Strategy to Empower Nontargeted Metabolomics by Triple-Dimensional Combinatorial Derivatization with MS-TDF Software.

Chemical derivatization is a widely employed strategy in metabolomics to enhance metabolite coverage by improving chromatographic behavior and increasing the ionization rates in mass spectroscopy (MS). However, derivatization might complicate MS data, posing challenges for data mining due to the lack of a corresponding benchmark database. To address this issue, we developed a triple-dimensional combinatorial derivatization strategy for nontargeted metabolomics. This strategy utilizes three structurally similar derivatization reagents and is supported by MS-TDF software for accelerated data processing. Notably, simultaneous derivatization of specific metabolite functional groups in biological samples produced compounds with stable but distinct chromatographic retention times and mass numbers, facilitating discrimination by MS-TDF, an in-house MS data processing software. In this study, carbonyl analogues in human plasma were derivatized using a combination of three hydrazide-based derivatization reagents: 2-hydrazinopyridine, 2-hydrazino-5-methylpyridine, and 2-hydrazino-5-cyanopyridine (6-hydrazinonicotinonitrile). This approach was applied to identify potential carbonyl biomarkers in lung cancer. Analysis and validation of human plasma samples demonstrated that our strategy improved the recognition accuracy of metabolites and reduced the risk of false positives, providing a useful method for nontargeted metabolomics studies. The MATLAB code for MS-TDF is available on GitHub at https://github.com/CaixiaYuan/MS-TDF.

Comments on "Planar Tetracoordinate Hydrogen: Pushing the Limit of Multicentre Bonding".

In a recent communication (Angew. Chem. Int. Ed. 2024, 63, e202317312), Kalita et al. studied In4H+ system within the frame of single-reference approximation (SRA) and found that the global energy minimum (1 a) adopted the singlet state and a planar tetracoordinate hydrogen (ptH), while the second lowest isomer (1 b) located 3.0 kcal/mol above 1 a and adopted the triplet state as well as non-planar structure with a quasi-ptH. They assessed the reliability of SRA by checking the T1-diagnostic values of coupled cluster calculations. However, according to our multi-configurational second-order perturbation theory calculations at the CASPT2(12,13)/aug-cc-pVQZ (aug-cc-pVQZ-PP for In) level, both 1 a and 1 b exhibit obvious multi-referential characters, as reflected by their largest reference coefficients of 0.928 (86.1 %) and 0.938 (88.0 %), respectively. Moreover, 1 b is 5.05 kcal/mol lower than 1 a at this level, that is, what can be observed in In4H+ system is the quasi-ptH.

3-D molecular stars with covalent axial bonding.

In designing three-dimensional (3-D) molecular stars, it is very difficult to enhance the molecular rigidity through forming the covalent bonds between the axial and equatorial groups because corresponding axial groups will generally break the delocalized π bond over equatorial frameworks and thus break their star-like arrangement. In this work, exemplified by designing the 3-D stars Be2 ©Be5 E5 + (E = Au, Cl, Br, I) with three delocalized σ bonds and delocalized π bond over the central Be2 ©Be5 moiety, we propose that the desired covalent bonding can be achieved by forming the delocalized σ bond(s) and delocalized π bond(s) simultaneously between the axial groups and equatorial framework. The covalency and rigidity of axial bonding can be demonstrated by the total Wiberg bond indices of 1.46-1.65 for axial Be atoms and ultrashort Be-Be distances of 1.834-1.841 Å, respectively. Beneficial also from the σ and π double aromaticity, these mono-cationic 3-D molecular stars are dynamically viable global energy minima with well-defined electronic structures, as reflected by wide HOMO-LUMO gaps (4.68-5.06 eV) and low electron affinities (4.70-4.82 eV), so they are the promising targets in the gas phase generation, mass-separation, and spectroscopic characterization.

