CYP3A4 and CYP2C19 genetic polymorphisms and myricetin interaction on tofacitinib metabolism.

Tofacitinib can effectively improve the clinical symptoms of rheumatoid arthritis (RA) patients. In this current study, a recombinant human CYP2C19 and CYP3A4 system was operated to study the effects of recombinant variants on tofacitinib metabolism. Moreover, the interaction between tofacitinib and myricetin was analyzed in vitro. The levels of M9 (the main metabolite of tofacitinib) was detected by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The findings revealed that 11 variants showed significant changes in the levels of M9 compared to CYP3A4.1, while the other variants didn't reveal any remarkable significances. Compared with CYP2C19.1, 11 variants showed increases in the levels of M9, and 10 variants showed decreases. Additionally, it was demonstrated in vitro that the inhibition of tofacitinib by myricetin was a non-competitive type in rat liver microsomes (RLM) and human liver microsomes (HLM). However, the inhibitory mechanism was a competitive type in CYP3A4.18, and mixed type in CYP3A4.1 and .28, respectively. The data demonstrated that gene polymorphisms and myricetin had significant effects on the metabolism of tofacitinib, contributing to important clinical data for the precise use.

Facile Tailoring of Metal-Organic Frameworks for Förster Resonance Energy Transfer-Driven Enhancement in Perovskite Photovoltaics.

Förster resonance energy transfer (FRET) has demonstrated its potential to enhance the light energy utilization ratio of perovskite solar cells by interacting with metal-organic frameworks (MOFs) and perovskite layers. However, comprehensive investigations into how MOF design and synthesis impact FRET in perovskite systems are scarce. In this work, nanoscale HIAM-type Zr-MOF (HIAM-4023, HIAM-4024, and HIAM-4025) is meticulously tailored to evaluate FRET's existence and its influence on the perovskite photoactive layer. Through precise adjustments of amino groups and acceptor units in the organic linker, HIAM-MOFs are synthesized with the same topology, but distinct photoluminescence (PL) emission properties. Significant FRET is observed between HIAM-4023/HIAM-4024 and the perovskite, confirmed by spectral overlap, fluorescence lifetime decay, and calculated distances between HIAM-4023/HIAM-4024 and the perovskite. Conversely, the spectral overlap between the PL emission of HIAM-4025 and the perovskite's absorption spectrum is relatively minimal, impeding the energy transfer from HIAM-4025 to the perovskite. Therefore, the HIAM-4023/HIAM-4024-assisted perovskite devices exhibit enhanced EQE via FRET processes, whereas the HIAM-4025 demonstrates comparable EQE to the pristine. Ultimately, the HIAM-4023-assisted perovskite device achieves an enhanced power conversion efficiency (PCE) of 24.22% compared with pristine devices (PCE of 22.06%) and remarkable long-term stability under ambient conditions and continuous light illumination.

Reticular chemistry guided precise construction of zirconium-pentacarboxylate frameworks with 5-connected Zr6 clusters.

Zirconium-based metal-organic frameworks (Zr-MOFs) have been extensively studied due to their very rich structural chemistry. The combination of nearly unlimited carboxylic acid-based linkers and Zr6 clusters with multiple connectivities has led to diverse structures and specific properties of resultant Zr-MOFs. Herein, we demonstrate the successful use of reticular chemistry to construct two novel Zr-MOFs, HIAM-4040 and HIAM-4040-OH, with zfu topology. Based on a thorough structural analysis of (4,4)-connected lvt-type Zr-tetracarboxylate frameworks and a judicious linker design, we have obtained the first example of a Zr-pentacarboxylate framework featuring unprecedented 5-connected organic linkers and 5-connected Zr6 clusters. Compared with HIAM-4040, a larger Stokes shift is achieved in HIAM-4040-OH via hydroxyl group induced excited-state intramolecular proton transfer (ESIPT). HIAM-4040-OH exhibits high chemical and thermal stability and is used for HClO detection in aqueous solution with excellent sensitivity and selectivity.

The effect of shikonin on the metabolism of lapatinib in vitro, and in vivo.

PURPOSE: The purpose of this study was to develop an assay for simultaneous determination of lapatinib and its metabolites (N-dealkylated lapatinib and O-dealkylated lapatinib) by ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), and to determine the interaction between shikonin and lapatinib in vitro, in vivo, in silico and its mechanism of action. METHODS: A new UPLC-MS/MS method for the determination of the concentrations of lapatinib and its metabolites was developed. In vivo, Sprague-Dawley (SD) rats were given lapatinib with or without shikonin. In vitro, to study the interaction mechanism, rat liver microsomes (RLMs), human liver microsomes (HLMs) and recombinant human CYP3A4.1 were used for determining enzyme kinetics. Lastly, we used in silico molecular docking to investigate the molecular mechanism of inhibition. RESULTS: The selectivity, precision, accuracy, stability, matrix effect and recovery of UPLC-MS/MS all met the requirements of quantitative analysis of biological samples. Administration of lapatinib combined with shikonin resulted in significantly increased pharmacokinetic parameters (AUC(0-t) and Cmax) of lapatinib, indicating that shikonin increased the exposure of lapatinib in rats. Moreover, in vitro kinetic measurements indicated that shikonin was a time-independent inhibitor, which inhibited the metabolism of lapatinib through a competitive mechanism in RLMs, while noncompetitive inhibition type in both HLMs and CYP3A4.1. Molecular docking analysis further verified the non-competitive inhibition of shikonin on lapatinib in CYP3A4.1. CONCLUSION: We developed an UPLC-MS/MS assay for simultaneous determination of lapatinib and its metabolites. It could be successfully applied to the study of pharmacokinetic interaction of shikonin on the inhibition of lapatinib metabolism in vivo and in vitro. In the end, further studies are needed to determine if such interactions are indeed valid in humans and if the interaction is clinically relevant.

