with association constants ranging from K = 30 to 460 M(-1) as determined by NMR titration experiments. The differences in the complex stabilities can be correlated with steric and electrostatic effects with the aid of calculated complex structures. For example, the electrostatic repulsion between the pyridine nitrogen lone pair and the bound carboxylate makes anion binding less efficient than with the analogous pyrrole receptors previously introduced by us for carboxylate binding in water. Furthermore, steric interactions between the receptor side chain as in 2 b and the bound substrate also disfavor complexation.     

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.     

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.     

Synthesis and Binding of Mannose-Specific Synthetic Carbohydrate Receptors

Synthetic carbohydrate receptors (SCRs) that selectively recognize cell-surface glycans could be used for detection, drug delivery, or as therapeutics. Here we report the synthesis of seven new C_2h symmetric tetrapodal SCRs. The structures of these SCRs possess a conserved biaryl core, and they vary in the four heterocyclic binding groups that are linked to the biaryl core via secondary amines. Supramolecular association between these SCRs and five biologically relevant C¹-O-octyloxy glycans, α/β-glucoside ( α/β-Glc ), α/β-mannoside ( α/β-Man ), and β-galactoside ( β-Gal ), was studied by mass spectrometry, ¹H NMR titrations, and molecular modeling. These studies revealed that selectivity can be achieved in these tetrapodal SCRs by varying the heterocyclic binding group. We found that SCR017 (3-pyrrole), SCR021 (3-pyridine), and SCR022 (2-phenol) bind only to β-Glc. SCR019 (3-indole) binds only to β-Man. SCR020 (2-pyridine) binds β-Man and α-Man with a preference to the latter. SCR018 (2-indole) binds α-Man and β-Gal with a preference to the former. The glycan guests bound within their SCR hosts in one of three supramolecular geometries: center-parallel, center-perpendicular, and off-center. Many host–guest combinations formed higher stoichiometry complexes, 2:1 glycan⋅SCR or 1:2 glycan⋅SCR , where the former are driven by positive allosteric cooperativity induced by glycan–glycan contacts.     

Synthetic Lectins

Improving on Mother Nature? The carbohydrate recognition demonstrated by supramolecular systems in water can now compete with that of natural systems, both in terms of affinity and selectivity. A synthetic carbohydrate receptor displays similar affinity for N‐acetyl‐D ‐glucosamine derivatives as the lectin wheat germ agglutinin and even greater selectivity (see picture: gray C, white H, blue N, red O).

     

Selective Pyrophosphate Recognition by Cyclic Peptide Receptors in Physiological Saline

The anion binding ability of a family of bis(Zn^II‐Dpa) functionalized cyclic peptides has been investigated using displacement assays with a fluorescent coumarin indicator in water, saline solution, and Krebs buffer. Non‐binding side‐chain steric bulk, the relative position of binding sites, and the scaffold size were all found to affect the ability of these receptors to discriminate between polyphosphate ions. Most receptors showed some selectivity for pyrophosphate over ATP and ADP in water and saline, and this selectivity was significantly enhanced in the biologically relevant Krebs buffer giving chemosensing ensembles capable of selective recognition of pyrophosphate in the presence of excess ATP.     

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.     

Platform Synthetic Lectins for Divalent Carbohydrate Recognition in Water

Biomimetic carbohydrate receptors (“synthetic lectins”) have potential as agents for biological research and medicine. However, although effective strategies are available for “all‐equatorial” carbohydrates (glucose, etc.), the recognition of other types of saccharide under natural (aqueous) conditions is less well developed. Herein we report a new approach based on a pyrene platform with polar arches extending from aryl substituents. The receptors are compatible with axially substituted carbohydrates, and also feature two identical binding sites, thus mimicking the multivalency observed for natural lectins. A variant with negative charges forms 1:2 host/guest complexes with aminosugars, with K₁>3000 m ^?1 for axially substituted mannosamine, whereas a positively charged version binds the important α‐sialyl unit with K₁≈1300 m ^?1.     

基于大环合成受体的超分子纳米阀门

在特定外界刺激下, 修饰于介孔纳米材料表面的超分子纳米阀门可以有效地控制所包封物质如药物模型分子、 抗癌药物分子和寡核酸等生物分子的靶向释放, 在药物释放、 基因转染及传感等领域有广泛的应用前景. 本文结合本课题组的工作, 综述了国内外在基于大环合成受体的超分子纳米阀门体系的化学构筑及功能等方面的研究进展.