Chiral Stability Research Articles

Corannulene‐based Quintuple [6]/[7]helicenes: Well‐preserved Bowl Core, Inhibited Bowl Inversion and Supramolecular Assembly with Fullerenes

Herein, corannulene‐based quintuple [6]helicenes (Q[6]H‐1 andQ[6]H‐2) and [7]helicene (Q[7]H) were synthesized via penta‐fold Heck and Mallory reaction. Notably, Q[7]H represents the highest reported helicene based on corannulene. X‐ray crystallography reveals that Q[6]H‐2 adopts a propeller‐shaped conformation with a well‐preserved corannulene core, while Q[6]H‐1 and Q[7]H exhibit quasi‐propeller‐shaped conformations. Upon heating, conformer Q[6]H‐1 undergoes conversion to the thermodynamically more stable conformer Q[6]H‐2, whereas conformer Q[7]H remains unchanged due to larger steric congestion. Racemization of the enantiomer of Q[6]H‐1 and conformational conversion were observed simultaneously at elevated temperature, with DFT studies indicating a racemization barrier of 28.64 kcal·mol‐1. In contrast, the racemization barrier for Q[6]H‐2 was calculated to be 45.46 kcal·mol‐1, indicating exceptional chiral stability. Surprisingly, the bowl inversions of Q[6]H‐1 and Q[6]H‐2 conformers are somewhat inhibited by the helical blades, whereas this was not observed for other possible conformers of Q[6]H. These results first demonstrated that subtle conformational variations can lead to significant changes in chiral stability and bowl inversions of multihelicenes. Due to the well‐preserved corannulene core, propeller‐shaped conformation and electron complementarity, Q[6]H‐2 can recognize fullerenes in both solution and solid state, which is a rare instance of co‐crystallization assembly between multiple helicenes and fullerenes.

Corannulene-based Quintuple [6]/[7]helicenes: Well-preserved Bowl Core, Inhibited Bowl Inversion and Supramolecular Assembly with Fullerenes.

Herein, corannulene-based quintuple [6]helicenes (Q[6]H-1 andQ[6]H-2) and [7]helicene (Q[7]H) were synthesized via penta-fold Heck and Mallory reaction. Notably, Q[7]H represents the highest reported helicene based on corannulene. X-ray crystallography reveals that Q[6]H-2 adopts a propeller-shaped conformation with a well-preserved corannulene core, while Q[6]H-1 and Q[7]H exhibit quasi-propeller-shaped conformations. Upon heating, conformer Q[6]H-1 undergoes conversion to the thermodynamically more stable conformer Q[6]H-2, whereas conformer Q[7]H remains unchanged due to larger steric congestion. Racemization of the enantiomer of Q[6]H-1 and conformational conversion were observed simultaneously at elevated temperature, with DFT studies indicating a racemization barrier of 28.64 kcal·mol-1. In contrast, the racemization barrier for Q[6]H-2 was calculated to be 45.46 kcal·mol-1, indicating exceptional chiral stability. Surprisingly, the bowl inversions of Q[6]H-1 and Q[6]H-2 conformers are somewhat inhibited by the helical blades, whereas this was not observed for other possible conformers of Q[6]H. These results first demonstrated that subtle conformational variations can lead to significant changes in chiral stability and bowl inversions of multihelicenes. Due to the well-preserved corannulene core, propeller-shaped conformation and electron complementarity, Q[6]H-2 can recognize fullerenes in both solution and solid state, which is a rare instance of co-crystallization assembly between multiple helicenes and fullerenes.

Second-Generation Chiral Amino Acid Derivatives Afford High Stereoselectivity and Stability in Aqueous RNA Acylation.

