R1 Position Research Articles

The interaction of the azetidine thiazole side chain with the active site loop (ASL) 3 drives the evolution of IMP metallo-β-lactamase against tebipenem.

Imipenemase (IMP) metallo-β-lactamases (MBLs) hydrolyze almost all available β-lactams including carbapenems and are not inhibited by any commercially available β-lactamase inhibitor. Tebipenem (TP) pivoxil is the first orally available carbapenem and possesses a unique bicyclic azetidine thiazole moiety located at the R2 position. TP has potent in vitro activity against Enterobacterales producing extended-spectrum and/or AmpC β-lactamases. Thus far, the activity of TP against IMP-producing strains is understudied. To address this knowledge gap, we explored the structure activity relationships of IMP MBLs by investigating whether IMP-6, IMP-10, IMP-25, and IMP-78 [MBLs with expanded hydrolytic activity against meropenem (MEM)] would demonstrate enhanced activity against TP. Most of the Escherichia coli DH10B strains expressing IMP-1 variants displayed a ≥twofold MIC difference between TP and MEM, while those expressing VIM or NDM variants demonstrated comparable MICs. Catalytic efficiency (kcat/KM) values for the TP hydrolysis by IMP-1, IMP-6, IMP-10, IMP-25, and IMP-78 were significantly lower than those obtained for MEM. Molecular dynamic simulations reveal that V67F and S262G substitutions (found in IMP-78) reposition active site loop 3, ASL-3, to better accommodate the bicyclic azetidine thiazole side chain, allowing microbiological/catalytic activity to approach that of comparison MBLs used in this study. These findings suggest that modifying the R2 side chain of carbapenems can significantly impact hydrolytic stability. Furthermore, changes in conformational dynamics due to single amino acid substitutions should be used to inform drug design of novel carbapenems.

Tactfully regulating the ESIPT and TICT mechanism in the AIE-active multifunctional triphenylamine Schiff-base compound (TPASB) by methyl substitution

The triphenylamine Schiff-base (TPASB) with dual proton transfer sites (N1…H1–O1 [R1] and N2…H2–O2 [R2]), which is crucial in the field of optoelectronic materials. Herein, a novel molecular design strategy for preparing of TPASB-1 and TPASB-2 via the selective methylation of the hydroxyl group at the R2 or R1 position was proposed. The analysis of electronic structures and potential energy surfaces revealed that a single excited state intramolecular proton transfer (ESIPT) process of TPASB occurs only at R1. Nevertheless, the ESIPT process of TPASB-2 was successfully turned on at R2. More noteworthy is that compared to TPASB, the methylation of hydroxyl group at the R2 position triggers the TICT process of TPASB-1, effectively reducing the potential barrier of ESIPT at the R1 position. This theoretical study explains the role of the substituent effect in regulating ESIPT behaviour, and provides valuable guidance for synthesising efficacious ESIPT-active compounds.

Structure-Activity Relationship of Pyrrolidine Pentamine Derivatives as Inhibitors of the Aminoglycoside 6'-N-Acetyltransferase Type Ib.

Resistance to amikacin and other major aminoglycosides is commonly due to enzymatic acetylation by the aminoglycoside 6'-N-acetyltransferase type I enzyme, of which type Ib [AAC(6')-Ib] is the most widespread among Gram-negative pathogens. Finding enzymatic inhibitors could be an effective way to overcome resistance and extend the useful life of amikacin. Small molecules possess multiple properties that make them attractive for drug development. Mixture-based combinatorial libraries and positional scanning strategy have led to the identification of a chemical scaffold, pyrrolidine pentamine, that, when substituted with the appropriate functionalities at five locations (R1-R5), inhibits AAC(6')-Ib-mediated inactivation of amikacin. Structure-activity relationship studies have shown that while truncations to the molecule result in loss of inhibitory activity, modifications of functionalities and stereochemistry have different effects on the inhibitory properties. In this study, we show that alterations at position R1 of the two most active compounds, 2700.001 and 2700.003, reduced inhibition levels, demonstrating the essential nature not only of the presence of an S-phenyl moiety at this location but also the distance to the scaffold. On the other hand, modifications on the R3, R4, and R5 positions had varied effects, demonstrating the potential for optimization. A correlation analysis between molecular docking values (ΔG) and the dose required for two-fold potentiation of the compounds described in this and the previous studies showed a significant correlation between ΔG values and inhibitory activity.

