Recent Advances in π-Stacking Interaction-Controlled Asymmetric Synthesis.

The π-stacking interaction is one of the most important intramolecular and intermolecular noncovalent interactions in organic chemistry. It plays an important role in stabilizing some structures and transition states in certain reactions via both intramolecular and intermolecular interactions, facilitating different selectivities, such as chemo-, regio-, and stereoselectivities. This minireview focuses on the recent examples of the π-stacking interaction-controlled asymmetric synthesis, including auxiliary-induced asymmetric synthesis, kinetic resolution, asymmetric synthesis of helicenes and heterohelicenes, and multilayer 3D chiral molecules.

Structural Properties of Hachimoji Nucleic Acids and Their Building Blocks: Comparison of Genetic Systems with Four, Six and Eight Alphabets.

Expansion of the genetic alphabet is an ambitious goal. A recent breakthrough has led to the eight-base (hachimoji) genetics having canonical and unnatural bases. However, very little is known on the molecular-level features that facilitate the candidature of unnatural bases as genetic alphabets. Here we amalgamated DFT calculations and MD simulations to analyse the properties of the constituents of hachimoji DNA and RNA. DFT reveals the dominant syn conformation for isolated unnatural deoxyribonucleosides and at the 5'-end of oligonucleotides, although an anti/syn mixture is predicted at the nonterminal and 3'-terminal positions. However, isolated ribonucleotides prefer an anti/syn mixture, but mostly prefer anti conformation at the nonterminal positions. Further, the canonical base pairing combinations reveals significant strength, which may facilitate replication of hachimoji DNA. We also identify noncanonical base pairs that can better tolerate the substitution of unnatural pairs in RNA. Stacking strengths of 51 dimers reveals higher average stacking stabilization of dimers of hachimoji bases than canonical bases, which provides clues for choosing energetically stable sequences. A total of 14.4 µs MD simulations reveal the influence of solvent on the properties of hachimoji oligonucleotides and point to the likely fidelity of replication of hachimoji DNA. Our results pinpoint the features that explain the experimentally observed stability of hachimoji DNA.

Discovery of aromatic 2-(3-(methylcarbamoyl) guanidino)-N-aylacetamides as highly potent chitinase inhibitors.

Chitinases are important glycoside hydrolases that are closely related to bacterial pathogenesis, fungal cell wall remodelling, and insect moulting. Consequently, chitinases have become attractive targets for therapeutic drugs and pesticides. In this study, we designed and synthesised a series of novel chitinase inhibitors based on the N-methylcarbamoylguanidinyl group of the natural product argifin. The most active compound 8h showed strong inhibitory activity against the group I chitinases HsChit1, SmChiB, and OfChi-h, with IC50 values of 0.19 µM, 4.2 nM, and 25 nM, respectively. Binding mode studies revealed that the compound 8h formed π-π stacking/hydrophobic interactions at +1 or +2 subsite of chitinases. In addition, a key hydrogen bond net was formed between the pharmacophore N-methylcarbamoylguanidinyl and key residues at the -1 subsite. Together, the findings of this study provide novel insights into the development of potent small-molecule chitinase inhibitors using a combination of planar structures and N-methylcarbamoylguanidinyl.

Trapping an Ester Hydrate Intermediate in a π-Stacked Macrocycle with Multiple Hydrogen Bonds.

Ester hydrates, as the intermediates of the esterification between acid and alcohol, are very short-lived and challenging to be trapped. Therefore, the crystal structures of ester hydrates have rarely been characterized. Herein, we present that the mono-deprotonated ester hydrates [CH3OSO2(OH)2]-, serving as the template for the self-assembly of a π-stacked boat-shaped macrocycle (CH3OSO2(OH)2)0.67(CH3OSO3)1.33@{[ClLCoII]6}·Cl4·13CH3OH·9H2O (1) (L = tris(2-benzimidazolylmethyl) amine), can be trapped in the host by multiple NH···O hydrogen bonds. In the solution of CoCl2, L, and H2SO4 in MeOH, HSO4- reacts with MeOH, producing [CH3OSO3]- via the ester hydrate intermediate of [CH3OSO3(OH)2]-. Both the product and the intermediate serve as the template directing the self-assembly of the π-stacked macrocycle, in which the short-lived ester hydrate is firmly trapped and stabilized, as revealed by single-crystal analysis.

π-π Stacking Interaction of Metal Phenoxyl Radical Complexes.

