Cis And Trans Research Articles

Isomer Differentiation by UHPLC-Q-Exactive-Orbitrap MS led to Enhanced Identification of Daphnane Diterpenoids in Daphne tangutica.

Liquid chromatography-mass spectrometry (LC-MS) has enhanced the rapid, accurate analysis of complex plant extracts, eliminating the need for extensive isolation. Tandem mass spectrometry (MS/MS) further enhances this process by providing detailed structural information. However, differentiating structural isomers remains a challenge due to their minor spectral and structural differences. This study aimed to extend the applicability of LC-MS/MS for the structural identification of daphnane diterpenoids, with a particular focus on distinguishing functional isomers. LC-MS analyses were performed using an UHPLC-Q-Exactive-Orbitrap MS. The MS conditions for distinguishing isomers were optimized using in-source CID and HCD modes with reference compounds. A qualitative analysis was then conducted on the extract of Daphne tangutica. The chemical structures of the detected daphnane diterpenoids were estimated by analyzing the fragmentation patterns in both the mass spectra and product ion spectra. These identifications were further validated by isolation and comparison with an in-house daphnane diterpenoid library. By optimizing MS conditions, especially in the negative ion mode, it was possible to accurately distinguish structural isomers such as yuanhuajine and gniditrin. Qualitative analysis of D. tangutica identified a total of 28 daphnanes, including seven previously unreported compounds. Furthermore, a novel geometric isomer of gniditrin was isolated by conducting isolation on the crude diterpenoid fraction. This study demonstrated that LC-MS/MS analysis can effectively distinguish functional isomers of daphnane diterpenoids, thereby enhancing the identification of daphnanes in plant extracts and highlighting its potential as a powerful tool for phytochemical analysis.

Complete Epoxy Phosphonate Conversion to Dimethyl (1E)-3-Hydroxyprop-1-Enylphosphonate with Photobiocatalysts’ Assistance

Phosphonates derivatives are compounds of interests and are applied as drugs of, e.g., antibacterial antiviral activities, connected with their inhibitory activity towards different enzymes, which is related to the configuration of particular compound isomers. The biological synthesis of such molecules is the method of choice and can be carried out using enzymes or whole cells from organisms. Photobiocatalysts employed in the bioconversion of epoxymethyl dimethyl phosphonate are able to convert this substrate into a pure geometric isomer of the unsaturated product, dimethyl (1E)-3-hydroxyprop-1-enylphosphonate, which is a rare and expensive compound of high added value. Six different strains were screened towards dimethyl epoxy phosphonate and in the case of Synechococcus bigranulatus, over 99% conversion was achieved. The product structure was confirmed with Mass Spectroscopy (MS); 1H, 13C, 31P, and 2D Nuclear Magnetic Resonance (NMR); and Infrared Spectroscopy (IR).

Stereo‐ and Chemoselective Enrichment of sp3 Character in Post‐Ugi Morpholines

AbstractWe conducted a systematic study on synthesis and modification of morpholine core using Ugi adducts derived from propiolic acid and glycolaldehyde dimer. The assembly step involved triphenylphosphine‐promoted 6‐exo‐dig umpolung oxa‐Michael cyclization of Ugi‐derived hydroxypropargylamides yielding 2‐methylenemorpholin‐3‐one derivatives. Subsequent heterogeneous catalytic hydrogenation of the exocyclic double bond proceeded in a highly diastereoselective fashion establishing a relative cis configuration in the resulting sp3‐enriched morpholinone scaffold. Finally, chemoselective amide reduction with lithium aluminum hydride (LAH) allowed to obtain fully saturated morpholines while leaving the more sterically hindered exocyclic amide moiety intact. Taken together these findings outline the strategy for controlled reduction of the inherent rigidity of post‐Ugi scaffolds.

Non-Canonical C16 Homoterpene Biosynthesis Widespread in Actinobacteria.

