Acyclic Receptors Research Articles

Enhanced anion recognition by ammonium [2]catenane functionalisation of a halogen bonding acyclic receptor.

Ammonium-dibenzo[24]crown-8 [2]catenane functionalisation of a 3,5-bis-iodotriazole-pyridine motif produces a potent halogen bonding (XB) receptor capable of binding anions in aqueous-acetone solvent mixtures of up to 20% water. Exploiting the kinetically inert nature of the mechanically bonded cationic ammonium [2]catenane substituents, the XB receptor is demonstrated to exhibit superior anion recognition behaviour in comparison to labile sodium cation complexed bis-benzo[15]crown-5 XB and HB triazole-pyridine heteroditopic receptor analogues.

Selective Recognition of Ammonium over Potassium Ion with Acyclic Receptor Molecules Bearing 3,4,5-Trialkylpyrazolyl Groups

Among the 1,3,5-trisubstituted 2,4,6-triethylbenzenes bearing pyrazolyl groups, the compounds with 3,5-dimethylpyrazolyl moieties were found to be effective receptors for ammonium ions (NH4 +). The current study investigated the extent to which the incorporation of an additional alkyl group in the 4-position of the pyrazole ring affects the binding properties of the new compounds. 1H NMR spectroscopic titrations and investigations using isothermal titration calorimetry revealed that this small structural variation leads to a significant increase in the binding strength towards NH4 + and also improves the binding preference for NH4 + over K+. In addition to the studies in solution, crystalline complexes of the new triethyl- and trimethylbenzene derivatives, bearing 3,4,5-trialkylpyrazolyl groups, with NH4 +PF6 − were obtained and analyzed in detail. It is noteworthy that two of the crystal structures discussed in this work are characterized by the presence of two types of ammonium complexes. Studies focusing on the development of new artificial ammonium receptors are motivated, among other things, by the need for more selective ammonium sensors than those based on the natural ionophore nonactin.

Molecular Recognition of Disaccharides in Water: Preorganized Macrocyclic or Adaptive Acyclic?

When facing the dilemma of following a preorganized or adaptive design approach in conceiving the architecture of new biomimetic receptors for carbohydrates, shape‐persistent macrocyclic structures were most often chosen to achieve effective recognition of neutral saccharides in water. In contrast, acyclic architectures have seldom been explored, even though potentially simpler and more easily accessible. In this work, comparison of the binding properties of two structurally related diaminocarbazolic receptors, featuring a macrocyclic and an acyclic tweezer‐shaped architecture, highlighted the advantages provided by the acyclic receptor in terms of selectivity in the recognition of 1,4‐disaccharides of biological interest. Selective recognition of GlcNAc2, the core fragment of N‐glycans exposed on the surface of enveloped viruses, stands as an emblematic example. NMR spectroscopic data and molecular modeling calculations were used to ascertain the differences in binding mode and to shed light on the origin of recognition efficacy and selectivity.

Positional isomeric effect of acyclic hosts on supramolecular recognition of anionic guests

• Anion coordinated neutral/charged self-assemblies of positional isomeric receptors. • Acyclic positional isomeric receptor with different functionalities is discussed. • Anion-coordinated different types of molecular assemblies are summarized. • Aerial CO 2 uptake, extraction, transport phenomena are also discussed. Two or more supramolecular hydrogen-bonding receptor scaffolds having identical molecular formulas act as positional isomers only when the position of a substituent or a receptor arm or double/triple bond of one isomer differ from another isomer. The review summarizes the research on anion coordination chemistry of last decade affected by the positional isomeric acyclic receptors. The detailed and comprehensive account of reported examples of one or more anionic guest/hydrated-anionic guest assisted self-assemblies (neutral or charged) of artificial acyclic isomers (monopodal or linear, dipodal, triodal, hexapodal), affected by the terminal aryl substituents or the receptor arms with respect to central aryl spacer are systematically incorporated in the review. The review specifically consolidates the underexplored broad area of anion recognition chemistry affected by positional isomerism of acyclic amine, amide, urea, thiourea functionalized receptors/sensors in solid as well as in solution state. These substituent dependent isomeric systems could provide insights into the fundamental hydrogen-bonded anion-receptor chemistry and also useful for understanding the biological and environmental processes followed by the crystal engineering as well as extraction, aerial CO 2 fixation, sensing or transport phenomena of anions. Discussions relating to the construction of some typical examples of anion-coordinated self-assembled supramolecular architectures such as molecular capsules, barrels, helicates, foldamer, tetrahedral cages and mechanically interlocked systems by these positional isomeric podands are also included in this review.

Solvent-Controlled Self-Assembled Oligopyrrolic Receptor.