π-π stacking interaction is well-known to be one of the weak interactions. Its importance in the stabilization of protein structures and functionalization has been reported for various systems. We have focused on a single copper oxidase, galactose oxidase, which has the π-π stacking interaction of the alkylthio-substituted phenoxyl radical with the indole ring of the proximal tryptophan residue and catalyzes primary alcohol oxidation to give the corresponding aldehyde. This stacking interaction has been considered to stabilize the alkylthio-phenoxyl radical, but further details of the interaction are still unclear. In this review, we discuss the effect of the π-π stacking interaction of the alkylthio-substituted phenoxyl radical with an indole ring.

The Bifurcated σ-Hole···σ-Hole Stacking Interactions.

The bifurcated σ-hole···σ-hole stacking interactions between organosulfur molecules, which are key components of organic optical and electronic materials, were investigated by using a combined method of the Cambridge Structural Database search and quantum chemical calculation. Due to the geometric constraints, the binding energy of one bifurcated σ-hole···σ-hole stacking interaction is in general smaller than the sum of the binding energies of two free monofurcated σ-hole···σ-hole stacking interactions. The bifurcated σ-hole···σ-hole stacking interactions are still of the dispersion-dominated noncovalent interactions. However, in contrast to the linear monofurcated σ-hole···σ-hole stacking interaction, the contribution of the electrostatic energy to the total attractive interaction energy increases significantly and the dispersion component of the total attractive interaction energy decreases significantly for the bifurcated σ-hole···σ-hole stacking interaction. Another important finding of this study is that the low-cost spin-component scaled zeroth-order symmetry-adapted perturbation theory performs perfectly in the study of the bifurcated σ-hole···σ-hole stacking interactions. This work will provide valuable information for the design and synthesis of novel organic optical and electronic materials.

The CH-π Interaction in Protein-Carbohydrate Binding: Bioinformatics and In Vitro Quantification.

The molecular recognition of carbohydrates by proteins plays a key role in many biological processes including immune response, pathogen entry into a cell, and cell-cell adhesion (e.g., in cancer metastasis). Carbohydrates interact with proteins mainly through hydrogen bonding, metal-ion-mediated interaction, and non-polar dispersion interactions. The role of dispersion-driven CH-π interactions (stacking) in protein-carbohydrate recognition has been underestimated for a long time considering the polar interactions to be the main forces for saccharide interactions. However, over the last few years it turns out that non-polar interactions are equally important. In this study, we analyzed the CH-π interactions employing bioinformatics (data mining, structural analysis), several experimental (isothermal titration calorimetry (ITC), X-ray crystallography), and computational techniques. The Protein Data Bank (PDB) has been used as a source of structural data. The PDB contains over 12 000 protein complexes with carbohydrates. Stacking interactions are very frequently present in such complexes (about 39 % of identified structures). The calculations and the ITC measurement results suggest that the CH-π stacking contribution to the overall binding energy ranges from 4 up to 8 kcal mol-1 . All the results show that the stacking CH-π interactions in protein-carbohydrate complexes can be considered to be a driving force of the binding in such complexes.

Correlations between functional porphyrin positions and accumulation in cancer cells.

Porphyrin is accumulated in tumours due to its interaction with protein. Cancer therapy with porphyrin as a carrier molecule is attracting attention. Porphyrin displays two functional sites termed ß- and meso-positions. A correlation between the functional position on the porphyrin molecule and the ability to accumulate in cancer cells is observed in the present study. The accumulation of porphyrin derivatives was determined by measuring fluorescence intensity after incubation for 2 and 24 h. The accumulation of cancer cells depended on the position and length of functional groups. Estimated binding constants between porphyrin and bovine serum albumin suggest that the position of functional groups leads to changes in binding affinity and influences the accumulation of porphyrin derivatives in cancer cells.

Molecular beacon immobilized on graphene oxide for enzyme-free signal amplification in electrochemiluminescent determination of microRNA.