A novel biosynthetic pathway towards the rare and underexplored non-canonical family of homoterpenes was discovered in actinobacteria through targeted genome mining and enzymatic in vitro reconstitution. The pathway comprises initial methylation-induced double bond isomerization of farnesyl diphosphate (FPP) to (2E,7E)-6-methyl-farnesyl diphosphate, catalyzed by a novel family of methyltransferases with unique dual function. The resulting linear C16 double bond isomer of FPP constitutes the specific substrate for a distinct family of type I terpene cyclases, catalyzing diverse cyclization reactions. Functional characterization of nine enzyme pairs led to discovery of five unprecedented homoterpene natural products. The enzymological novelty enables the development of novel biocatalytic and genetically programmable synthetic strategies towards methylated terpenoids with potentially unique properties ("magic methyl effect").

Vibrational and DFT Studies and Anticancer Activity of Novel Pd(II) and Pt(II) Complexes with Chloro Derivatives of 7-Azaindole-3-Carbaldehyde

This study investigates the structural, vibrational, and biological properties of novel palladium(II) and platinum(II) complexes with 5-chloro-7-azaindole-3-carbaldehyde (5ClL) and 4-chloro-7-azaindole-3-carbaldehyde (4ClL) ligands. Infrared and Raman spectroscopy, combined with DFT (ωB97X-D) calculations, provided valuable information about metal–ligand interactions, the cis or trans conformation of the aldehyde group in the ligands, and the presence of trans isomers in the metal complexes obtained in the solid state. In vitro tests were used to evaluate the antiproliferative activity of the novel complexes against several cancer cell lines, including ovarian cancer (A2780), cisplatin-resistant ovarian cancer (A2780cis), colon cancer (HT-29), and triple-negative breast cancer (MDA-MB-231), as well as normal mouse fibroblasts (BALB/3T3). The platinum complex, trans-[PtCl2(5ClL)2], exhibited superior activity against A2780cis (IC50 = 4.96 ± 0.49 µM) and MDA-MB-231 (IC50 = 4.83 ± 0.38 µM) compared to cisplatin, while the palladium complexes (trans-[PdCl2(4ClL)2] and trans-[PdCl2(5ClL)2]) demonstrated enhanced selectivity with reduced toxicity to normal fibroblasts (IC50 = 11.29 ± 6.65 µM and 14.98 ± 5.59 µM, respectively).

Visible light‐responsive azo‐based smart materials: Design, performance, and applications in energy storage

AbstractAzobenzene and its derivatives are the most extensively investigated and applied molecular photoswitches, which can undergo reversible transformation between trans and cis isomers upon irradiation with light at specific wavelengths. Through structural geometry transformation, the property alterations can be integrated into smart materials to meet diverse application requirements. Most azo‐based photoswitches require UV light for activation. However, complete activation within the visible or even near‐infrared light range could offer several benefits for photoswitch applications, including improved biocompatibility, better light penetration, and enhanced solar light utilization efficiency. This review presents an overview of the development of visible‐light responsive azo‐based materials, covering molecular design strategies and their applications in energy storage. Recent efforts aimed at enhancing the performance of azo‐based energy storage materials are highlighted. According to the different strategies for improving energy storage properties, these materials are categorized as those that directly increase isomerization energy and those that introduce phase transition energy. Furthermore, we discuss the challenges and opportunities in this field with a view to inspire further exploration.

Design and Study of Azobenzene‐Modified AESO Photopolymerization Coating for Information Reversible Storage Performance

