Stereochemical Preference Research Articles

Enantiomer-Dependent Supramolecular Antibacterial Therapy for Drug-Resistant Bacterial Keratitis.

Bacteria have the potential to exhibit divergent stereochemical preferences for different levels of chiral structures, including from molecule, supramolecule, to nanomicroscale helical structure. Accordingly, the structure-activity relationship between chirality and bactericidal activity remains uncertain. In this study, we seek to understand the multivalent molecular chirality effect of chiral supramolecular polymers on antibacterial activity. Two n-butylazobenzene-modified l- and d-tripeptides (abbreviated C4Azo-l-VKK-OH and C4Azo-d-VKK-OH) were synthesized and subsequently self-assembled in water into chiral supramolecular polymers (designated l-Fiber and d-Fiber, respectively). The l-Fiber and d-Fiber displayed comparable nonhelical nanofiber morphologies but exhibited opposite multivalent molecular chirality. A comparative study demonstrated that the l-Fiber exhibited a markedly higher affinity for bacteria, thereby demonstrating significantly enhanced bactericidal efficiency against methicillin-resistant Staphylococcus aureus (MRSA) in comparison to that of the d-Fiber. Following disassembly into monomers via host-guest chemistry, the bactericidal potency of both the l-Fiber and d-Fiber was found to be almost lost, suggesting the multivalent molecular chirality effect. Of note, the l-Fiber exhibited superior efficacy in curing MRSA-infected keratitis in comparison to the d-Fiber. These findings highlight the importance of multivalent molecular chirality in the design and development of chiral supramolecular polymers for antibacterial applications. This research also presents an effective chiral supramolecular antibacterial strategy for the treatment of drug-resistant bacteria-infected keratitis.

Understanding the Functional Dynamics of the TokK Enzyme in Carbapenem Biosynthesis via MD Simulations and QM/MM Calculations.

Due to the recent surge in antibiotic resistance, developing novel antibiotics is the demand of the time, and thus, a precise understanding of the catalytic mechanisms of enzymes involved in antibiotic biosynthesis becomes crucial. Here, we present a comprehensive investigation into the catalytic mechanism of TokK, a freshly characterized B12-dependent RSMT enzyme that plays an important role in carbapenem biosynthesis. Using MD simulations, we show how the plasticity of the active site facilitates substrate recognition while the quantum mechanics/molecular mechanics calculations provide a detailed mechanistic understanding of the methyl transfer process, elucidating stereochemical preferences. Notably, we demonstrate the indispensable role of Trp215 in orchestrating the proper orientation of the 5'-dA• radical for efficient substrate methylation, which strongly correlates with the previous findings where the mutation of Trp215 has severely affected the enzyme activity.

A Theoretical Perspective on the Stereochemistry of Benzoanellated Aroyl‐X,N‐Ketene Acetal Derivatives

ABSTRACTKetene 1,3‐oxazoles and their derivatives present intriguing structures for the study of rotational barriers due to their pseudo–double‐bond character stemming from resonance in the ketene moiety. A diverse range of compounds featuring this motif underwent quantum‐chemical investigation to elucidate the nature of the stereochemical singularity observed in numerous cases. Because rotational barriers in most instances are too high to permit rapid interconversion, the findings are ascribed to thermodynamic rather than kinetic factors in the gas phase and within an implicit polar medium. The stabilities are attributed to internal hydrogen bonding where feasible. However, in cases where this is not possible, chalcogen bonding rather than steric effects governs the stereochemical preferences, particularly when S and Se comprise the heterocycle of these compounds. These findings hold promise for guiding the design of compounds whose properties hinge on stereochemistry and resonant structures, such as dyes.

Modeling the Initiation Phase of the Catalytic Cycle in the Glycyl-Radical Enzyme Benzylsuccinate Synthase.