We report a fully organic pyridine-tetrapyrrolic U-shaped acyclic receptor 10, which prefers a supramolecular pseudo-macrocyclic dimeric structure (10)2 in a less polar, non-coordinating solvent (e.g., CHCl3). Conversely, when it is crystalized from a polar, coordinating solvent (e.g., N,N-dimethylformamide, DMF), it exhibited an infinite supramolecular one-dimensional (1D) “zig-zag” polymeric chain, as inferred from the single-crystal X-ray structures. This supramolecular system acts as a potential receptor for strong acids, e.g., p-toluenesulfonic acid (PTSA), methane sulfonic acid (MSA), H2SO4, HNO3, and HCl, with a prominent colorimetric response from pale yellow to deep red. The receptor can easily be recovered from the organic solution of the host–guest complex by simple aqueous washing. It was observed that relatively stronger acids with pKa < −1.92 in water were able to interact with the receptor, as inferred from 1H NMR titration in tetrahydrofuran-d8 (THF-d8) and ultraviolet–visible (UV–vis) spectroscopic titrations in anhydrous THF at 298 K. Therefore, this new dynamic supramolecular receptor system may have potentiality in materials science research.

Complexes Formed between Artificial Receptors and β‐Glucopyranoside in the Crystalline State

In contrast to numerous known crystal structures of protein‐carbohydrate complexes, which act as a source of structural information about carbohydrate‐mediated recognition processes, there are only individual literature reports on crystal structures of complexes formed between artificial receptors and sugars. In this context, the new crystalline complexes of acyclic receptors and β‐d‐glucopyranoside described in this article provide particularly valuable model systems to study the basic molecular features of carbohydrate recognition. The detailed analyses of the binding modes observed in these complexes have shown their remarkable similarity to those used by carbohydrate‐binding proteins. It is noteworthy that many of the basic molecular features of protein‐carbohydrate interactions, that have been summarized years ago in some literature reports, apply to interactions observed in complexes formed by the artificial receptors.

Effective Recognition of Caffeine by Diaminocarbazolic Receptors.

Caffeine is a competitive inhibitor of adenosine receptors and possesses wide pharmacological activity. Artificial receptors recognizing caffeine potentially have a wide range of biomedical and industrial applications. Herein, we describe two structurally related and readily available artificial receptors: 1) a macrocyclic receptor, which binds caffeine with the unprecedented affinity of 9.3 μM, though with poor selectivity; and 2) a tweezers-like structure, showing an affinity of 26 μM and a 4.5-fold and 6-fold selectivity compared to theophylline and theobromine, respectively. Binding affinities were measured by 1 H NMR titrations and were confirmed by isothermal titration calorimetry. The X-ray structure of the complex between caffeine and the acyclic receptor revealed the origin of the recognition, explained the selectivity, and shed light on the role of hydrogen bonding and CH-π/π-π interactions.

Molecular Recognition of Pyrophosphate with Extended Bis(Zn(II)-DPA) Derivatives.

A series of pyrophosphate (PPi) receptors were synthesized, and their binding affinities toward both PPi and adenosine triphosphate were evaluated in N-(2-hydroxyethyl)piperazine-N'-ethanesulfonic acid-buffered solution. The presence of two hydrogen bond donors slightly retarded the reaction rate of anionic guest exchange, while four had a significant retardation effect. A macrocyclic receptor, 17, exhibited superior selectivity toward PPi compared with acyclic receptors, presumably due to effective steric interactions. Isothermal titration calorimetry experiments and potentiometric titration experiments revealed the effect of the substituent structure on the degree of anion guest stabilization and the deprotonation of water molecules bound to zinc(II) ions, as well as the guest binding thermodynamics.

Pharmaceutical Applications of Molecular Tweezers, Clefts and Clips.

Synthetic acyclic receptors, composed of two arms connected with a spacer enabling molecular recognition, have been intensively explored in host-guest chemistry in the past decades. They fall into the categories of molecular tweezers, clefts and clips, depending on the geometry allowing the recognition of various guests. The advances in synthesis and mechanistic studies have pushed them forward to pharmaceutical applications, such as neurodegenerative disorders, infectious diseases, cancer, cardiovascular disease, diabetes, etc. In this review, we provide a summary of the synthetic molecular tweezers, clefts and clips that have been reported for pharmaceutical applications. Their structures, mechanism of action as well as in vitro and in vivo results are described. Such receptors were found to selectively bind biological guests, namely, nucleic acids, sugars, amino acids and proteins enabling their use as biosensors or therapeutics. Particularly interesting are dynamic molecular tweezers which are capable of controlled motion in response to an external stimulus. They proved their utility as imaging agents or in the design of controlled release systems. Despite some issues, such as stability, cytotoxicity or biocompatibility that still need to be addressed, it is obvious that molecular tweezers, clefts and clips are promising candidates for several incurable diseases as therapeutic agents, diagnostic or delivery tools.