ABSTRACTThe photo‐induced cis‐trans isomerization of azobenzene molecules, known for their significant color changes, is extensively utilized in the functional modification of polymeric materials. However, the research on the functionalization of biomass‐based polyesters with azobenzene is limited. A key raw material for biomass‐based coatings possess reactive double bonds and excellent film‐forming capabilities, offering significant advantages for azobenzene functionalization in biomass‐based polyester applications. In this study, AESO served as the polyester matrix and acrylate azobenzene derivatives as the functional molecules. Under ultraviolet radiation, AESO underwent a carbon–carbon crosslinking reaction with the azobenzene derivatives to synthesize a novel resin. The coating of this resin on a PET substrate exhibited excellent pencil hardness (3B), adhesion (5B), and solvent resistance. By alternating exposure to ultraviolet and blue light, the coating displayed reversible switching between cis and trans isomers, enabling reversible writing and erasing of patterns. Even after 20 cycles of writing and erasing, high‐resolution patterns could still be observed (clearly visible under a 12x microscope). Furthermore, the image could be retained for up to 2 h under sunlight irradiation. This study presents a new method for functionalizing biobased polyesters.

Geometrical isomers of lutein and fucoxanthin: Unveiling their antioxidant potentials and skin-related biological activities

Although carotenoids are most commonly found in dietary sources as all-E-isomers, some carotenoids accumulate in the skin as Z-isomers; their roles are largely unknown. This study investigated the effects of E/Z-isomers of lutein and fucoxanthin, two xanthophyll carotenoids, on their antioxidant potential and skin-related biological activities. Evaluation of ultraviolet (UV)-blocking abilities demonstrated the superior performance of Z-isomer-rich lutein and fucoxanthin against UV-A and UV-B radiation, with Z-isomer-rich lutein exhibiting higher UV-B protection. Antioxidant assays revealed that all-E- and Z-isomer-rich lutein and fucoxanthin had potent singlet oxygen and hydroxyl radical scavenging activities. Moreover, Z-isomer-rich lutein and fucoxanthin exhibited enhanced lipid peroxidation scavenging compared with their all-E counterparts. Both isomers of lutein and fucoxanthin exhibited potent skin-antiaging and skin-whitening effects in several in vitro assays, including anti-elastase and anti-tyrosinase activities. These findings suggest that geometric isomers may enhance the therapeutic efficacy of carotenoids in skin care applications.

Cyclodextrin-based nanosponges for the dispersive-solid phase extraction of pesticides from environmental waters

In this work, harmless, biodegradable, and low-cost cyclodextrin-based nanosponges (CDNS) were synthetized with an optimized green approach based on the use of a natural cyclodextrin (α-CD, β-CD) as the monomer, citric acid as the cross-linker, and NaH2PO4 as the catalyst. The resulting materials were studied using thermal analysis (TGA, DSC), IR spectroscopy, and SEM imaging. For the first time, α-CDNS and β-CDNS were successfully applied for the dispersive-solid phase extraction (d-SPE) from surface waters of eleven pesticides, including achiral compounds (ametocradin, methoxyfenozide, tebufenozide, pyraclostrobin, spiromesifen), optical stereoisomers (mandipropamid, penconazole, difenoconazole, pyriproxyfen, hexythiazox) and geometric stereoisomers (dimetomorph). The extracts were analysed by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). A cholesteryl-bonded silica column allowed the baseline separation of the geometric stereoisomers of dimethomorph, while a polysaccharide-based column was effective in the separation of the optical stereoisomers. Although no nanosponge displayed stereo-discrimination, all of them provided absolute recoveries depending on the analyte logP, steric hindrance, and spike level. In particular, β-CDNS gave yields between 26 and 93 %, and intra-day and inter-day precision of 2–9 % and 4–18 %. Limits of detection and limits of quantitation were 0.05–40 ng/L and 0.2–120 ng/L, respectively. After validation, the d-SPE-HPLC-MS/MS method was applied to the analysis of water samples from the Tiber River: ametoctradin, mandipropamid, penconazole, pyraclostrobin and pyriproxyfen were detected at concentrations between 16 and 43 ng/L. Last but not least, recycling tests have proved that CDNSs can be reused three times with unvaried extraction yields.

Metal-Catalyzed Hydrogen Atom Transfer (MHAT) Hydroalkylation with Electron-Deficient Alkynes.