[(OB)2-M©B7O7-BO]- (M = Mn, Tc, Re): Chemically Stable and Triply Aromatic Ballet Rotors.

Single-molecule nanorotors are generally constructed based on boron atoms to obtain structural fluxionality via possessing the delocalized multicenter bonds. However, the electron-deficient boron atoms are commonly exposed in these nanorotors, which leads to extremely high chemical reactivity, which blocks the synthesis in the condensed phase. In this work, we computationally designed a series of transition-metal-doped boron oxide clusters MB10O10- (in structural configuration of [(OB)2-M©B7O7-BO]-, M = Mn, Tc, Re, © means "centered" in a planar or quasi-planar hypercoordinate environment), which can be vividly named as "ballet rotors" to label their anthropomorphic dynamic rotational behaviors. The rotational fluxionality in ballet rotors originates from the completely delocalized nature of the bonding within their MB10 core moieties. Remarkably, compared with single-molecule nanorotors having bare boron atoms and the narrow HOMO-LUMO gaps (≤4.00 eV) as well as low vertical detachment energies (VDEs, ≤4.46 eV for anions), the ballet rotors possess significantly improved chemical stability, as evidenced sterically by the absence of exposed boron atoms and electronically by much wider HOMO-LUMO gaps (5.66-5.98 eV) as well as obviously higher VDEs between 5.36 and 5.47 eV. Specifically, the ballet rotors are mainly stabilized by the delicately placed peripheral oxygen atoms, which can compensate for all electron-deficient boron atoms via O → B π back bonds and sterically protect them. Simultaneously, they are additionally stabilized by aromatic stabilization effect from possessing the novel S + P + D triple aromaticity. We expect that the proposal of chemically stable ballet rotors in this work can arouse the rational design of nanorotors for experimental realization in the condensed phase.

[Sc©[3]CPP]+: A Viable Metal-Centered [3]Cycloparaphenylene.

[n]Cycloparaphenylenes ([n]CPPs, n denotes the number of phenyl groups) are difficult to synthesize because of the strain related to their bent phenyl rings. In particular, the strain in [3]CPP is high enough to destroy the π electron delocalization, leading to the spontaneous structural transition to an energetically more stable "bond-shift" (BS) isomer ([3]BS). In this contribution, we propose to achieve [3]CPP by enhancing the π electron delocalization through hosting a guest metal atom. Our computations revealed that Sc could stabilize [3]CPP by forming the [Sc©[3]CPP]+ complex through the favorable π-Sc donation-backdonation interactions. Thermodynamically, the binding energy between the Sc atom and [3]CPP was -205.7 kcal/mol, which could well compensate not only the energy difference of 44.2 kcal/mol between [3]CPP and [3]BS but also the extremely high strain energy of 170.3 kcal/mol in [3]CPP. Simultaneously, the [Sc©[3]CPP]+ complex is stable up to 1500 K in dynamic simulations, suggesting its high viability in the synthesis.

NAl4X4 + (X = S, Se, Te): Clusters with a planar tetracoordinate nitrogen and significantly improved stability.

The design of clusters featuring non-classical planar hypercoordinate atoms (phAs) often depends on the delocalized multicenter bonds involving reactive electron-deficient elements, which both destabilize the clusters and lead to difficulty in achieving the phA arrangement for electronegative elements such as nitrogen due to their preference for localized bonds. In this work, we computationally designed a series of aluminum chalcogenide clusters NAl4X4 + (X = S, Se, Te) with a desired planar tetracoordinate nitrogen and meaningfully improved chemical stability, as evidenced by the wide gaps (6.51-7.23 eV) between their highest occupied molecular orbitals and lowest unoccupied molecular orbitals, high molecular rigidity (dynamically stable up to 1500 K), and exclusively low global energy minima nature (their isomers locate at least 51.2 kcal/mol higher). Remarkably, these clusters are stabilized by peripheral chalcogen atoms, which not only sterically protect the NAl4 core moiety but also electronically compensate for the electron-deficient aluminum atoms via X → Al π back bonds, meeting the description of our recently proposed "electron-compensation" strategy.