Microwave-assisted click synthesis, characterisation, and In silico studies of novel 2H-chromene-1,2,3-triazolyl glycoconjugates as potent anticancer and antibacterial agents

A series of novel 2H-chromene-1,2,3-triazolyl glycoconjugates 10a-w were synthesized, well characterized and evaluated for their in vitro antimicrobial and anticancer activities. Among the tested compounds, 10a, 10b, 10u, 10v, and 10w exhibited the most excellent potency against both gram-positive (S. aureus) and gram-negative (E. coli) bacterial strains relative to the standard drug, Gentamicin. The anticancer results showed that in MCF-7 cell line all the tested compounds exhibited better activity as compared to other two cancer cell lines (MDA-MB-231 and A549). Compounds 10t, 10u, 10v, and 10w showed significant cytotoxicity against MCF-7 cell line. The molecular docking studies suggested that all the four potent compounds exhibited a greater affinity for the selected receptors. Experimentally and computationally observed structure-activity relationships indicates, -OCH3 group at R2 position in benzopyran ring with tosyl-protected sugar containing compound 10b and benzyl-protected sugar containing compound 10t enhanced the antibacterial and anticancer activity respectively. Frontier molecular orbital analysis of compounds using the global reactivity parameters indicated that benzyl-protected sugar and acetyl-protected sugar containing compounds are stable and exhibits low reactivity. Moreover, molecular electrostatic potential analysis plots clearly showed that the compounds have strong electrophonic reaction potential. Moreover, the assessment of ADMET predictions revealed favourable pharmacokinetic properties of the investigated compounds. Collectively, it was observed that compounds 10u, 10v, and 10w could be considered as promising dual anticancer antibiotic inhibitors.

Elucidating the Gas-Phase Behavior of Nitazene Analog Protomers Using Structures for Lossless Ion Manipulations Ion Mobility-Orbitrap Mass Spectrometry.

2-Benzylbenzimidazoles, or "nitazenes", are a class of novel synthetic opioids (NSOs) that are increasingly being detected alongside fentanyl analogs and other opioids in drug overdose cases. Nitazenes can be 20× more potent than fentanyl but are not routinely tested for during postmortem or clinical toxicology drug screens; thus, their prevalence in drug overdose cases may be under-reported. Traditional analytical workflows utilizing liquid chromatography-tandem mass spectrometry (LC-MS/MS) often require additional confirmation with authentic reference standards to identify a novel nitazene. However, additional analytical measurements with ion mobility spectrometry (IMS) may provide a path toward reference-free identification, which would greatly accelerate NSO identification rates in toxicology laboratories. Presented here are the first IMS and collision cross section (CCS) measurements on a set of fourteen nitazene analogs using a structures for lossless ion manipulations (SLIM)-orbitrap MS. All nitazenes exhibited two high intensity baseline-separated IMS distributions, which fentanyls and other drug and druglike compounds also exhibit. Incorporating water into the electrospray ionization (ESI) solution caused the intensities of the higher mobility IMS distributions to increase and the intensities of the lower mobility IMS distributions to decrease. Nitazenes lacking a nitro group at the R1 position exhibited the greatest shifts in signal intensities due to water. Furthermore, IMS-MS/MS experiments showed that the higher mobility IMS distributions of all nitazenes possessing a triethylamine group produced fragment ions with m/z 72, 100, and other low intensity fragments while the lower mobility IMS distributions only produced fragment ions with m/z 72 and 100. The IMS, solvent, and fragmentation studies provide experimental evidence that nitazenes potentially exhibit three gas-phase protomers. The cyclic IMS capability of SLIM was also employed to partially resolve four sets of structurally similar nitazene isomers (e.g., protonitazene/isotonitazene, butonitazene/isobutonitazene/secbutonitazene), showcasing the potential of using high-resolution IMS separations in MS-based workflows for reference-free identification of emerging nitazenes and other NSOs.