We present a novel strategy for olefin construction via the reductive coupling of electron-neutral alkenes with electron-deficient alkynes under metal-catalyzed hydrogen atom transfer conditions. This methodology provides selective access to both trans and the more challenging-to-synthesize cis isomers and permits the olefin to be installed next to sterically hindered centers, key factors in the synthesis of biologically active compounds. The reaction exhibits broad functional group tolerance and proceeds under mild, nontoxic conditions with high atom efficiency.

Copper(II)-Oxyl Formation in a Biomimetic Complex Activated by Hydrogen Peroxide: The Key Role of Trans-Bis(Hydroxo) Species.

Enzymes in nature, such as the copper-based lytic polysaccharide monooxygenases (LPMOs), have gained significant attention for their exceptional performance in C-H activation reactions. The use of H2O2 by LPMOs enzymes has also increased the interest in understanding the oxidation mechanism promoted by this oxidant. While some literature proposes Fenton-like chemistry involving the formation of Cu(II)-OH species and the hydroxyl radical, others contend that Cu(I) activation by H2O2 yields a Cu(II)-oxyl intermediate. In this study, we focused on a bioinspired Cu(I) complex to investigate the reaction mechanism of its oxidation by H2O2 using density functional theory and ab initio molecular dynamics simulations. The latter approach was found to be critical for finding the key Cu intermediates. Our results show that the highly flexible coordination environment of copper strongly influences the nature of the oxidized Cu(II) species. Furthermore, they suggest the favorable formation of trans-Cu(II)-(OH)2 moieties in low-coordinated Cu(II) species. This trans configuration hinders the formation of Cu(II)-oxyl species, facilitating intramolecular H-abstraction reactions in line with experimentally observed ligand oxidation processes.

Computational Study on the Photo‐Induced Antibiotic Activity of an Azoquinolone with Promising Applications in Photopharmacology

Azocompounds are among the most important group of molecular photoswitches due to their multiple applications in various scientific areas. We studied the thermal and photochemical reactions of an azocompound with photo‐induced antibiotic properties using ab‐initio calculations based on Kohn‐Shan, Spin‐Flip and time‐dependent Density Functional Theory. Our primary goal is to understand the absorption spectra and isomerization pathways governing the molecule’s light‐controlled antibiotic activity. The nuclear ensemble approach was used for the most stable trans and cis isomers, and the absorption spectra were calculated and fitted to predict the cis/trans isomer ratios in the carboxylate form, using experimental measurements as a reference. We stablished that rotation is involved in the most favorable cis⇄cis and trans⇄trans thermal isomerization pathways, while the inversion mechanism is the most likely for cis⇄trans isomerizations. We found that the photochemical trans→cis isomerization follows a consistent mechanism across all trans isomers, involving excitation to S2(ππ*), an in‐plane ultrafast internal conversion to S1(nπ*), followed by rotation of the azo bond up to a twisted S1(nπ*)/S0 conical intersection. We used a custom approach to evaluate the most favorable decay pathway from the S1(nπ*)/S0 conical intersections to trans and cis photoproducts using static calculations.

Unveiling the versatility of the thioredoxin framework: Insights from the structural examination of Francisella tularensis DsbA1

In bacteria the formation of disulphide bonds is facilitated by a family of enzymes known as the disulphide bond forming (Dsb) proteins, which, despite low sequence homology, belong to the thioredoxin (TRX) superfamily. Among these enzymes is the disulphide bond-forming protein A (DsbA); a periplasmic thiol oxidase responsible for catalysing the oxidative folding of numerous cell envelope and secreted proteins. Pathogenic bacteria often contain diverse Dsb proteins with distinct functionalities commonly associated with pathogenesis. Here we investigate FtDsbA1, a DsbA homologue from the Gram-negative bacterium Francisella tularensis. Our study shows that FtDsbA1 shares a conserved TRX-like fold bridged by an alpha helical bundle showcased by all DsbA-like proteins. However, FtDsbA1 displays a highly unique variation on this structure, containing an extended and flexible N-terminus and secondary structural elements inserted within the core of the TRX fold itself, which together twist the overall DsbA-like architecture. Additionally, FtDsbA1 exhibits variations to the well conserved active site with an unusual dipeptide in the catalytic CXXC redox centre (CGKC), and a trans configuration for the conserved cis-proline loop, known for governing DsbA-substrate interactions. FtDsbA1’s redox properties are comparable to other DsbA enzymes, however, consistent with its atypical structure, functional analysis reveals FtDsbA1 has a high degree of substrate specificity suggesting a specialised role within F. tularensis’ oxidative folding pathway. Overall, this work underscores the remarkable malleability of the TRX catalytic core, a ubiquitous and ancestral protein fold. This not only contributes to broadening the structural and functional diversity seen within proteins utilising this core fold but will also enhance the accuracy of AI-driven protein structural prediction tools.