The dual inhibition against the activity and expression of tyrosine phosphatase PRL-3 from a rhodanine derivative.

Increasing evidences demonstrated that PRL-3 was associated with metastatic potential in a variety of cancers including CRC, gastric cancer, ovarian cancer and so on. PRL-3 knock down inhibited the development of metastasis by reducing the size of primary tumors and inhibiting the invasion and growth of cancer cells. Therefore, PRL-3 is a promising diagnostic marker and therapeutic target in tumors. So far, only several PRL-3 inhibitors have been reported. In this study, six rhodanine derivatives were synthesized and characterized. The compounds were evaluated against tyrosine phosphatase PRL-3. Among these compounds, 5-(5-chloro-2-(trifluoromethyl)benzylidene)-2-thioxothiazolidin-4-one (4) could effectively inhibit PRL-3 with IC50 value of 15.22 µM. Fluorescent assays suggested compound 4 tightly bound to tyrosine phosphatase PRL-3 with the molar ratio of 1:1, and the binding constant of 1.74 × 106 M-1. Compound 4 entered into SW-480 cells, selectively inhibited the expression of PRL-3 and increased the phosphorylation of PRL-3 substrates, and decreased the survival rate of SW-480 cells with IC50 of 6.64 µM and induced apoptosis. The results revealed that compound 4 is a dual functional inhibitor against the activity and expression of PRL-3 and a promising anti-cancer candidate targeting PRL-3.

Peijingsu effectively improves sperm DNA integrity.

Intact human sperm DNA is an essential prerequisite for successful fertilization and embryo development. Abnormal sperm DNA fragmentation is a independent factor for male infertility. The objective of this study was to investigate the effects of Peijingsu, a health product, on the DNA integrity of human sperm. Peijingsu was administered for 15 days to 22 patients who had an abnormal sperm DNA fragmentation index (DFI). The DFIs before and after treatment were compared and analyzed using paired t-test. DFIs decreased significantly (P = 0.0008) after treatment, therefore it was concluded that Peijingsu effectively improved sperm DNA integrity in infertile patients who had an abnormal sperm DFI.

Influence of stepwise oxidation on the structure, stability, and properties of planar pentacoordinate carbon species CAl5.

Computational design has played an important role in planar hyper-coordinate carbon (phC) chemistry. However, none of numerous computationally predicted phC species were subsequently successfully synthesized in the condensed phase, perhaps due to the frustrating issue of oxidation. In the present work, we studied the influence of stepwise oxidation on the structure, stability, and properties of phC species using the milestone planar pentacoordinate carbon (ppC) species CAl5+ as an example. Our results indicated that the ppC structure of CAl5+ would be directly destroyed with one, two, or six O atom(s) per molecule present and indirectly with three or four O atoms, but maintained with five O atoms due to the ppC isomer of CAl5O5+ being a kinetically stable global energy minimum displaying σ and π double aromaticity. Moreover, the magnitudes of the first to fifth vertical oxygen affinities (VOAs) for CAl5+ were determined to be very high (-85.5 to -116.3 kcal mol-1), probably due to the existence of peripheral diffuse Al-Al bond(s). However, the sixth VOA was reduced significantly to -50.2 kcal mol-1, consistent with the absence of any diffuse Al-Al bond in the corresponding CAl5O5+ species. So CAl5O5+ may be insensitive to oxidation. Therefore, the ppC species D5h CAl5O5+ might be resistant to being degraded under a delicate control of oxidation level (producing five O atoms per CAl5+ molecule).

Effect of silencing HIF-1α gene on testicle spermatogenesis function in varicocele rats.