An electrochemiluminescence (ECL) based biosensor is described for determination of microRNAs in the A549 cell line. Firstly, graphene oxide (GO) is dripped onto a glassy carbon electrode surface to form an interface to which one end of the capture probe (with a stem-loop structure) can be anchored through π-interaction via dangling unpaired bases. The other end of the capture probe is directed away from the GO surface to make it stand upright. Target microRNAs can open the hairpin structure to form a double-stranded DNA-RNA structure. Two auxiliary probes, generating a hybridization chain reaction, are used to elongate the DNA duplex. Finally, doxorubicin-modified cadmium telluride quantum dot nanoparticles (Dox-CdTe QD) are intercalated into the base pairs of the hybrid duplexes to act as signalling molecules. The ECL signal of the Dox-CdTe QD increases proportionally with the concentration of microRNAs, specifically for microRNA-21. The assay covers a wide linear range (1 fM to 0.1 nM), has a low detection limit for microRNA-21 (1 fM), and is selective, reproducible, and stable. Graphical abstract An enzyme-free amplification electrochemiluminescent assay is described to quantitative detection of microRNA in the A549 cell line. Graphene oxide was used to immobilize capture probes obviating the special modification. Doxorubicin-modified cadmium telluride quantum dot nanoparticles are intercalated into the base pairs of the hybrid duplexes to act as signalling molecules.

A multifunctional probe based on the use of labeled aptamer and magnetic nanoparticles for fluorometric determination of adenosine 5'-triphosphate.

A multifunctional fluorescent probe is synthesized for the determination of adenosine 5'-triphosphate (ATP). The 6-carboxyfluorescein-labeled aptamer (FAM-aptamer) was bound to the surface of magnetite nanoparticles coated with polydopamine (Fe3O4@PDA) by π-π stacking interaction to form the multifunctional probe. The probe has three functions including recognition, magnetic separation, and yielding a fluorescent signal. In the presence of ATP, FAM-aptamer on the surface of the probe binds to ATP and returns to the solution. Thus, the fluorescence of the supernatant is enhanced and can be related to the concentration of ATP. Fluorescence intensities were measured at excitation/emission wavelengths of 494/526 nm. Response is linear in the 0.1-100 µM ATP concentration range, and the detection limit is 89 nM. The probe was applied to the quantitation of ATP in spiked human urine and serum samples, with recoveries ranging between 94.8 and 102%. Graphical abstract A multifunctional fluorescent probe based on the use of FAM-aptamer and Fe3O4@PDA is described for the determination of ATP in spiked human urine and serum samples. FAM-aptamer: 6-carboxyfluorescein-labeled aptamer; Fe3O4@PDA: magnetite nanoparticles coated with polydopamine. ATP: adenosine 5'-triphosphate.

Photoelectrochemical aptasensor for sulfadimethoxine using g-C3N4 quantum dots modified with reduced graphene oxide.

A novel photoelectrochemical (PEC) aptasensor with graphitic-phase carbon nitride quantum dots (g-C3N4; QDs) and reduced graphene oxide (rGO) was fabricated. The g-C3N4 QDs possess enhanced emission quantum yield (with an emission peak at 450 nm), improved charge separation ability and effective optical absorption, while rGO has excellent electron transfer capability. Altogether, this results in improved PEC performance. The method is making use of an aptamer against sulfadimethoxine (SDM) that was immobilized on electrode through π stacking interaction. Changes of the photocurrent occur because SDM as a photogenerated hole acceptor can further accelerate the separation of photoexcited carriers. Under optimized conditions and at an applied potential of +0.2 V, the aptasensor has a linear response in the 0.5 nM to 80 nM SDM concentration range, with a 0.1 nM detection limit (at S/N = 3). The method was successfully applied to the analysis of SDM in tap, lake and waste water samples. Graphical abstract Graphitic-phase carbon nitride (g-C3N4) quantum dots (QDs) and reduced graphene oxide (rGO) were used to modify fluorine-doped SnO2 (FTO) electrodes for use in a photoelectrochemical (PEC) aptasensor. SDM oxidized by the hole on valance band (VB) of g-C3N4 QDs promote the separation of electron in the conductive band (CB), which made the changes of photocurrent signal.

Van Der Waals heterogeneous layer-layer carbon nanostructures involving π···H-C-C-H···π···H-C-C-H stacking based on graphene and graphane sheets.