Activated acyl species have proven versatile in the esterification of 2'-OH groups in RNA, enabling structure mapping, caging, profiling, and labeling of the biopolymer. Nearly all reagents developed for this reaction have been achiral; however, a recent study reported that simple chiral amino acid acylimidazole derivatives could yield diastereoselective reactions at RNA 2'-OH in water, enabling up to 4:1 selectivity in screening. Here, we investigated the effect of steric bulk on the stereoselectivity of RNA reaction and on the stability of adducts with a library of 36 chiral acylimidazole scaffolds with increasing steric demand. The results document the highest stereoselectivity yet achieved in RNA acylation reactions, with as high as >99:1 diastereoselectivity at >70% conversion. Also notably, the bulky adducts were found to have markedly improved stability on RNA.

Enantiomeric separation of tryptophan via novel chiral polyamide composite membrane.

The separation of chiral drugs continues to pose a significant challenge. However, in recent years, the emergence of membrane-based chiral separation has shown promising effectiveness due to its environmentally friendly, energy-efficient, and cost-effective characteristics. In this study, we prepared chiral composite membrane via interfacial polymerization (IP), utilizing β-cyclodextrin (β-CD) and piperazine (PIP) as mixed monomers in the aqueous phase. The chiral separation process was facilitated by β-CD, serving as a chiral selective agent. The resulting membrane were characterized using SEM, FT-IR, and XPS. Subsequently, the chiral separation performance of the membrane for DL-tryptophan (Trp) was investigated. Lastly, the water flux, dye rejection, and stability of the membrane were also examined. The results showed that the optimized chiral PIP0.5β-CD0.5 membrane achieved an enantiomeric excess percentage (ee%) of 43.0% for D-Trp, with a solute flux of 66.18 nmol·cm-2·h-1, and maintained a good chiral separation stability. Additionally, the membrane demonstrated positive performance in the selective separation of mixed dyes, allowing for steady operation over a long period of time. This study offers fresh insights into membrane-based chiral separations.

Impact of helical elongation of symmetric oxa[n]helicenes on their structural, photophysical, and chiroptical characteristics.

The adjustment of the main helical scaffold in helicenes is a fundamental strategy for modulating their optical features, thereby enhancing their potential for diverse applications. This work explores the influence of helical elongation (n = 5-9) on the structural, photophysical, and chiroptical features of symmetric oxa[n]helicenes. Crystal structure analyses revealed structural variations with helical extension, impacting torsion angles, helical pitch, and packing arrangements. Through theoretical investigations using density functional theory (DFT) calculations, the impact of helical extension on aromaticity, planarity distortion, and heightened chiral stability were discussed. Photophysical features were studied through spectrophotometric analysis, with insights gained through time-dependent DFT (TD-DFT) calculations. Following optical resolution via chiral high-performance liquid chromatography (HPLC), the chiroptical properties of both enantiomers of oxa[7]helicene and oxa[9]helicene were investigated. A slight variation in the main helical scaffold of oxa[n]helicenes from [7] to [9] induced an approximately three-fold increase in dissymmetry factors with the biggest values of|glum| of oxa[9]helicene (2.2 × 10-3) compared to|glum|of oxa[7]helicene (0.8 × 10-3), findings discussed and supported by TD-DFT calculations.

Potential Application Prospects of Biomolecule-Modified Two-Dimensional Chiral Nanomaterials in Biomedicine.

Chirality, one of the most fundamental properties of natural molecules, plays a significant role in biochemical reactions. Nanomaterials with chiral characteristics have superior properties, such as catalytic properties, optoelectronic properties, and photothermal properties, which have significant potential for specific applications in nanomedicine. Biomolecular modifications such as nucleic acids, peptides, proteins, and polysaccharides are sources of chirality for nanomaterials with great potential for application in addition to intrinsic chirality, artificial macromolecules, and metals. Two-dimensional (2D) nanomaterials, as opposed to other dimensions, due to proper surface area, extensive modification sites, drug loading potential, and simplicity of preparation, are prepared and utilized in diagnostic applications, drug delivery research, and tumor therapy. Current advanced studies on 2D chiral nanomaterials for biomedicine are focused on novel chiral development, structural control, and materials sustainability applications. However, despite the advances in biomedical research, chiral 2D nanomaterials still confront challenges such as the difficulty of synthesis, quality control, batch preparation, chiral stability, and chiral recognition and selectivity. This review aims to provide a comprehensive overview of the origins, synthesis, applications, and challenges of 2D chiral nanomaterials with biomolecules as cargo and chiral modifications and highlight their potential roles in biomedicine.