The reaction of benzylsuccinate synthase, the radical-based addition of toluene to a fumarate cosubstrate, is initiated by hydrogen transfer from a conserved cysteine to the nearby glycyl radical in the active center of the enzyme. In this study, we analyze this step by comprehensive computer modeling, predicting (i) the influence of bound substrates or products, (ii) the energy profiles of forward- and backward hydrogen-transfer reactions, (iii) their kinetic constants and potential mechanisms, (iv) enantiospecificity differences, and (v) kinetic isotope effects. Moreover, we support several of the computational predictions experimentally, providing evidence for the predicted H/D-exchange reactions into the product and at the glycyl radical site. Our data indicate that the hydrogen transfer reactions between the active site glycyl and cysteine are principally reversible, but their rates differ strongly depending on their stereochemical orientation, transfer of protium or deuterium, and the presence or absence of substrates or products in the active site. This is particularly evident for the isotope exchange of the remaining protium atom of the glycyl radical to deuterium, which appears dependent on substrate or product binding, explaining why the exchange is observed in some, but not all, glycyl-radical enzymes.

Divergent self-assembly propensity of enantiomeric phenylalanine amphiphiles that undergo pH-induced nanofiber-to-nanoglobule conversion.

This study presents the pathway diversity in the self-assembly of enantiomeric single phenylalanine derived amphiphiles (single F-PDAs), viz.L-NapF-EDA and D-NapF-EDA, that form supramolecular hydrogels at varied concentrations (≥1 mg mL-1 and ≥3 mg mL-1, respectively). By fitting the variable temperature circular dichroism (VT-CD) data to the isodesmic model, various thermodynamic parameters associated with their self-assembly, such as association constant (K), changes in enthalpy (ΔH), entropy (ΔS), and Gibbs free energy (ΔG), were extracted. The self-assembly of these single F-PDAs was found to be enthalpy-driven but entropically-disfavored. Although self-assembly of the D-isomer was slow, it also exhibited greater free energy of association than the L-isomer. Consequently, thermally and mechanically more robust self-assemblies were formed by the D-isomer than the L-isomer. We term these results as the "butterfly effect in self-assembly" wherein the difference in the stereochemical orientation of the residues at a single chiral center present in these molecules resulted in strong differences in the self-assembly propensity as well as in their thermal and mechanical stability. These single F-PDAs form helical nanofibers of opposite chirality upon self-assembly at basic pH (≥8) that produce intense CD signals. However, upon decreasing the pH, a gradual nanofiber-to-nanoglobular transformation was noticed due to protonation-induced structural changes in the PDAs.

Design, Synthesis and Catalytic Activity of (Cyclopentadienone)iron Complexes Containing a Stereogenic Plane and a Stereogenic Axis.

Herein, we report the synthesis and characterization of several chiral (cyclopentadienone)iron complexes (CICs) featuring either two (R)-BINOL-derived stereoaxes or a combination of one (R)-BINOL-derived stereoaxis and a stereogenic plane. The stereoplane-containing CICs were obtained as epimer mixtures, which were separated by flash column chromatography and assigned an absolute configuration based on XRD analysis, NMR and order of elution. The library was tested in the asymmetric hydrogenation of ketones showing good catalytic activity and a moderate stereoselectivity which, notably, is mostly imparted by the stereogenic plane. Indeed, the two epimers of each CIC possessing a stereoplane show opposite and equally strong stereochemical preference.

Pathway Complexity in Nanotubular Supramolecular Polymerization: Metal-Organic Nanotubes with a Planar-Chiral Monomer.

Here, we report an anomalous pathway complexity in the supramolecular polymerization of a chiral monomer, which displays an unusual chiroptical feature that does not follow any of the known stereochemical rules such as "chiral self-sorting" and "majority rule". We newly developed a planar-chiral ferrocene-cored tetratopic pyridyl monomer FcL, which underwent AgBF4-mediated supramolecular polymerization to give nanotubes FcNTs composed of metal-organic nanorings FcNRs. Although FcNRs must be homochiral because of a strong geometrical constraint, FcNRs were formed even efficiently from racemic FcL and AgBF4. Detailed studies revealed the presence of two competing pathways for producing homochiral FcNRs as the constituents of FcNTs: (i) spontaneous cyclization of initially formed acyclic polymers -[FcL-Ag+]n- and (ii) template (FcNR)-assisted cyclization via a Ag+···Ag+ metallophilic interaction. The dominance of the two pathways changes depending on the %ee of chiral FcL. Namely, when the %ee of FcL is high, -[FcL-Ag+]n- must contain sufficiently long homochiral sequences that can be readily cyclized into FcNRs. Meanwhile, when the %ee of FcL is low, the homochiral sequences in -[FcL-Ag+]n- must be short and therefore are hardly eligible for spontaneous cyclization. Why were FcNRs formed? Even though the probability is very low, homochiral -[FcL-Ag+]n- can be statistically generated and undergo spontaneous cyclization to give FcNRs minutely. We found that FcNRs can be amplified by heterochirally templating their own synthesis using metallophilic interaction. Because of this stereochemical preference, the growth of FcNRs into FcNTs via the template-assisted mechanism occurs only when both (R,R)FcL and (S,S)FcL are present in the polymerization system.