Unveiling the potential of TPA-based molecules to tune the optoelectronic properties and enhance the efficiency of dye-sensitized solar cells.

The world's energy and environmental requirements are changing due to rapid population growth and industrial growth, and solar cells can be used to meet these demands. Dye-sensitized solar cells (DSSCs) are solar cells in which energy conversion occurs via a process similar to photosynthesis in plants. DSSC development is still in its infancy. DSSCs can operate under cloudy conditions and indirect sunlight and have attracted considerable attention due to their low cost and high efficiency. We designed two metal-free TPA-based dyes (Dye2 and Dye3) based on the reference dye Mg207 (Dye1) by increasing the donor strength of the molecule, as such dyes have shown enhanced efficiency in DSSCs. Moreover, the triphenylamine (TPA) moiety has been demonstrated to be a good donor that prevents charge recombination. Intramolecular charge transfer (ICT) from the donor to acceptor moiety was found in the sensitizers, and electrons were promoted to the conduction band (CB) of the TiO2 semiconductor. The negative binding energy of the dye@TiO2 clusters indicated that dye adsorption on the semiconductor surface was stable. The double donor increased the electron injection and electronic coupling constants in Dye2 and Dye3, indicating that these newly designed dyes have superior charge injection capacity. Accordingly, the efficiencies of DSSCs with Dye2 and Dye3 were 9.77% and 9.62%, respectively, and substitution with the TPA unit at the -R1 and -R2 positions in Dye1 resulted in better power conversion compared to the parent compound (9.09%). Increased donor strength improved photovoltaic performance by increasing current density and light-harvesting efficiency. This is a good molecular design approach for preparing targeted donor- -acceptor (D- -A) organic dyes with high DSSC efficiency. To predict the charge transport and optoelectronic characteristics of the TPA dyes, quantum chemical calculations were carried out using Gaussian16. The ground-state (S0) optimized geometries of the sensitizers were computed by utilizing DFT at the B3LYP/6-31G** level. The absorption spectra ( max) were computed by employing TD-DFT with various functionals (B3LYP, PBE1PBE, CAM-B3LYP, and BHandHLYP) in the gas and solvent (DCM) phases. Among the studied functionals, BHandHLYP was found to be best at successfully reproducing the experimental data. Thus, the absorption spectra of the newly designed dyes and dye@TiO2 were calculated at the BHandHLYP/6-31G** level. The dye@TiO2 cluster optimizations were carried out at the B3LYP/6-31G**(LANL2DZ) level.

3D-QSAR and molecular docking studies of peptide-hybrids as dengue virus NS2B/NS3 protease inhibitors

Global warming and climate change have made dengue disease a global health issue. More than 50 % of the world's population is at danger of dengue virus (DENV) infection, according to the World Health Organization (WHO). Therefore, a clinically approved dengue fever vaccination and effective treatment are needed. Peptide medication development is new pharmaceutical research. Here we intend to recognize the structural features inhibiting the DENV NS2B/NS3 serine protease for a series of peptide-hybrid inhibitors (R1–R2-Lys-R3-NH2) by the 3D-QSAR technique. Comparative molecular field analysis (q2 = 0.613, r2 = 0.938, r2pred = 0.820) and comparative molecular similarity indices analysis (q2 = 0.640, r2 = 0.928, r2pred = 0.693) were established, revealing minor, electropositive, H-bond acceptor groups at the R1 position, minor, electropositive, H-bond donor groups at the R2 position, and bulky, hydrophobic groups at the R3 position for higher inhibitory activity. Docking studies revealed extensive H-bond and hydrophobic interactions in the binding of tripeptide analogues to the NS2B/NS3 protease. This study provides an insight into the key structural features for the design of peptide-based inhibitors of DENV NS2B/NS3 protease.

Key structural requirements of benzamide derivatives for histone deacetylase inhibition: design, synthesis and biological evaluation.