Experimental evidence on the sustainability of crystallographic and chiral symmetry of L-alanine under dynamic shocked conditions

Over the years, crystallographic phase transitions of the polar and non-polar amino acids under static high-pressure-temperature conditions have been well documented, especially after the development of the diamond anvil cell techniques. In contrast, the crystallographic structural science of such primary amino acids under dynamic shocked conditions is still to be explored substantially as it is in a premature stage which requires being loaded with a few possible deep insights whereby exploring the structural kinetics could be a reality. In the present context, we have performed the acoustic shock wave recovery experiment on non-polar amino acid of L-Alanine powder samples such that X-ray diffraction (XRD) and circular dichroism (CD) spectroscopic techniques have been enabled to investigate the structural and chiral stability under shocked conditions. Based on the observed results, it is observed that the crystallographic structure with the P212121 space group and the same chirality is maintained even at the 200-shocked condition with a transient pressure of 2.0 MPa. The observed dynamic shock wave loading structural stability outcome is identified to be well-matched with the previous static high-pressure compression results.

Two-Dimensional Hetero- to Homochiral Phase Transition from Dynamic Adsorption of Barbituric Acid Derivatives.

Barbituric acid derivative (TDPT) is an achiral molecule, and its adsorption on a surface results in two opposite enantiomerically oriented motifs, namely TDPT-Sp and Rp. Two types of building blocks can be formed; block I is enantiomer-pure and is built up of the same motifs (format SpSp or RpRp) whereas block II is enantiomer-mixed and composes both motifs (format SpRp), respectively. The organization of the building blocks determines the formation of different nanoarchitectures which are investigated using scanning tunneling microscopy at a liquid/HOPG interface. Sophisticated, highly symmetric "nanowaves" are first formed from both building blocks I and II and are heterochiral. The "nanowaves" are metastable and evolve stepwisely into more close-packed "nanowires" which are formed from enantiomer-pure building block I and are homochiral. A dynamic hetero- to homochiral transformation and simultaneous multi-scale phase transitions are demonstrated at the single-molecule level. Our work provides novel insights into the control and the origin of chiral assemblies and chiral transitions, revealing the various roles of enantiomeric selection and chiral competition, driving forces, stability and molecular coverage.

Discovery of Acyl-Indole Derivatives as Pan-Serotype Dengue Virus NS4B Inhibitors.

In the absence of any approved dengue-specific treatment, the discovery and development of a novel small-molecule antiviral for the prevention or treatment of dengue are critical. We previously reported the identification of a novel series of 3-acyl-indole derivatives as potent and pan-serotype dengue virus inhibitors. We herein describe our optimization efforts toward preclinical candidates 24a and 28a with improved pan-serotype coverage (EC50's against the four DENV serotypes ranging from 0.0011 to 0.24 μM for 24a and from 0.00060 to 0.084 μM for 28a), chiral stability, and oral bioavailability in preclinical species, as well as showing a dose-proportional increase in efficacy against DENV-2 infection in vivo in mice.

Design and Electrochemical Chiral Sensing of the Robust Sandwich Chiral Composite d-His-ZIF-8@Au@ZIF-8.