Stereoselective oxidation of phenoxathiin-based thiacalix[4]arenes - stereomutation of sulfoxide groups.

A phenoxathiin-based macrocycle represents an inherently chiral building block, well accessible in two steps from the starting thiacalix[4]arene. The oxidized derivatives bearing one sulfoxide group and three sulfonyl groups were found to exhibit unexpected stereochemical preferences of the sulfoxide group during transformations. The sulfoxide moiety is always pointing out of the cavity (SO out), while the opposite (SO in) configuration was never obtained by direct oxidation. In order to achieve full oxidation to sulfone, the configuration of the sulfoxide group must first be changed by a photochemical inversion before the final oxidation occurs. The phenomenon of stereomutation of the sulfoxide group in the thiacalixarene series was studied using a combination of experimental (NMR and single crystal X-ray analysis) and theoretical (DFT) approaches.

Opioid toxicity: histamine, hypersensitivity, and MRGPRX2.

Insights into the pathophysiology of many non-immune-mediated drug reactions referred to as toxicities, sensitivities, intolerances, or pseudoallergies have resulted from research identifying the mastocyte-related G-protein-coupled receptor (GPCR) member X2 (MRGPRX2), a human mast cell receptor mediating adverse reactions without the involvement of antibody priming. Opioid-induced degranulation of mast cells, particularly morphine, provoking release of histamine and other preformed mediators and causing hemodynamic and cutaneous changes seen as flushing, headache and wheal and flare reactions in the skin, is an example of results of MRGPRX2 activation. Opioids including morphine, codeine, dextromethorphan and metazocine as well as endogenous prodynorphin opioid peptides activate MRGPRX2 at concentrations causing mast cell degranulation. Unlike the canonical opioid receptors, MRGPRX2 shows stereochemical recognition preference for dextro rather than levo opioid enantiomers. Opioid analgesic drugs (OADs) display a range of histamine-releasing potencies from the strong releaser morphine to doubtful releasers like hydromorphone and the non-releaser fentanyl. Whether there is a correlation between histamine release by individual OADs, MRGPRX2 activation, and presence or absence of adverse cutaneous effects is not known. To investigate the question, ongoing research with recently pursued methodologies and strategies employing basophil and mast cell tests resulting from MRGPRX2 insights should help to elucidate whether or not an opioid's histamine-releasing potency, and its property of provoking an adverse reaction, are each a reflection of its activation of MRGPRX2.