Background: Histone deacetylase inhibitors (HDACIs) are important as anticancer agents. Objective: This study aimed to investigate some key structural features of HDACIs viathedesign, synthesisand biological evaluation of novel benzamide-based derivatives. Methods: Novel structures, designed using amolecular modification approach, were synthesized and biologically evaluated. Results: The results indicated that asubset of molecules with CH3/NH2 at R2 position possessselective antiproliferative activity. However, only those with an NH2 group showed HDACI activity. Importantly, the shorter the molecule length, the stronger HDACI. Among all, 7j was the most potent HDAC1-3 inhibitor and antiproliferative compound. Conclusion: The results of the present investigation couldprovide valuable structural knowledge applicable for the development of the HDACIs and benzamide-based antiproliferative agents in the future.

Design of saccharide based organic binder for low-grade iron ore pelletization using atomistic simulations and machine learning methods

Inorganic binders like bentonite, used for pelletization of low-grade iron ore, generate iron ore slimes with comparatively high silica and alumina content necessitating extra steps for their removal during iron making process. This demands the usage of organic binders as full or partial replacement of bentonite for iron ore pelletization. In this work, adsorption of organic binders with saccharides skeleton and –H, –OH, –CH2OH and –CH2CH2OH as polar substituents, on goethite surface was studied using density functional theory, molecular dynamics and machine learning. It was observed that adsorption energy of binders on goethite surface had weak dependence on number of hydrogen bonds between them. With this favorable interaction in mind, a library containing 64 organic binders was constructed and adsorption energy of 30 of these binders was computed using molecular dynamics, followed by training of a linear regression model, which was then used to predict the adsorption energy of rest of the binders in the library. It was found that the introduction of –CH2CH2OH at R2 position resulted in statistically significant higher adsorption energy. Binder34 and Binder44 were identified as viable candidates for both goethite and hematite ore pelletization and adsorption of their n-mers on goethite and hematite surfaces was also quantified.

Phenolylazoindole scaffold for facilely synthesized and bis-functional photoswitches combining controllable fluorescence and antifungal properties using theoretical methods.

Functionalization is a major challenge for the application of photoswitches. With the aim to develop novel bis-functional azo photoswitches with stationary photophysical properties, a series of phenolylazoindole derivatives were designed, synthesized, and characterized via NMR spectroscopy studies and high-resolution mass spectrometry (HRMS). Herein, UV/Vis and 1H NMR spectra revealed that the photostationary state (PSS) proportions for PSScis and PSStrans were 76-80% and 68-81%, respectively. Furthermore, the thermal half-lives (t1/2) of compounds A2-A4 and B2 ranged from 0.9 to 5.3 h, affected by the diverse substituents at the R1 and R2 positions. The results indicated that azo photoswitches based on the phenolylazoindole scaffold had stationary photophysical properties and wouldn't be excessively affected by modifying the functional groups. Compounds A4 and B2, which were modified with an aryl group, also exhibited fluorescence emission properties (the quantum yields of A4 and B2 were 2.32% and 13.34%) through the modification of the flexible conjugated structure (benzene) at the R2 position. Significantly, compound C1 was obtained via modification with a pharmacophore in order to acquire antifungal activities against three plant fungi, Rhizoctonia solani (R. solani), Botrytis cinerea (B. cinerea), and Fusarium graminearum (F. graminearum). Strikingly, the inhibitory activity of the cis-isomer of compound C1towards R. solani (53.3%) was significantly better than that of the trans-isomer (34.2%) at 50 μg mL-1. In order to further reveal the antifungal mechanism, molecular docking simulations demonstrated that compound C1 effectively integrates into the cavity of succinate dehydrogenase (SDH); the optically controlled cis-isomer showed a lower binding energy with SDH than that of the trans-isomer. This research confirmed that phenolylazoindole photoswitches can be appropriately applied as molecular regulatory devices and functional photoswitch molecules via bis-functionalization.