Recognition and Sensing of Guanidine-containing Biomolecules in Aqueous Medium

A dicarboxylate-based fluorescent receptor has been synthesized for the recognition of the guanidinium ion and guanidine-containing biomolecules in aqueous medium to address the issue of biomolecular interaction. The acyclic receptor binds to guests in a 1: 2 mode due to the flexibility of its binding motifs. The host-guest binding behavior was studied by means of UV and fluorescence titration. The binding of the host with the guanidinium ion was found to be stronger than with the other guanidine-containing guests.

Macrocyclic bis-urea receptor: Synthesis, crystal structure and phosphate binding properties

A macrocyclic bis-urea receptor (L1) and two acyclic bis-urea analogues (L2 and L3) have been synthesized. The crystal structure of L1 was obtained. The experimental results show that the receptor L1 has high selectivity to H2PO4−. Meanwhile, compared with the acyclic receptors L2 and L3, L1 has higher binding ability to H2PO4−. The results of density functional theory (DFT) calculations deepened our understanding on L1 conformations stability and its anion-binding property.

Binding consistency of anions by the effect of aromatic meta-substitution of bis-urea receptors: entrapment of hexafluorosilicate clusters

The solid as well as solution state preferential and discriminating binding of hexafluorosilicate anions depending on aromatic meta-substitution with respect to adjacent urea moieties by self-assembly of isomeric neutral bis-urea acyclic receptors.

Acyclic retinoid and angiotensin-II receptor blocker exert a combined protective effect against diethylnitrosamine-induced hepatocarcinogenesis in diabetic OLETF rats

BackgroundInsulin resistance (IR) is closely associated with the progression of hepatocellular carcinoma (HCC). Acyclic retinoid (ACR) targets retinoid X receptor α and reportedly prevents HCC recurrence in clinical practice. Angiotensin-II receptor blocker (ARB) can also inhibit experimental hepatocarcinogenesis and HCC development. These are reported to suppress IR-based hepatocarcinogenesis; however, limited data are available regarding the combined effects of both these agents. This study aimed to investigate the combined chemopreventive effect of ACR and ARB on liver tumorigenesis on rats with congenital diabetes.MethodsMale diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats underwent 70% partial hepatectomy following a single intraperitoneal injection of diethylnitrosamine to induce hepatocarcinogenesis and the administration of ACR (peretinoin, 40 mg/kg/day), ARB (losartan, 30 mg/kg/day), and a combination of ACR and ARB. Six weeks thereafter, we assessed the size and number of the pre-neoplastic lesions (PNL) as well as the altered angiogenesis, oxidative stress, and chronic inflammation in the liver. Moreover, we assessed the effects exerted by ACR and ARB on in vitro cell growth in human HCC cell lines and human umbilical vascular endothelial cells (HUVECs).ResultsOLETF rats showed increase in the size and number of PNLs compared to LETO rats. ACR suppressed the augmentation in size and number of PNLs in the OLETF rats with suppression of cell growth, intrahepatic angiogenesis, lipid peroxidation, oxidative DNA damage, and proinflammatory cytokine production. Combining ACR with ARB enhanced the tumor-suppressive effect and ameliorated intrahepatic angiogenesis, lipid peroxidation, and proinflammatory status; however, cell growth and oxidative DNA damage remained unchanged. IR-mimetic condition accelerated in vitro proliferative activity in human HCC cells, while ACR inhibited this proliferation with G0/G1 arrest and apoptosis. Furthermore, ACR and ARB significantly attenuated the HUVECs proliferation and tubular formation under the IR-mimetic condition, and a combination of both agents demonstrated greater inhibitory effects on HUVEC growth than each single treatment.ConclusionsACR and ARB exert a combined inhibitory effect against IR-based hepatocarcinogenesis by the inhibition of cell growth, intrahepatic angiogenesis, and oxidative stress. Thus, this combination therapy appears to hold potential as a chemopreventive treatment therapy against HCC.

Synthetic Receptors for the Recognition and Discrimination of Post-Translationally Methylated Lysines.

Post-translational modifications (PTMs) describe the chemical alteration of proteins after their biosynthesis in ribosomes. PTMs play important roles in cell biology, including the regulation of gene expression, cell-cell interactions and the development of different diseases. A prominent class of PTMs is the side-chain methylation of lysine. For the analysis and discrimination of differently methylated lysines, antibodies are widely used, although methylated peptide and protein targets are known to be particularly difficult to differentiate by antibody-based affinity reagents; an additional challenge can be batch-to-batch reproducibility. The application of mass spectrometry techniques for methyllysine discrimination requires a complex sample preparation procedure and is not suited for working in cells. The desire to overcome the above-mentioned challenges has promoted the development of synthetic receptor molecules that recognise and bind methyllysines. Such "artificial antibodies" are of interest for a number of applications, for example, as reagents in biochemical assays, for the isolation and purification of post-translationally methylated proteins and for the tracking of signalling pathways. Moreover, they offer new approaches in diagnostics and therapy. This review delivers an overview of the broad field of methyllysine binding and covers a wide range of synthetic receptors used for the recognition of methylated lysines, including calixarenes, resorcinarenes, pillararenes, disulfide cyclophanes, cucurbiturils and acyclic receptors.