This study uses the CRISPR/Cas9 gene editing technique to silence the expression of hypoxia-inducible factor-1α (HIF-1α) gene and investigate its effect on testicle spermatogenesis function in varicocele (VC) rats. Sprague Dawley rats were divided into four groups; the control, VC model, VC+HIF-1α-lentivirus and VC+Luciferase-lentivirus group. The sperm count and survival rate were analyzed using computer-aided sperm analysis. The morphological changes of seminiferous tubules were observed by a microscope. Expressions of HIF-1α, Bax, cleaved caspase-3 and Bcl-2 were detected via Western blot, immunofluorescence and real-time polymerase chain reaction methods. One-way ANOVA was used to analyze the differences between groups. The sperm count and survival rate were significantly lower (p < 0.05) and the seminiferous epithelium was more disordered in the VC group than that in the control group. The expression of Bax and cleaved caspase-3 were increased and Bcl-2 was reduced in the VC group than the control group. Compared with the VC group, sperm count and survival rate noticeably increased (p < 0.05), seminiferous epithelium was inordered arrangement and fewer spermatogenic cells were injured in the VC+HIF-1α-lentivirus group. Expression of Bax and cleaved caspase-3 were decreased significantly in the VC+HIF-1α-lentivirus group compared with the VC group and VC+Luciferase-lentivirus group (p < 0.05), whereas the expression of Bcl-2 was increased (p < 0.05). No significant difference was observed between the control group and the VC+HIF-1α-lentivirus group (p > 0.05). Results show that the apoptosis of spermatogenic cells was decreased and the testicle spermatogenesis function was significantly improved after silencing HIF-1α gene in testis of VC rats. HIF-1α may play a crucial role during spermatogenesis in VC inducing male infertility.

Viable aromatic BenHn stars enclosing a planar hypercoordinate boron or late transition metal.

Monocyclic Bn rings can act as n-electron σ-donors to stabilize a non-classical planar hypercoordinate atom at ring center, forming wheel-like structures. Herein, we report that BenHn rings can also serve as n-electron σ-donors to construct star-like structures including B©Be6H6+ and TM©Be7H7q (TM is a group 10-12 metal with q = -1, 0, and 1, respectively) by complying with octet or 18-electron rules. Electronic structure analyses show that these species are stabilized by the σ-donation and π-backdonation between the central atom and the peripheral BenHn ring, the favorable Coulomb attraction due to the negative-positive-negative charge population pattern on the central atom, the middle Ben layer, and the outer Hn layer, as well as the σ-π double aromaticity. Importantly, three of the ten species, including B©Be6H6+, Cu©Be7H7, and Au

Linear, planar, and tubular molecular structures constructed by double planar tetracoordinate carbon D2hC2(BeH)4 species via hydrogen-bridged -BeH2Be- bonds.

This computational study identifies the rhombic D2hC2 (BeH)4 (2a) to be a species featuring double planar tetracoordinate carbons (ptCs). Aromaticity and the peripheral BeBeBeBe bonding around CC core contribute to the stabilization of the ptC structure. Although the ptC structure is not a global minimum, its high kinetic stability and its distinct feature of having a bonded C2 core from having two separated carbon atoms in the global minimum and other low-lying minima could make the ptC structure to be preferred if the carbon source is dominated by C2 species. The electron deficiency of the BeH group allows the ptC species to serve as building blocks to construct large/nanostructures, such as linear chains, planar sheets, and tubes, via intermolecular hydrogen-bridged bonds (HBBs). Formation of one HBB bond releases more than 30.0 kcal/mol of energy, implying the highly exothermic formation processes and the possibility to synthesize these nano-size structures.

Computational design of organometallic oligomers featuring 1,3-metal-carbon bonding and planar tetracoordinate carbon atoms.