Structure design of light-resistance fluorane dyes and preparation of color changing materials

Fluorane dyes were widely applicated in the thermochromic area, especially in the form of smart textiles, as they could adjust color via electron transfer. However, developing perfect bright color and light-resistance fluorane dyes had remained challenging due to the intrinsic structural limitations. Here, we reported a series of new fluorane dyes with different electron withdrawing groups that controlled the electron cloud density of the lactone ring, which enhance the thermochromic stability and light-resistance properties. The red shift or blue shift of the absorption wavelength, which could broaden the dye's spectrum, was controlled by the number of electron-absorbing substituents. Moreover, fluorane dyes with a withdrawing group introduced at the R3 position of the lactone ring had excellent light-resistance ability, which was 66%∼57.2% lower than that of commercial dye after 14 h of light irradiation. But, the excess substituents would have weakened its original light-resistance. We also explain the photostability associated with the electron distributon using Density Functional Theory (DFT) simulation. This achievement in the development of light-resistance fluorane offers a promising solution for the application of color-changing materials with a broad absorption spectrum and light-resistance.

Rational design and performance prediction of organic photosensitizer based on TATA+ dye for hydrogen production by photocatalytic decomposition of water.

In comparison to metal complexes, organic photosensitive dyes employed in photocatalytic hydrogen production exhibit promising developmental prospects. Utilizing the organic dye molecule TA+0 as the foundational structure, a series of innovative organic dyes, denoted as TA1-1 to TA2-6, were systematically designed. Employing first-principles calculations, we methodically explored the modifying effects of diverse electron-donating groups on the R1 and R2 positions to assess their application potential. Our findings reveal that, relative to the experimentally synthesized TATA+03, the TA2-6 molecule boasts a spatial structure conducive to intramolecular electron transfer, showcasing the most negative reduction potential (Ered = -2.11eV) and the maximum reaction driving force (△G0 2 = -1.26eV). This configuration enhances its compatibility with the reduction catalyst, thereby facilitating efficient hydrogen evolution. The TA2-6 dye demonstrates outstanding photophysical properties and a robust solar energy capture capacity. Its maximum molar extinction coefficient (ε) stands at 2.616 × 104M-1·cm-1, representing a remarkable 292.8% improvement over TATA+03. In conclusion, this research underscores the promising potential of the TA2-6 dye as an innovative organic photosensitizer, positioning it as an efficacious component in homogeneous photocatalytic systems.

Quantitative investigations of Zebrafish olfactory receptor ORA1 responsiveness to three pheromones: Microscopic and macroscopic characterizations via an advanced statistical physics treatment

In this work, an adsorption phenomenon putatively involved in the olfactory sense of phenylacetic acid, 4-chlorophenylacetic acid, and 4-methoxyphenylacetic acid pheromones in the Zebrafish olfactory receptor ORA1 was a helpful mechanism in interpreting and characterizing the olfaction process at a molecular level. Hence, the experimental dose-olfactory response curves were fitted by applying the one-layer adsorption model with a single energy (1LM1E). On one hand, the different parameters introduced in the selected model were used to microscopically study the three olfactory systems. Indeed, the fitting results showed that phenylacetic acid displayed the greatest maximum olfactory response at saturation, due to the effect of functional groups at the R4 position. The three pheromones were docked via a non-parallel orientation and the adsorption process was a multi-molecular mechanism. The sizes of different binding pockets of ORA1 were determined through the estimation of the olfactory receptor site size distributions (stereographic characterization). The estimated adsorption energies, ranging from 17.340 to 21.332 kJ/mol, can be used to describe the energetic interactions between the studied pheromones and the Zebrafish ORA1 binding pockets. The spectrums of the adsorption energy distributions of phenylacetic acid, 4-chlorophenylacetic acid, and 4-methoxyphenylacetic acid, which were spread out from 10 to 32.5 kJ/mol, 5 to 30 kJ/mol, and 10 to 32.5 kJ/mol, respectively, was determined to estimate the corresponding olfactory bands (energetic characterization). On the other hand, three thermodynamic functions were estimated in order to macroscopically study the three olfactory systems.

Structures and Reactivities of N-Alkenyl-Substituted Anilides: The "Magic" Methyl Effect on Alkene.