Noncovalent interactions involving aromatic rings, such as π···π stacking, CH···π are very essential for supramolecular carbon nanostructures. Graphite is a typical homogenous carbon matter based on π···π stacking of graphene sheets. Even in systems not involving aromatic groups, the stability of diamondoid dimer and layer-layer graphane dimer originates from C - H···H - C noncovalent interaction. In this article, the structures and properties of novel heterogeneous layer-layer carbon-nanostructures involving π···H-C-C-H···π···H-C-C-H stacking based on [n]-graphane and [n]-graphene and their derivatives are theoretically investigated for n = 16-54 using dispersion corrected density functional theory B3LYP-D3 method. Energy decomposition analysis shows that dispersion interaction is the most important for the stabilization of both double- and multi-layer-layer [n]-graphane@graphene. Binding energy between graphane and graphene sheets shows that there is a distinct additive nature of CH···π interaction. For comparison and simplicity, the concept of H-H bond energy equivalent number of carbon atoms (noted as NHEQ), is used to describe the strength of these noncovalent interactions. The NHEQ of the graphene dimers, graphane dimers, and double-layered graphane@graphene are 103, 143, and 110, indicating that the strength of C-H···π interaction is close to that of π···π and much stronger than that of C-H···H-C in large size systems. Additionally, frontier molecular orbital, electron density difference and visualized noncovalent interaction regions are discussed for deeply understanding the nature of the C-H···π stacking interaction in construction of heterogeneous layer-layer graphane@graphene structures. We hope that the present study would be helpful for creations of new functional supramolecular materials based on graphane and graphene carbon nano-structures. © 2017 Wiley Periodicals, Inc.

RNAMotifScanX: a graph alignment approach for RNA structural motif identification.

RNA structural motifs are recurrent three-dimensional (3D) components found in the RNA architecture. These RNA structural motifs play important structural or functional roles and usually exhibit highly conserved 3D geometries and base-interaction patterns. Analysis of the RNA 3D structures and elucidation of their molecular functions heavily rely on efficient and accurate identification of these motifs. However, efficient RNA structural motif search tools are lacking due to the high complexity of these motifs. In this work, we present RNAMotifScanX, a motif search tool based on a base-interaction graph alignment algorithm. This novel algorithm enables automatic identification of both partially and fully matched motif instances. RNAMotifScanX considers noncanonical base-pairing interactions, base-stacking interactions, and sequence conservation of the motifs, which leads to significantly improved sensitivity and specificity as compared with other state-of-the-art search tools. RNAMotifScanX also adopts a carefully designed branch-and-bound technique, which enables ultra-fast search of large kink-turn motifs against a 23S rRNA. The software package RNAMotifScanX is implemented using GNU C++, and is freely available from http://genome.ucf.edu/RNAMotifScanX.

Dynamic Cooperation of Hydrogen Binding and π Stacking in ssDNA Adsorption on Graphene Oxide.

Functional nanoscale structures consisting of a DNA molecule coupled to graphene or graphene oxide (GO) have great potential for applications in biosensors, biomedicine, nanotechnology, and materials science. Extensive studies using the most sophisticated experimental techniques and theoretical methods have still not clarified the dynamic process of single-stranded DNA (ssDNA) adsorbed on GO surfaces. Based on a molecular dynamics simulation, this work shows that an ssDNA segment could be stably adsorbed on a GO surface through hydrogen bonding and π-π stacking interactions, with preferential binding to the oxidized rather than to the unoxidized region of the GO surface. The adsorption process shows a dynamic cooperation adsorption behavior; the ssDNA segment first captures the oxidized groups of the GO surface by hydrogen bonding interaction, and then the configuration relaxes to maximize the π-π stacking interactions between the aromatic rings of the nucleobases and those of the GO surface. We attributed this behavior to the faster forming hydrogen bonding interaction compared to π-π stacking; the π-π stacking interaction needs more relaxation time to regulate the configuration of the ssDNA segment to fit the aromatic rings on the GO surface.

Experimental and theoretical insights in the alkene-arene intramolecular π-stacking interaction.

Chiral acrylic esters derived from biomass were developed as models to have a better insight in the aryl-vinyl π-stacking interactions. Quantum chemical calculations, NMR studies and experimental evidences demonstrated the presence of equilibriums of at least four different conformations: π-stacked and face-to-edge, each of them in an s-cis/s-trans conformation. The results show that the stabilization produced by the π-π interaction makes the π-stacked conformation predominant in solution and this stabilization is slightly affected by the electron density of the aromatic counterpart.

Crystal structure of 7-bromo-4-oxo-4H-chromene-3-carbaldehyde.

In the title compound, C10H5BrO3, a brominated 3-formyl-chromone derivative, all atoms are essentially coplanar (r.m.s. = 0.0631 Šfor the non-H atoms), with the largest deviation from the least-squares plane [0.215 (3) Å] being for the formyl O atom. In the crystal, mol-ecules are linked into tapes through C-H⋯O hydrogen bonds and these tapes are assembled by stacking inter-actions [centroid-centroid distance between the pyran rings = 3.858 (3) Å] to form supra-molecular layers that stack along the c axis.