The distribution of carbonate in apatite: The environment model

Abstract The environment model is used to describe the location of carbonate in nine carbonated apatites containing varied percentages of carbonate and Na+, K+, or NH4+ ions. Unlike the traditional model for carbonate substitution, which identifies different locations and orientations of the carbonate ion in the apatite structure, the environment model utilizes the different structural surroundings to describe the different types of carbonate. The A-type carbonate environment is assigned to channels lined only with calcium ions (A-channel configuration = Ca6) or to channels containing one Na+ or a vacancy (A′-channel configuration = Ca5Na or Ca5☐), and the B-type carbonate environment is the surroundings of the replaced phosphate ion. The assignments are made by peak-fitting the carbonate asymmetric stretch region (ν3) of the IR spectrum, following previously published criteria. These assignments lead to the conclusion that the percentage of channel carbonate (A- and A′-environments) is greater than that of B-type for each of these carbonated apatites. In general, the use of triammonium phosphate as the phosphate source in the synthesis produces apatites with larger amounts of channel carbonate (A- and A′-environments), while the use of sodium-containing phosphate reagents produces smaller amounts of channel carbonate. The environment model provides explanations for the differences within IR and NMR spectra obtained for apatites containing a range of total carbonate content. The B-type appearance of the carbonate ν3 region of the IR spectrum is found primarily in apatites containing sodium, which allows increased amounts of carbonation via co-substitution of Na+ with carbonate and creation of A′-environments with populations equal to that of B-type carbonate. The presence of ammonium or alkali metal salts with cations larger than Na+ results in the utilization of a charge-balance mechanism that produces vacancies rather than cation substitution in the channel. The carbonated apatites formed with primary utilization of the vacancy mechanism generally contain greater percentages of carbonate in the A-environment and carbonate IR spectra that contain an obvious high-frequency peak at about 1550 cm–1. The multiple peaks in the solid state 13C NMR spectra previously observed for carbonated apatite are attributed to substitution in the A-, A′-, and B-environments rather than different stereo-chemical orientations of the carbonate ion.

Discrete terpyridine-lanthanide molecular and supramolecular complexes

Integrating the advantages of terpyridine (tpy) ligands with excellent chromophoric sensitization ability and lanthanides (Lns) with characteristic luminescent and magnetic properties, discrete terpyridine-lanthanide (tpy-Ln) molecular and supramolecular complexes are of great value in many fields and have drawn significant attention from the community of supramolecular chemistry, coordination chemistry and materials science. Compared to the well-documented coordination behavior between transition metals and tpy, the construction of tpy-Ln molecular and supramolecular complexes remains a longstanding challenge due to the high coordination diversity and the lack of stereochemical preference of Lns. Nevertheless, with the advancement of self-assembly strategies, i.e., employing diverse anions as capping components and utilizing secondary auxiliary ligands as well as engineering of tpy ligands, diverse tpy-Ln molecular and supramolecular complexes have been constructed and their potential applications have been explored. This review comprehensively summarizes the progress of discrete tpy-Ln molecular and supramolecular complexes in the past decades, covering the structures of mononuclear, binuclear and multinuclear architectures. Beyond structures, the potential applications of these tpy-Ln complexes are also introduced. This review aims to shed more light on the design and construction of novel discrete tpy-Ln supramolecular complexes and materials with molecular level precision and multiple functions through coordination-driven self-assembly.

The mechanism of sugar produced from simple glycolaldehyde derivative at ambient conditions

AbstractA benchmark of sugar produced from simple glycolaldehyde derivative has been achieved at ambient conditions (Science, 2004, 305, 1752), which is the most important step to produce life in nature. However, the mechanism has never been clearly understood. Here, we report a reaction mechanism which includes a two‐step synthesis of sugars by selective aldol reactions based on the density functional theory (DFT) calculations. Results show that the prochirality of attacking orientation of the enamine intermediate and steric effect in proton transfer is the main cause for stereochemical preference. This work provides the theoretical insight of sugar produced in glycolaldehyde procedure and may assist the improvement of catalyst design for this procedure.

Continuous Shape Measures Study of the Coordination Spheres of Actinide Complexes – Part 1: Low Coordination Numbers

AbstractStructural analyses of a large set of molecular structures of actinide compounds allow us to establish trends for stereochemical preferences, common distortion paths, geometrical constraints imposed by different ligand topologies, and the existence of incipient bonds or of Van der Waals intramolecular interactions on purportedly vacant coordination sites. In this study the relative abundance of coordination numbers in actinide chemistry appears to be on average higher than that among the lanthanides. The detailed continuous shape measures study of normalized coordination polyhedra with coordination numbers between 1 and 6 presented here is based on more than 1,800 solid state and gas phase structural data sets.