Methyl substitution at the double bond of N-alkenyl anilides influences both the preferred conformation and the susceptibility to acidic hydrolysis. The R1-substituted amide favors the trans conformation, whereas amides substituted at R2 or R3 favor the cis conformation. Substitution at the R1 and R3 positions increases the ratio of the trans conformer. DFT study indicated that these conformational preferences can be explained in terms of substituent-induced torsion twisting of the N-alkenyl moiety relative to the amide plane. R1 substitution enhances the susceptibility to acidic hydrolysis, whereas R2 or R3 substitution increases the stability. The effect of the double bond on the conformational effect was showcased by contrasting the preferred conformation of R1-substituted anilide (trans) and hydrogenated N-isopropyl amide (cis).

Disjointness graphs of segments in [formula omitted] are almost all hamiltonian

Let P be a set of n≥1 points in general position in R2. The edge disjointness graphD(P) of P is the graph whose vertices are all the segments with endpoints in P, two of which are adjacent in D(P) if and only if they are disjoint. In this note, we give a full characterization of all those edge disjointness graphs that are hamiltonian. More precisely, we shall show that there are exactly 9 order types of P for which D(P) is not hamiltonian. Additionally, from one of these 9 order types, we derive a counterexample to a criterion for the existence of hamiltonian cycles due to A. D. Plotnikov in 1998.

The Parallel Structure-Activity Relationship Screening of Three Compounds Identifies the Common Agonist Pharmacophore of Pyrrolidine Bis-Cyclic Guanidine Melanocortin-3 Receptor (MC3R) Small-Molecule Ligands.

The melanocortin receptors are involved in numerous physiological pathways, including appetite, skin and hair pigmentation, and steroidogenesis. In particular, the melanocortin-3 receptor (MC3R) is involved in fat storage, food intake, and energy homeostasis. Small-molecule ligands developed for the MC3R may serve as therapeutic lead compounds for treating disease states of energy disequilibrium. Herein, three previously reported pyrrolidine bis-cyclic guanidine compounds with five sites for molecular diversity (R1-R5) were subjected to parallel structure-activity relationship studies to identify the common pharmacophore of this scaffold series required for full agonism at the MC3R. The R2, R3, and R5 positions were required for full MC3R efficacy, while truncation of either the R1 or R4 positions in all three compounds resulted in full MC3R agonists. Two additional fragments, featuring molecular weights below 300 Da, were also identified that possessed full agonist efficacy and micromolar potencies at the mMC5R. These SAR experiments may be useful in generating new small-molecule ligands and chemical probes for the melanocortin receptors to help elucidate their roles in vivo and as therapeutic lead compounds.

Dynamic behavior and alkyne insertion reactions of alkenyl- and thiolate-bridged diiron carbonyl complexes

The alkenyl- and thiolate-bridged diiron carbonyl complexes [Fe2(μ-SC6H4CR1CH)(CO)6] (R1 = H or Me), which are derived from [Fe3(CO)12] and benzothiophenes, reacted with alkynes (R2CCR3) under photoirradiation conditions to form the acyl complexes [Fe2{μ-SC6H4CR1CHCR2C(R3)CO}(CO)5]. In this reaction, an alkyne and CO are inserted into the Fe–alkenyl bond, and the bulky substituents of alkynes, including a redox active ferrocenyl group, occupy the R3 position. To elucidate the reaction pathway, the reaction of the in situ generated acetonitrile complex [Fe2(μ-SC6H4CHCH)(CO)5(NCCH3)] with ethynylbenzene was monitored by 1H NMR spectroscopy. The results demonstrated that the acetonitrile complex undergoes facile insertion of the alkyne, which is followed by CO insertion to give the corresponding acyl complex [Fe2{μ-SC6H4(CH)3C(Ph)CO}(CO)5]. The reactivity of the bridging alkenyl moiety is related to the dynamic behavior of the alkenyl-thiolate ligand (SC6H4CHCH)2- as well as the entering alkyne. Temperature dependent 31P NMR measurements of the dmpm-bridged complex [Fe2(μ-SC6H4CHCH)(μ-dmpm)(CO)4] (dmpm = bis(dimethylphosphino)methane) revealed that the activation parameters for the flip-flop motion of the alkenyl-thiolate ligand are ΔH‡ = 46.7(7) kJ mol-1 and ΔS‡ = −46(2) J mol-1 K-1.