An Octacarboxylate-Linked Sodium Metal-Organic Framework with High Porosity.

Alkali metal-based metal-organic frameworks (MOFs) with permanent porosity are scarce because of their high tendency to coordinate with solvents such as water. However, these MOFs are lightweight and bear gravimetric benefits for gas adsorption related applications. In this study, we present the successful construction of a microporous MOF, designated as HIAM-111, built solely on sodium ions by using an octacarboxylate linker. The structure of HIAM-111 is based on 8-connected Na4 clusters and exhibits a novel topology with an underlying 32,42,8-c net. Remarkably, HAM-111 possesses a robust and highly porous framework with a BET surface area of 1561 m2/g, significantly surpassing that of the previously reported Na-MOFs. Further investigations demonstrate that HIAM-111 is capable of separating C2H2/CO2 and purifying C2H4 directly from C2H4/C2H2/C2H6 with high adsorption capacities. The current work may shed light on the rational design of robust and porous MOFs based on alkali metals.

Inhibitory effect of napabucasin on arbidol metabolism and its mechanism research.

As a broad-spectrum antiviral, and especially as a popular drug for treating coronavirus disease 2019 (COVID-19) today, arbidol often involves drug-drug interactions (DDI) when treating critical patients. This study established a rapid and effective ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to detect arbidol and its metabolite arbidol sulfoxide (M6-1) levels in vivo and in vitro. In this study, a 200 µL incubation system was used to study the inhibitory effect of the antitumor drug napabucasin on arbidol in vitro, with IC50 values of 2.25, 3.91, and 67.79 µM in rat liver microsomes (RLMs), human liver microsomes (HLMs), and CYP3A4.1, respectively. In addition, we found that the mechanism of inhibition was non-competitive inhibition in RLM and mixed inhibition in HLM. In pharmacokinetic experiments, it was observed that after gavage administration of 48 mg/kg napabucasin and 20 mg/kg arbidol, napabucasin inhibited the metabolism of arbidol in vivo and significantly changed the pharmacokinetic parameters of arbidol, such as AUC(0-t) and AUC(0-∞), in rats. We also found that napabucasin increased the AUC(0-t) and AUC(0-∞) of M6-1, the main metabolite of arbidol. This study provides a reference for the combined use of napabucasin and arbidol in clinical practice.

Carboxyl position-directed structure diversity in zirconium-tricarboxylate frameworks.

Herein, three tritopic carboxylic acids were used to construct three Zr-MOFs, HIAM-4033, HIAM-4034, and HIAM-4035, to investigate the effect of carboxyl position on the MOF structures. The results showed that HIAM-4033 and HIAM-4034 possess (3,9)-c models with different underlying nets, whereas HIAM-4035 exhibits the same underlying net as UiO-68. Nanosized HIAM-4033 exhibits excellent sensitivity and selectivity for detecting aromatic acids, such as benzoic acid and 2-fluorobenzoic acid, compared with aliphatic acids and inorganic acids. This study offers new insights into achieving an organic linker directed structure evolution of Zr-MOFs, which might facilitate the discovery of unprecedented underlying nets.

Development of a UPLC-MS/MS method for the determination of lacosamide and its metabolite and its application to drug-drug interaction.