Density functional theory computations (B3LYP) have been used to explore the chemistry of titanium-aromatic carbon "edge complexes" with 1,3-metal-carbon (1,3-MC) bonding between Ti and planar tetracoordinate Cß . The titanium-coordinated, end-capping chlorides are replaced with OH or SH groups to afford two series of difunctional monomers that can undergo condensation to form oxide- and sulfide-bridged oligomers. The sulfide-linked oligomers have less molecular strain and are more exergonic than the corresponding oxide-linked oligomers. The HOMO-LUMO gap of the oligomers varies with their composition and decreases with growing oligomer chain. This theoretical study is intended to enrich 1,3-MC bonding and planar tetracoordinate carbon chemistry and provide interesting ideas to experimentalists. Organometallic complexes with the TiE2 (E = OH and SH) decoration on the edge of aromatic hydrocarbons have been computationally designed, which feature 1,3-metal-carbon (1,3-MC) bonding between titanium and planar tetracoordinate ß-carbon. Condensation of these difunctional monomers by eliminating small molecules (H2O and H2S) produce chain-like oligomers. The HOMO-LUMO gaps of the oligomers decreases with growing oligomer chain, a trend that suggests possible semiconductor properties for oligomers with longer chains.

The degree of π electron delocalization and the formation of 3D-extensible sandwich structures.

DFT B3LYP/6-31G(d) calculations were performed to examine the feasibility of graphene-like C42H18 and starbenzene C6(BeH)6 (SBz) polymers as ligands of 3D-extensible sandwich compounds (3D-ESCs) with uninterrupted sandwich arrays. The results revealed that sandwich compounds with three or more C42H18 ligands were not feasible. The possible reason may be the localization of π electrons on certain C6 hexagons due to π-metal interactions, which makes the whole ligand lose its electronic structure basis (higher degree of π electron delocalization) to maintain the planar structure. For comparison, with the aid of benzene (Bz) molecules, the SBz polymers can be feasible ligands for designing 3D-ESCs because the C-Be interactions in individual SBz are largely ionic, which will deter the π electrons on one C6 ring from connecting to those on neighbouring C6 rings. This means that high degree of π electron delocalization is not necessary for maintaining the planarity of SBz polymers. Such a locally delocalized π electron structure is desirable for the ligands of 3D-ESCs. Remarkably, the formation of a sandwich compound with SBz is thermodynamically more favourable than that found for bis(Bz)chromium. The assembly of 3D-ESCs is largely exothermic, which will facilitate future experimental synthesis. The different variation trends on the HOMO-LUMO gaps in different directions (relative to the sandwich axes) suggest that they can be developed to form directional conductors or semiconductors, which may be useful in the production of electronic devices.

Ultrashort Beryllium-Beryllium Distances Rivalling Those of Metal-Metal Quintuple Bonds Between Transition Metals.

Chemical bonding is at the heart of chemistry. Recent work on high bond orders between homonuclear transition metal atoms has led to ultrashort metal-metal (TM-TM) distances defined as dM-M <1.900 Å. The present work is a computational design and characterization of novel main group species containing ultrashort metal-metal distances (1.728-1.866 Å) between two beryllium atoms in different molecular environments, including a rhombic Be2 X2 (X=C, N) core, a vertical Be-Be axis in a 3D molecular star, and a horizontal Be-Be axis supported by N-heterocyclic carbene (NHC) ligands. The ultrashort Be-Be distances are achieved by affixing bridging atoms to attract the beryllium atoms electrostatically or covalently. Among these species are five global minima and one chemically viable diberyllium complex, which provide potential targets for experimental realization.

A novel electrochemical sensor based on zirconia/ordered macroporous polyaniline for ultrasensitive detection of pesticides.