In the pursuit of chiral materials with significant chiral recognition effects and stability, various strategies have been explored, among which the integration of metal nanoparticles and chiral metal-organic frameworks (CMOFs) is highly promising. However, metal nanoparticles (MNPs)/CMOFs show high chiral properties but inferior stabilities due to the MNPs being easily detached from the outside layer under certain conditions. Sandwich MOFs@MNPs@CMOF chiral materials can overcome this dilemma because the sandwich structure can maximize the regulation of the chiral interface activity, while the controlled outer layer can stop the MNPs from falling off in the procedure of chiral recognition. Here, a novel sandwich chiral material (d-His-ZIF-8@Au@ZIF-8) was synthesized by a ligand-assisted strategy with a well-defined sandwich morphology and chiral recognition capabilities. The electrochemical chiral recognition showed that d-His-ZIF-8@Au@ZIF-8 was the most efficient for the enantiomer of phenylalanine (Phe). This experiment presents a novel perspective for the fabrication of a chiral electrochemical sensing platform based on a solid sandwich chiral nanocomposite.

Chiral Skeletons of Mesoporous Silica Nanospheres to Mitigate Alzheimer's β-Amyloid Aggregation.

Chiral mesoporous silica (mSiO2) nanomaterials have gained significant attention during the past two decades. Most of them show a topologically characteristic helix; however, little attention has been paid to the molecular-scale chirality of mSiO2 frameworks. Herein, we report a chiral amide-gel-directed synthesis strategy for the fabrication of chiral mSiO2 nanospheres with molecular-scale-like chirality in the silicate skeletons. The functionalization of micelles with the chiral amide gels via electrostatic interactions realizes the growth of molecular configuration chiral silica sols. Subsequent modular self-assembly results in the formation of dendritic large mesoporous silica nanospheres with molecular chirality of the silica frameworks. As a result, the resultant chiral mSiO2 nanospheres show abundant large mesopores (∼10.1 nm), high pore volumes (∼1.8 cm3·g-1), high surface areas (∼525 m2·g-1), and evident CD activity. The successful transfer of the chirality from the chiral amide gels to composited micelles and further to asymmetric silica polymeric frameworks based on modular self-assembly leads to the presence of molecular chirality in the final products. The chiral mSiO2 frameworks display a good chiral stability after a high-temperature calcination (even up to 1000 °C). The chiral mSiO2 can impart a notable decline in β-amyloid protein (Aβ42) aggregation formation up to 79%, leading to significant mitigation of Aβ42-induced cytotoxicity on the human neuroblastoma line SH-ST5Y cells in vitro. This finding opens a new avenue to construct the molecular chirality configuration in nanomaterials for optical and biomedical applications.

Enantioselectivity of indoxacarb enantiomers in Bombyx mori larvae: toxicity, bioaccumulation and biotransformation.

Indoxacarb is a chiral insecticide with excellent insecticidal activity against lepidopterous insects. Because of their enantioselectivity, chiral pesticides' environmental behavior at the enantiomeric level has been highlighted. The chiral stability, enantioselective bioaccumulation, biotransformation behavior of indoxacarb to a non-target insect silkworm are still unclear. A chiral analysis method for indoxacarb and its metabolite DCJW in silkworm was developed using liquid chromatography and high-resolution mass spectrometry (HPLC/HRMS). In silkworms, the recoveries of indoxacarb and DCJW were 86.06%-104.52% with relative standard deviation (RSD) < 9.01%. The 96-h lethal concentration (LC50 ) values of R-indoxacarb, S-indoxacarb, and enriched S-indoxacarb (2.333 S/1R) were 1.08 × 102 , 1.92, and 6.89 mg a.i. L-1 , respectively, according to the acute toxicity test results. When silkworm larvae were exposed to 1/50 of the LC50 concentration, the bioconcentration factor (BCF) of R-indoxacarb was 0.0296-0.318, and the BCF of S-indoxacarb was 0.0125-0.211. In silkworm larvae, the amount of R-DCJW produced by R-indoxacarb was 0.00610 to 2.34 times that of the parent R-indoxacarb, and the amount of S-DCJW produced by S-indoxacarb was 0.125-36.9 times that of the parent S-indoxacarb. There was no chiral transition from S-indoxacarb to R-indoxacarb or a transformation from R-indoxacarb to S-indoxacarb. Indoxacarb was preferentially bioaccumulated in silkworm larva, while S-indoxacarb bioconversion into the metabolite S-DCJW was much greater than R-indoxacarb bioconversion into R-DCJW. This study could improve understanding of the indoxacarb accumulation and transformation process in insects, as well as provide more scientific data for indoxacarb environmental and ecological risk assessment. © 2023 Society of Chemical Industry.