Synthesis, Characterization and Study of E/Z Isomerization in 3-(2-(2,4-Dimethylphenyl) Hydrazono)-6-Fluoroquinolin-(1H, 3H)-2, 4-Dione

The compound 6-fluoro-4-hydroxyquinolin-2(1H)-one (1) was synthesized and reacted with diazotized 2, 4-dimethylaniline in a basic medium, yielding the hydrazone derivative (2) as a deep yellow crystalline compound. The structure of the purified product was confirmed through FT-IR, 1D and 2D NMR, and mass spectroscopic analyses. The results showed that the product exclusively adopts a hydrazone structure, existing as an equilibrium mixture of E and Z geometrical isomers in solution. DFT quantum calculations at the B3LYP/6-311++G (d, p) level indicated that the hydrazone form of compound (2) is more stable than the proposed azo structure, with the Z-hydrazone isomer having the lowest total energy. Additionally, UV-Vis spectroscopy studies of the E and Z isomers of hydrazone compound (2) in solvents of varying polarities showed that the E isomer is the predominant species in non-polar solvents.

Robust Organocatalytic Three-Component Approach to 1,3-Diarylallylidene Pyrazolones via Consecutive Double Condensation Reactions.

A robust pyrrolidine-BzOH salt-catalyzed one-pot three-component reaction involving 4-unsubstituted pyrazolones, aryl/heteroarylaldehydes, and aryl methyl ketones is reported for the first time. This catalytic process fortifies an efficient method, allowing for the practical synthesis of a wide array of synthetically useful 1,3-diarylallylidene pyrazolones in good to high yields exclusively in their single geometrical isomer forms. Furthermore, this catalyst facilitates a sequential double condensation reaction under thermal conditions, thereby enabling two consecutive C═C bonds through displacement of aryl groups. Moreover, this organocatalytic technique achieves a 100% carbon atom economy, marking a significant step forward toward efficient and sustainable synthesis.

Catalyst‐Free Diborylation and Silaboration of Azoarenes: A Simple Photoinduced Approach

AbstractThe diborylation of the N=N double bond of azoarenes has been achieved using a commercially available diboron reagent, B2cat2 [bis(catecholato)diboron]. By utilizing the photo‐switchable nature of azoarenes under blue‐LED light irradiation, an uncatalyzed diborylation and silaboration yielded a broad range of functionalized hydrazine derivatives. The mechanistic origin validates the importance of cis configuration, which is corroborated by theoretical calculations.

Catalyst-Free Diborylation and Silaboration of Azoarenes: A Simple Photoinduced Approach.

The diborylation of the N=N double bond of azoarenes has been achieved using a commercially available diboron reagent, B2cat2 [bis(catecholato)diboron]. By utilizing the photo-switchable nature of azoarenes under blue-LED light irradiation, an uncatalyzed diborylation and silaboration yielded a broad range of functionalized hydrazine derivatives. The mechanistic origin validates the importance of cis configuration, which is corroborated by theoretical calculations.

Segregation of Trans Mutations in the CDH23 Gene in an Emirati Family with Sensorineural Hearing Loss.