A simple and mild strategy was proposed to develop a novel electrochemical sensor based on zirconia/ordered macroporous polyaniline (ZrO2/OMP) and further used for the detection of methyl parathion (MP), one of the organophosphate pesticides (OPPs). Due to the strong affinity of phosphate groups with ZrO2 and the advantages of OMP such as high catalytic activity and good conductivity, the developed sensor showed a limit of detection as low as 2.28 × 10(-10) mol L(-1) (S/N = 3) by square-wave voltammograms, and good selectivity, acceptable reproducibility and stability. Most importantly, this novel sensor was successfully applied to detect MP in real samples of apple and cabbage. It is expected that this method has potential applications in electrochemical sensing platforms with simple, sensitive, selective and fast analysis.

4-[(5-Bromo-2-hy-droxy-benzyl-idene)amino]-3-ethyl-1H-1,2,4-triazole-5(4H)-thione.

The title compound, C11H11BrN4OS, crystallized as a racemic twin with two symmetry-independent mol-ecules in the asymmetric unit. The dihedral angles between the benzene and triazole rings of the two independent mol-ecules are 56.41 (18) and 54.48 (18)°. An intra-molecular O-H⋯N hydrogen bond occurs in each mol-ecule. In the crystal, pairs of symmetry-independent mol-ecules are linked by pairs of almost linear N-H⋯S hydrogen bonds, forming cyclic dimers characterized by an R 2 (2)(8) motif. There are weak π-π inter-actions between the benzene rings of symmetry-independent mol-ecules, with a centroid-centroid distance of 3.874 (3) Å.

2-[(E)-(4-Bromo-phenyl)imino-methyl]-4-chloro-phenol.

In the title compound, C13H9BrClNO, the dihedral angle between the substituted benzene rings is 44.25 (11)°. There are strong intra-molecular O-H⋯N hydrogen bonds, which generate S(6) rings, and also inter-molecular Cl⋯Cl [3.431 (3) Å] and Br⋯ Br [3.846 (1) Å] contacts. The crystal packing a C-H⋯O and C-H⋯π inter-actions.

4-[(5-Chloro-2-hy-droxy-benzyl-idene)amino]-3-ethyl-1H-1,2,4-triazole-5(4H)-thione.

The title compound, C11H11ClN4OS, crystallizes with two mol-ecules, A and B, in the asymmetric unit in which the dihedral angles between the triazole and benzene rings are 54.6 (3) and 56.0 (3)°. Both mol-ecules feature an intra-molecular O-H⋯N hydrogen bond, which generates an S(6) ring. In the crystal, A-B dimers are linked by pairs of weak C-H⋯S hydrogen bonds along with π-π stacking inter-actions between the triazole rings [centroid-centroid separations = 3.631 (3) and 3.981 (4)Å]. N-H⋯S hydrogen bonds link the dimers into [100] chains, which feature R 2 (2)(8) loops.

CBe4H6: a molecular rotor with a built-in on-off switch.

It is highly challenging to control (stop and resume as needed) molecular rotors because their intramolecular rotations are electronically enabled by delocalized σ bonding, and the desired control needs to be able to destroy and restore such σ bonding, which usually means difficult chemical manipulation (substitution or doping atom). In this work, we report CBe4H6, a molecular rotor that can be controlled independently of chemical manipulation. This molecule exhibited the uninterrupted free rotation of Be and H atoms around the central carbon in first-principles molecular dynamics simulations at high temperatures (600 and 1000 K), but the rotation cannot be witnessed in the simulation at room temperature (298 K). Specifically, when a C-H bond in the CBe4H6 molecule adopts the equatorial configuration at 298 K, it destroys the central delocalized σ bonding and blocks the intramolecular rotation (the rotor is turned "OFF"); when it can adopt the axial configuration at 600 and 1000 K, the central delocalized σ bonding can be restored and the intramolecular rotation can be resumed (the rotor is turned "ON"). Neutral CBe4H6 is thermodynamically favorable and electronically stable, as reflected by a wide HOMO-LUMO gap of 7.99 eV, a high vertical detachment energy of 9.79 eV, and a positive electron affinity of 0.24 eV, so it may be stable enough for the synthesis, not only in the gas phase, but also in the condensed phase.