A double-helical S,C-bridged tetraphenyl-para-phenylenediamine and its persistent radical cation.

A structurally constrained, double-helical S,C-bridged tetraphenyl-para-phenylenediamine (TPPD) has been synthesized. The stable radical cation of the S,C-bridged TPPD was generated by chemical oxidation, and the electron spin was found to be delocalized over the entire π-conjugated framework. The excellent conformational stability of the neutral molecule facilitated the separation of its enantiomers.

Electrochemical synthesis of heterodehydro[7]helicenes

Dehydrohelicenes are some of the most attractive chiroptical materials with unique helical chirality. However, to our knowledge, there are no prior reports on their direct construction by asymmetric methods. In this work, sequential synthesis of aza-oxa-dehydro[7]helicenes via the electrochemical oxidative hetero-coupling of 3-hydoxycarbazoles and 2-naphthols followed by dehydrative cyclization and intramolecular C–C bond formation has been realized. In addition, an efficient enantioselective synthesis through chiral vanadium-catalyzed hetero-coupling and electrochemical oxidative transformations afforded heterodehydro[7]helicene without any racemization. The obtained dehydro[7]helicenes showed intense blue-colored circularly polarized luminescence (|glum| ≈ 2.5 × 10−3 at 433 nm). Thermodynamic and kinetic studies of the racemization barrier of heterodehydro[7]helicenes indicated significant chiral stability with ΔG‡> 140 kJ mol−1.

Grafting (S)-2-Phenylpropionic Acid on Coordinatively Unsaturated Metal Centers of MIL-101(Al) Metal-Organic Frameworks for Improved Enantioseparation.

Chiral metal-organic frameworks (cMOFs) are emerging chiral stationary phases for enantioseparation owing to their porosity and designability. However, a great number of cMOF materials show poor separation performance for chiral drugs in high-performance liquid chromatography (HPLC). The possible reasons might be the irregular shapes of MOFs and the low grafting degree of chiral ligands. Herein, MIL-101-Ppa@SiO2 was synthesized by a simple coordination post-synthetic modification method using (S)-(+)-2-Phenylpropionic acid and applied as the chiral stationary phase to separate chiral compounds by HPLC. NH2-MIL-101-Ppa@SiO2 prepared via covalent post-synthetic modification was used for comparison. The results showed that the chiral ligand density of MIL-101-Ppa@SiO2 was higher than that of NH2-MIL-101-Ppa@SiO2, and the MIL-101-Ppa@SiO2 column exhibited better chiral separation performance and structural stability. The binding affinities between MIL-101-Ppa@SiO2 and chiral compounds were simulated to prove the mechanism of the molecular interactions during HPLC. These results revealed that cMOFs prepared by coordination post-synthetic modification could increase the grafting degree and enhance the separation performance. This method can provide ideas for the synthesis of cMOFs.

First eco-toxicological evidence of ivabradine effect on the marine bacterium Vibrio fischeri: A chiral view