A new series of bioactive Mo(V)2O2S2-based thiosemicarbazone complexes: Solution and DFT studies, and antifungal and antioxidant activities

This paper deals with the synthesis, characterization, and studies of biological properties of a series of 5 coordination compounds based on binuclear core [Mo(V)2O2S2]2+ with thiosemicarbazones ligands bearing different substituents on the R1 position of the ligand. The complexes are first studied using MALDI-TOF mass spectrometry and NMR spectroscopy to determine their structures in solution in relation to single-crystal X-Ray diffraction data. In a second part, the antifungal and antioxidative activities are explored and the high potential of these coordination compounds compared to the uncoordinated ligands is demonstrated for these properties. Finally, DFT calculation provides important support to the solution studies by identifying the most stable isomers in each [Mo2O2S2]2+/Ligand system, while the determination of HUMO and LUMO levels is performed to explain the antioxidative properties of these systems.

Mechanism of generation of substituted β-O-4 lignin dimer CH4 based on bimolecular pyrolysis study

Reactants, radicals, intermediates and products during lignin pyrolysis coexisted in a complex pyrolysis system. They interacted with each other and dominate the lignin pyrolysis process. Different from the traditional unimolecular decomposition mechanism, this paper focuses on the bimolecular reaction pyrolysis mechanism. The density functional theory (DFT) GGA/RPBE method was used. A total of 27 β-O-4 type lignin dimer model compounds with different substituents (-OCH3, –OH, –CH2OH) were selected for the study, and 36 reaction pathways were simulated and calculated. The reaction of intermolecular interactions between methyl radicals and lignin was used to explore the effect law of different positions of substituents on intermolecular interactions. The results show that, There were strong interactions between the lignin molecules and methyl radicals, which could promote the pyrolysis of lignin and the stabilization of free radicals. The lignin molecules acted as the hydrogen donor and donated hydrogen to the methyl radical to generate CH4. The hydrogen donation capability of Cα position was better than that of Cβ position, which was more easily influenced by the OCH3 substituent on the A-ring (The benzene ring far from the O atom was the A-ring). Moreover, the OH substituent at the Cα position will facilitate the reaction. Both the A and B rings had an effect on the hydrogen donation capability of Cβ position. Furthermore, the CH2OH substitution at the Cβ position will inhibit the reaction. When the H atoms at the R1 and R2 positions were replaced by OCH3 substituents, the SH-type (S for syringyl unit, H for p-hydroxyphenyl unit) lignin, which has the strongest hydrogen donation capability. SH-type lignin has the strongest interaction with methyl radicals among the types and is the model compound most likely to produce CH4.

Strong inhibition of organic cation transporter 2 by flavonoids and attenuation effects on cisplatin-induced cytotoxicity

Organic cation transporter 2 (OCT2) is predominantly expressed in the basolateral membrane of renal proximal tubule cells and contributes to the renal excretion of various drugs such as metformin, cisplatin, oxaliplatin, cimetidine, and lamivudine. Cisplatin, an anticancer agent for various cancers, is a substrate of OCT2, and cisplatin-induced nephrotoxicity is in part attributed to OCT2 activity in the kidney, which increases the renal accumulation of cisplatin. In this study, we aimed to identify flavone derivatives with strong inhibitory effects on OCT2 transport. Among the 80 flavonoids tested, 24 showed moderate to strong inhibitory effects against OCT2 transport activity. The IC50 values were less than 5 μM for 10 flavonoids. All 10 compounds alleviated cisplatin-induced cytotoxicity in cells expressing OCT2, even though the magnitude of the effects varied depending on the functional moieties in each position. Multiple factor analysis revealed that the methyl group at the R1 position and methoxy group at the R6 position of the flavonol backbone are important for OCT2 inhibition. Information on the functional moieties in the flavonol backbone would help develop effective OCT2 inhibitors by providing a structural association with OCT2 inhibitory effects. In addition, the compounds with strong inhibitory effects on OCT2 identified in this study may be potential candidates for clinical use to mitigate cisplatin-induced nephrotoxicity.