A glycoluril dimer-triptycene hybrid receptor: synthesis and molecular recognition properties.

The strategic combination of the methylene bridged glycoluril dimer and triptycene skeletons delivers acyclic water soluble hybrid receptor 1 which is analogous to cucurbit[6]uril. The molecular recognition properties of host 1 toward hydrophobic cationic guests are investigated in detail by a combination of 1H NMR spectroscopy and isothermal titration calorimetry (ITC) studies. The fluorescence emission of 1 can be selectively and efficiently quenched upon the formation of 1·26 and 1·28 complexes.

Assembly-enhanced molecular recognition of calix[6]arene

We comparatively investigated the molecular recognition of the amphiphilic derivatives of p-sulfonatocalix[n]arenes (SCnA-Rs, n = 4 and 6) both in aqueous solution and at the interface of liposome. When the recognition events transfer from aqueous solution to the self-assembled interface, the binding capability of SC6A-R increases drastically, but not for SC4A-R. It originates from the conformational regulation that the complicated conformation of SC6A-R in aqueous solution was immobilized to the cone shape upon embedding SC6A-R into the liposome. The resulting cone shape is privileged to accommodate guests into its cavity. Such an assembly-enhanced molecular recognition strategy could be transferable to other macrocyclic, acyclic, artificial, and natural receptors with conformational flexibility.

8-Propyldithieno[3,2-b:2',3'-e]pyridine-3,5-diamine (DITIPIRAM) Derivatives as Neutral Receptors Tailored for Binding of Carboxylates.

The DITIPIRAM (8-propyldithieno[3,2-b:2',3'-e]pyridine-3,5-diamine)-based receptors 11 and 12 were readily synthesized, and their anion-binding properties were studied both in solution and in the solid-state. 1H NMR titrations revealed that receptor 12 equipped with two phenyl-urea groups preferentially binds carboxylates, even in the highly competitive DMSO-d6/CD3OH solvent mixture. X-ray analysis showed that receptor 12 exhibited great complementarity for benzoate, which is cooperatively bound by the means of four highly directional hydrogen bonds from the two urea groups. Comparison with the most effective acyclic receptors based on a structurally related rigid carbazole platform demonstrates that the DITIPIRAM motif provides a better suited geometry in the binding pocket, and consequently stronger anion binding.

Acyclic halogen and hydrogen bonding diquat-containing receptors for the electrochemical sensing of anions

The first examples of halogen and hydrogen bonding anion receptors containing the redox-active dicationic diquat motif and their anion recognition and electrochemical sensing properties are described. The acyclic receptors demonstrated strong binding affinities for halide anions in competitive solvents, with the most potent anion binding behaviour observed for the halogen bonding analogue. The redox-active diquat group is shown to be an effective electrochemical sensing probe, undergoing significant cathodic perturbations of the diquat2+/diquat+ redox couple upon the addition of halides.

Neutral bimetallic rhenium(I)-containing halogen and hydrogen bonding acyclic receptors for anion recognition

Neutral bimetallic rhenium(I) bis-triazole pyrimidine halogen bonding (XB) and hydrogen bonding (HB) acyclic anion receptors are prepared and 1H NMR titration investigations reveal the XB receptor exhibits significantly superior anion recognition behaviour.

Investigation of structural mimetics of natural phosphate ion binding motifs.

Phosphates are ubiquitous in biology and nearly half of all proteins interact with their partners by means of recognition of phosphate residues. Therefore, a better understanding of the phosphate ion binding by peptidic structures is highly desirable. Two new receptors have been designed and synthesized and their anion binding properties in an acetonitrile solution have been determined. The structure of hosts mimics a part of the kinase active site that is responsible for the recognition of the phosphate residue. New hosts contain additional free amino groups with the aim to facilitate coordination of protonated anions, such as dihydrogen phosphate. According to spectrophotometric measurements, stepwise 1:1 and 1:2 binding modes have been observed for both receptors in the presence of acetate, hydrogen sulfate and dihydrogen phosphate. Compared with the acyclic receptor, the macrocyclic receptor has demonstrated a remarkably enhanced selectivity for dihydrogen phosphate over other anions. Fluorometric measurements have revealed different responses of the acyclic and macrocyclic receptors towards anions. However, in both cases, a 5–8 nm hypsochromic shift of fluorescence maximum has been observed upon interaction of acetate and dihydrogen phosphate with receptors.