Electrostatics Favor PNA : DNA Stability over Stereochemistry in Pyrrolidine‐Based Cationic Dual‐Backbone PNA Analogues

AbstractModifications to the peptide nucleic acid (PNA) backbone has been well known to alter the thermodynamical parameters of PNA : DNA complexes to broaden their utility for different applications. Electrostatic interactions between a modified PNA having a positively charged backbone and the negatively charged DNA has been shown to enhance thermal stabilities of PNA : DNA complexes at various instances. On the other hand, chiral introduction in PNA backbone leads to stereochemical preference that affects binding properties. However, the interplay between electrostatics and stereochemistry has not been systematically studied so far. Herein, we report the synthesis and biophysical characterization of cationic PNA named dapPNA, first of its kind, having a dual PNA backbone constituting of a pyrrolidine ring having a β‐substitution. One of the aims of this study was to investigate the role of electrostatics over stereochemical preferences. The results show that electrostatic attraction between cationic dapPNA and negatively charged DNA overcomes the unfavorable stereochemical effects and enhances stability of PNA : DNA complexes. Moreover, two different PNA backbones derived from a single PNA monomer expands the repertoire of pyrrolidine based PNA analogues.

Stereoisomeric Control in [RuCl2(PTA)2(2L)] Complexes (2L=2py or bpy): From Theoretical Calculations to a 2+2 Metallacycle of Pyridylporphyrins

AbstractTreatment of the Ru(II) precursor cis,cis,trans‐[RuCl2(dmso‐S)2(PTA)2] (1, PTA=1,3,5‐triaza‐7‐phosphaadamantane) with 2,2′‐bipyridine (bpy) in refluxing ethanol selectively affords cis,cis‐[Ru(bpy)Cl2(PTA)2] (2), whereas with pyridine (py), under the same conditions, it gives trans,cis,cis‐[RuCl2(PTA)2(py)2] (6). The slightly less stable stereoisomer of 2, cis,trans‐[Ru(bpy)Cl2(PTA)2] (3), is obtained selectively through a different synthetic route. Isomers 2 and 3 are thermally stable, but cleanly equilibrate upon irradiation of an aqueous solution of either one with blue light. Intrigued by the stereoisomeric outcome in the preparations of this homogeneous set of complexes, we also investigated 2, 3, and 6 (and the mono‐pyridine complex trans,mer‐[RuCl2(py)(PTA)3] (7)) through a topological analysis of the electron density map using the quantum theory of atoms in molecules (QTAIM). The wealth of acquired experimental and calculated data allow us to discuss the stereochemical preferences of the [RuCl2(PTA)2(2 L)] complexes (2 L=bpy or 2py) in terms of electronic and steric contributions. The results of this speculative study on model complexes are transferable to similar systems. As an example, our findings from the reactivity of 1 towards pyridine allowed us to prepare the 2+2 pyridylporphyrin metallacycle trans,cis,cis‐[RuCl2(PTA)2(4′‐cisDPyP)]2 (10, 4′‐cisDPyP=5,10‐(4′‐pyridyl)‐15,20‐(phenyl)‐porphyrin), whose X‐ray molecular structure is also reported.

Enzymatic Degradation of Organophosphorus Pesticides and Nerve Agents by EC: 3.1.8.2

The organophosphorus substances, including pesticides and nerve agents (NAs), represent highly toxic compounds. Standard decontamination procedures place a heavy burden on the environment. Given their continued utilization or existence, considerable efforts are being made to develop environmentally friendly methods of decontamination and medical countermeasures against their intoxication. Enzymes can offer both environmental and medical applications. One of the most promising enzymes cleaving organophosphorus compounds is the enzyme with enzyme commission number (EC): 3.1.8.2, called diisopropyl fluorophosphatase (DFPase) or organophosphorus acid anhydrolase from Loligo Vulgaris or Alteromonas sp. JD6.5, respectively. Structure, mechanisms of action and substrate profiles are described for both enzymes. Wild-type (WT) enzymes have a catalytic activity against organophosphorus compounds, including G-type nerve agents. Their stereochemical preference aims their activity towards less toxic enantiomers of the chiral phosphorus center found in most chemical warfare agents. Site-direct mutagenesis has systematically improved the active site of the enzyme. These efforts have resulted in the improvement of catalytic activity and have led to the identification of variants that are more effective at detoxifying both G-type and V-type nerve agents. Some of these variants have become part of commercially available decontamination mixtures.