Crystal structure of (3,5-dibromo-2-hy-droxyphenyl){1-[(naphthalen-1-yl)carbonyl]-1H-pyrazol-4-yl}methanone.

In the title compound, C21H12Br2N2O3, a 1,4-diaroyl pyrazole derivative, the dihedral angles between the naphthalene ring system and the pyrazole ring, the pyrazole and benzene rings, and the naphthalene ring system and benzene ring are 50.0 (2), 51.1 (2) and 1.34 (16)°, respectively. The phenolic proton forms an intra-molecular O-H⋯O hydrogen bond with the adjacent carbonyl O atom. In the crystal, mol-ecules are linked by C-H⋯O hydrogen bonds, forming inversion dimers. The dimers are linked by C-H⋯Br hydrogen bonds, forming double stranded chains along [01-1]. The chains are linked by π-π inter-actions between the pyrazole rings and between the naphthalene and benzene rings [centroid-centroid distances = 3.592 (4) and 3.632 (4) Å, respectively].

Crystal structure of (3,5-di-chloro-2-hy-droxy-phen-yl){1-[(naphthalen-1-yl)carbon-yl]-1H-pyrazol-4-yl}methanone.

The title compound, C21H12Cl2N2O3, is a 1,4-diaroyl pyrazole derivative and has three aromatic rings. The dihedral angles between the naphthalene ring system and the pyrazole ring, the pyrazole and phenyl rings and the naphthalene ring system and the phenyl ring are 49.44 (13), 49.87 (16) and 0.58 (11)°, respectively. The phenolic proton forms an intra-molecular O-H⋯O hydrogen bond with an adjacent carbonyl O atom. In the crystal, the mol-ecules are linked through stacking inter-actions between the pyrazole rings [centroid-centroid distances = 3.546 (3)] and between the naphthalene ring system and the phenyl ring [centroid-centroid distances = 3.609 (4) Å] along the a-axis direction. The mol-ecules are further connected through C-H⋯O hydrogen bonds, forming inversion dimers.

An Atlas of the base inter-RNA stacks involved in bacterial translation.

Nucleobase-specific noncovalent interactions play a crucial role in translation. Herein, we provide a comprehensive analysis of the stacks between different RNA components in the crystal structures of the bacterial ribosome caught at different translation stages. Analysis of tRNA||rRNA stacks reveals distinct behaviour; both the A-and E-site tRNAs exhibit unique stacking patterns with 23S rRNA bases, while P-site tRNAs stack with 16S rRNA bases. Furthermore, E-site stacks exhibit diverse face orientations and ring topologies-rare for inter-chain RNA interactions-with higher average interaction energies than A or P-site stacks. This suggests that stacking may be essential for stabilizing tRNA progression through the E-site. Additionally, mRNA||rRNA stacks reveal other geometries, which depend on the tRNA binding site, whereas 16S rRNA||23S rRNA stacks highlight the importance of specific bases in maintaining the integrity of the translational complex by linking the two rRNAs. Furthermore, tRNA||mRNA stacks exhibit distinct geometries and energetics at the E-site, indicating their significance during tRNA translocation and elimination. Overall, both A and E-sites display a more diverse distribution of inter-RNA stacks compared to the P-site. Stacking interactions in the active ribosome are not simply accidental byproducts of biochemistry but are likely invoked to compensate and support the integrity and dynamics of translation.

Engineering π-Conjugation of Phenylalanine Derivatives for Controllable Chiral Folding and Self-Assemblies.

π-π stacking interaction is an attractive interaction that involves aromatic groups containing π-conjugated domains. It is a promising strategy for stabilizing folded structures with interesting chiroptical properties and manipulating the supramolecular chiral self-assembly process. In this study, we report the engineering of π-conjugated amino acids that utilize π-π stacking interactions to manipulate chiral folding as well as self-assembly evolution. Stepwise conjugation of phenyl, naphthyl, and pyrenyl to N-terminal phenylalanine derivatives witnessed the folding through intramolecular π-interactions in solution phase, which facilitated the formation of chiral geometry and the emergence of chiral optics. Introduction of aromatic domains efficiently lowers the critical aggregation concentration in the aqueous media. Molecular folding enables a special concentration-dependent self-assembly, whereby the supramolecular chirality accomplished inversion with the evolution of helical nanoarchitectures. This work develops a strategy to engineer π-conjugated amino acids with controllable folding behaviors, which also offers implications for the rational design of functional chiral materials.