Hearing loss (HL) is a significant global health concern, affecting approximately 1 in every 1000 newborns, with over half of these cases attributed to genetic factors. This study focuses on identifying the genetic basis of autosomal recessive non-syndromic hearing loss (ARNSHL) in a consanguineous Emirati family. Clinical exome sequencing (CES) was performed on affected members of the family, followed by Sanger sequencing to validate the findings. Specific primers were used for PCR amplification of target CDH23 exons. Mutations were analyzed using various computational tools to assess their pathogenicity. We identified two heterozygous mutations in the CDH23 gene: a novel nonsense variant (c.264G>A, p.Trp88Ter) and a missense variant (c.5168G>A, p.Arg1723His). Both mutations were found in trans configuration, suggesting a compound heterozygous state contributing to the phenotype. In silico analysis predicted a significant impact on protein function, potentially leading to the observed ARNSHL. This study emphasizes the complexity of genetic factors in hearing loss, particularly in highly consanguineous populations. The identification of both nonsense and missense mutations in the CDH23 gene enhances understanding of its role in hearing loss and provides essential insights for genetic counseling and future therapeutic strategies.

A Rationally Designed Azobenzene Photoswitch for DNA G-Quadruplex Regulation in Live Cells.

G-quadruplex (G4) DNA structures are increasingly acknowledged as promising targets in cancer research, and the development of G4-specific stabilizing compounds may lay a fundamental foundation in precision medicine for cancer treatment. Here, we propose a light-responsive G4-binder for precise modulation of drug activation, providing dynamic and spatiotemporal control over G4-associated biological processes contributing to cancer cell death. We developed a specialized fluorinated azobenzene (AB) switch equipped with a quinoline unit and a positively charged carboxamide side chain, Q-Azo4F-C, designed for targeted binding to G4 structures within cells. Biophysical studies, combined with molecular dynamics simulations, provide insights into the unique coordination modes of the photoswitchable ligand in its trans and cis configurations when interacting with G4s. The observed variations in complexation processes between the two isomeric states in different cancer cell lines manifest in more than 25-fold reversible cytotoxic activity. Immunostaining conducted with the structure-specific G4 antibody (BG4), establishes a direct correlation between cytotoxicity and the varying extent of G4 induction regulated by the two isoforms. Finally, we demonstrate the photo-driven reversible regulation of G4 structures in lung cancer cells by Q-Azo4F-C. Our findings highlight the potential of light-responsive G4-binders in advancing precision cancer therapy through dynamic control of G4-mediated pathways.

A Rationally Designed Azobenzene Photoswitch for DNA G‐Quadruplex Regulation in Live Cells

AbstractG‐quadruplex (G4) DNA structures are increasingly acknowledged as promising targets in cancer research, and the development of G4‐specific stabilizing compounds may lay a fundamental foundation in precision medicine for cancer treatment. Here, we propose a light‐responsive G4‐binder for precise modulation of drug activation, providing dynamic and spatiotemporal control over G4‐associated biological processes contributing to cancer cell death. We developed a specialized fluorinated azobenzene (AB) switch equipped with a quinoline unit and a positively charged carboxamide side chain, Q‐Azo4F‐C, designed for targeted binding to G4 structures within cells. Biophysical studies, combined with molecular dynamics simulations, provide insights into the unique coordination modes of the photoswitchable ligand in its trans and cis configurations when interacting with G4s. The observed variations in complexation processes between the two isomeric states in different cancer cell lines manifest in more than 25‐fold reversible cytotoxic activity. Immunostaining conducted with the structure‐specific G4 antibody (BG4), establishes a direct correlation between cytotoxicity and the varying extent of G4 induction regulated by the two isoforms. Finally, we demonstrate the photo‐driven reversible regulation of G4 structures in lung cancer cells by Q‐Azo4F‐C. Our findings highlight the potential of light‐responsive G4‐binders in advancing precision cancer therapy through dynamic control of G4‐mediated pathways.