Ivabradine (S-ivabradine) is a contemporary antihypertensive drug designed and commercialized for cardiovascular diseases treatment over the world. In this work the enantiomer-specific stability and acute toxicity of ivabradine to the marine bacterium Vibrio fischeri as well as the potential mechanism of action were investigated for the first time. With this aim, real concentrations of ivabradine enantiomers under abiotic and biotic conditions were determined by Capillary Electrophoresis (CE) with cyclodextrins (CDs) as chiral selectors. A moderate chiral stability without enantiomeric interconversion was observed for ivabradine. The bioluminescence inhibition method revealed an enantioselective toxicity of ivabradine to marine bacterium. The order of ecotoxicity was R-ivabradine < racemic ivabradine < S-ivabradine with EC50 (t = 5 min) values about 75.98, 11.11 and 7.93 mg/L, respectively. Confocal Live/Dead stained images showed that bacterial envelops cells were seriously damaged after exposure to S-ivabradine. S-ivabradine also disturbed the esterase activity and significantly increased the ROS level compared with the control. Thus, oxidative stress originating membrane cells damage and enzymatic activity changes was shown to be the primary mechanism of S-ivabradine toxicity to marine bacterium. Our results highlight the need for more eco-toxicological evaluations of the cardiovascular drug S-ivabradine on other aquatic organisms to establish the risk on the environment.

Simple Double Hetero[5]helicenes Realize Highly Efficient and Narrowband Circularly Polarized Organic Light-Emitting Diodes

Simple Double Hetero[5]helicenes Realize Highly Efficient and Narrowband Circularly Polarized Organic Light-Emitting Diodes

Thiophene fused indenocorannulenes: synthesis, variable emission, and exceptional chiral configurational stability

Graph theory and isosteric replacement leads to the design and synthesis of (chiral) thiophene-fused indenocorannulenes with exceptional configurational stability and possible use as chiral catalysts, chiroptical materials, and sensors.

Skyrmion generation from irreversible fission of stripes in chiral multilayer films

Competing interactions produce finite-size textures in myriad condensed matter systems, typically forming elongated stripe or round bubble domains. Transitions between stripe and bubble phases, driven by field or temperature, are expected to be reversible in nature. Here we report on the distinct character of the analogous transition for nanoscale spin textures in chiral Co/Pt-based multilayer films, known to host N\'{e}el skyrmions, using microscopy, magnetometry, and micromagnetic simulations. Upon increasing field, individual stripes fission into multiple skyrmions, and this transition exhibits a macroscopic signature of irreversibility. Crucially, upon field reversal, the skyrmions do not fuse back into stripes, with many skyrmions retaining their morphology down to zero field. Both the macroscopic irreversibility and the microscopic zero-field skyrmion density are governed by the thermodynamic material parameter determining chiral domain stability. These results establish the thermodynamic and microscopic framework underlying ambient skyrmion generation and stability in chiral multilayer films and provide immediate directions for their functionalization in devices.

Non-clinical characterization of the disposition of EMA401, a novel small molecule angiotensin II type 2 receptor (AT2R) antagonist.

EMA401, (the S-enantiomer of 5-(benzyloxy)-2-(2,2-diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), also known as Olodanrigan, is an orally active selective angiotensin II type 2 receptor (AT2 R) antagonist that is in Phase IIb clinical development as a novel analgesic for the relief of chronic pain. The main purpose of the present work was to investigate the disposition of a single 14 C- labeled EMA401 in non-clinical studies. The in vitro metabolism studies of EMA401 were undertaken to understand the hepatic biotransformation pathways in animal species used in toxicology studies and how they compare to human. Furthermore, investigation of EMA401's PK was carried out in vivo in rats. The study demonstrates the rapid absorption and distribution of drug-related material mainly to the tissues associated with absorption and elimination (GI tract, liver, and kidney). EMA401was then readily eliminated metabolically via the bile (95% of dose) predominantly in the form of the direct acylglucuronide (40% of dose), which was further hydrolysed by the intestinal flora to the active parent drug. Other metabolic pathways such as dealkylations and hydroxylation were also involved in the elimination of EMA401 to a lesser extent. EMA401 was metabolically unstable in hepatocytes of all species investigated and the key metabolites produced in the in vitro model were also detected in vivo. Independent of the dosing route, the S-enantiomer EMA401 showed a good in vivo chiral stability. Overall, the present study provides the first full characterization of the disposition of EMA401 in preclinical species.