Acetylcholinesterase as a target of halogenated marine natural products from Laurencia dendroidea

The use of chemogenomics techniques applied to a marine natural products database has pointed out halogenated sesquiterpenes present in red alga Laurencia dendroidea as potential acetylcholinesterase inhibitors. Therefore, in this work five metabolites were studied using molecular docking and enzymatic inhibition assays. According to the results the most promising metabolite in relation to acetylcholinesterase inhibition capacity was (−)-elatol 1. Molecular docking of (−)-elatol 1 showed interactions with important specific residues of the enzyme gorge involved in the activity of drugs used to treat Alzheimer's disease. In this respect, interactions between halogens bromine and chlorine with the center of the benzene ring of Tryptophan 86 and Tryptophan 286 may be contributing to the observed activity. Enzyme kinetics was investigated to find out the type of enzyme inhibition involved in the observed activities. Results have also shown stereochemical preferences related to the inhibition by halogenated compounds. (−)-Elatol 1 was able to inhibit acetylcholinesterase, thus becoming a suitable skeleton in the search for new anti-Alzheimer drugs of natural and semi-synthetic origin.

Palladium-Catalyzed O - and N -Glycosylation with Glycosyl Chlorides

Despite the significant progress in carbohydrate chemistry, there remains a pressing need for efficient and practical glycosylation methods using simple glycosyl donors and with high atom economy. ...

Amino Alcohol Acrylonitriles as Activators of the Aryl Hydrocarbon Receptor Pathway: An Unexpected MTT Phenotypic Screening Outcome.

Lead (Z)-N-(4-(2-cyano-2-(3,4-dichlorophenyl)vinyl)phenyl)acetamide, 1 showed MCF-7 GI50 =30 nM and 400-fold selective c.f. MCF10A (normal breast tissue). Acetamide moiety modification (13 a-g) to introduce additional hydrophobicity was favoured with MCF-7 breast cancer cell activity enhanced at 1.3 nM. Other analogues were potent against the HT29 colon cancer cell line at 23 nM. Textbook SAR data was observed in the MCF-7 cell line, in an MTT assay, via the ortho (17 a), meta (17 b) and para (13 f). The amino alcohol -OH moiety was pivotal, but no stereochemical preference noted. But, these data did not fit our homology modelling expectations. Aberrant MTT ((3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) screening results and metabolic interference confirmed by sulforhodamine B (SRB) screening. Interfering analogues resulted in 120 and 80-fold CYP1A1 and CYP1A2 amplification, with no upregulation of SULT1A1. This is consistent with activation of the AhR pathway. Piperidine per-deuteration reduced metabolic inactivation. 3-OH / 4-OH piperidine analogues showed differential MTT and SRB activity supporting MTT assay metabolic inactivation. Data supports piperidine 3-OH, but not the 4-OH, as a CYP substrate. This family of β-amino alcohol substituted 3,4-dichlorophenylacetonitriles show broad activity modulated via the AhR pathway. By SRB analysis the most potent analogue was 23 b, (Z)-3-(4-(3-(4-phenylpiperidin-1-yl)-2-hydroxypropoxy)phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile.

Novel β- and γ-Amino Acid-Derived Inhibitors of Prostate-Specific Membrane Antigen.

Prostate-specific membrane antigen (PSMA) is an excellent biomarker for the early diagnosis of prostate cancer progression and metastasis. The most promising PSMA-targeted agents in the clinical phase are based on the Lys-urea-Glu motif, in which Lys and Glu are α-(l)-amino acids. In this study, we aimed to determine the effect of β- and γ-amino acids in the S1 pocket on the binding affinity for PSMA. We synthesized and evaluated the β- and γ-amino acid analogues with (S)- or (R)-configuration with keeping α-(l)-Glu as the S1'-binding pharmacophore. The structure-activity relationship studies identified that compound 13c, a β-amino acid analogue with (R)-configuration, exhibited the most potent PSMA inhibitory activity with an IC50 value of 3.97 nM. The X-ray crystal structure of PSMA in complex with 13c provided a mechanistic basis for the stereochemical preference of PSMA, which can guide the development of future PSMA inhibitors.