Lacosamide, a third-generation novel antiepileptic drug, was first approved in 2008 as an adjunct to partial seizures. In 2014, the U.S. Food and Drug Administration (FDA) approved it as a single agent for partial seizures. Since epilepsy is a chronic condition, most patients need long-term antiepileptic medicinal products, so it is even more important to consider the drug-drug interactions (DDIs). For the purpose of this experiment, an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay with accuracy and simplicity was optimized and fully validated for the simultaneous quantitative determination of lacosamide and O-Desmethyl-lacosamide (ODL), and DDIs between lacosamide and nisoldipine in vivo and in vitro was researched. The protein was precipitated with acetonitrile, the analytes were eluted with acetonitrile and a 0.1% formic acid solution in a gradient program, and lacosamide, ODL, and lamotrigine (Internal Standard, IS) were successfully separated by chromatography. The findings of the biological analysis revealed that the lower limit of quantification (LLOQ) for lacosamide in samples was 2 ng/mL and the linearity ranged from 2 to 10000 ng/mL. The LLOQ for ODL was 1 ng/mL, while the linearity range for this substance was 1-1,000 ng/mL. In rat liver microsomes (RLM), the LLOQ of ODL was 80 ng/mL and the linear range was 80-40000 ng/mL. The selectivity, stability, matrix effect and recovery rate were all satisfied with the need of quantitative analysis of samples. Then, the UPLC-MS/MS assay was employed successfully on the interactions of lacosamide and nisoldipine in vivo and in vitro. The half-maximal inhibitory concentration (IC50) was 3.412 µM in RLM, where nisoldipine inhibited the metabolism of lacosamide with a mixture of inhibition mechanism. In rat pharmacokinetic experiments, it was found that nisoldipine could significantly change the pharmacokinetic characteristics of lacosamide, including AUC(0-t), AUC(0-∞), Tmax, CLz/F and Cmax, but had no significant effect on ODL. In summary, the UPLC-MS/MS method could accurately and sensitively quantify lacosamide and ODL, and could be used for the interaction between nisoldipine and lacosamide in vivo and in vitro.

Linker engineering toward near-infrared-I emissive metal-organic frameworks for amine detection.

Herein, organic linker-based near-infrared-I (NIR-I) emissive metal-organic frameworks (MOFs), with a maximum emission peak at 741 nm, were synthesized via linker engineering. By integration of stronger acceptor and donor groups into one linker, a significant bathochromic-shift is realized. This MOF exhibits great selectivity and sensitivity for aniline and p-phenylenediamine detection. This finding provides new insights into the rational design of NIR-MOFs for sensing and related applications.

Size- and Emission-Controlled Synthesis of Full-Color Luminescent Metal-Organic Frameworks for Tryptophan Detection.

The development of nanoscaled luminescent metal-organic frameworks (nano-LMOFs) with organic linker-based emission to explore their applications in sensing, bioimaging and photocatalysis is of great interest as material size and emission wavelength both have remarkable influence on their performances. However, there is lack of platforms that can systematically tune the emission and size of nano-LMOFs with customized linker design. Herein two series of fcu- and csq-type nano-LMOFs, with precise size control in a broad range and emission colors from blue to near-infrared, were prepared using 2,1,3-benzothiadiazole and its derivative based ditopic- and tetratopic carboxylic acids as the emission sources. The modification of tetratopic carboxylic acids using OH and NH2 as the substituent groups not only induces significant emission bathochromic shift of the resultant MOFs, but also endows interesting features for their potential applications. As one example, we show that the non-substituted and NH2 -substituted nano-LMOFs exhibit turn-off and turn-on responses for highly selective and sensitive detection of tryptophan over other nineteen natural amino acids. This work sheds light on the rational construction of nano-LMOFs with specific emission behaviours and sizes, which will undoubtedly facilitate their applications in related areas.

Tuning and Directing Energy Transfer from the Blue to Near-Infrared Range in Multicomponent Metal-Organic Frameworks with seh Topology.

Luminescent metal-organic frameworks (MOFs) are emerging as one of several promising materials to study light-harvesting and energy-transfer processes. However, it is still a big challenge to tune and direct energy transfer in luminescent MOFs-based light-harvesting system. Herein, a series of new light-harvesting zinc-based luminescent MOFs with seh underlying topology were reported by successfully integrating 2,1,3-benzothiadiazole and its derivative-based carboxylic acids and pyridine-contained linkers into one structure. The strong spectra overlap between the emission and absorption spectra of carboxylic acids and pyridine-type linkers afforded an ideal platform to realize efficient energy transfer from the blue to near-infrared range. This work provides a novel approach to the rational design and synthesis of MOFs-based multicomponent light-harvesting materials with tunable energy transfer to mimic natural photosynthetic processes.

Reticular Chemistry with Art: A Case Study of Olympic Rings-Inspired Metal-Organic Frameworks.

Herein, we demonstrate the successful utilization of reticular chemistry as an excellent designing strategy for the deliberate construction of a zirconium-tetracarboxylate metal-organic framework (MOF) inspired by the Olympic rings. HIAM-4017, with an unprecedented (4,8)-c underlying net topology termed jcs, was developed via insightful reconstruction of the rings and judicious design of a nonsymmetric organic linker. HIAM-4017 exhibits high porosity and excellent chemical and thermal stability. Furthermore, excited-state intramolecular proton transfer (ESIPT) was achieved in an isoreticular MOF, HIAM-4018, with a large Stokes shift of 155 nm as a result of introducing the hydroxyl group to the linker skeleton to induce OH···N interactions. Such interactions were analyzed thoroughly by employing the time-dependent density functional theory (TD-DFT). Because of their good thermal and chemical stability, and strong luminescence, nanosized HIAM-4017 and HIAM-4018 were fabricated and used for Cr2O72- detection. Both MOFs demonstrate excellent sensitivity and selectivity. This work represents a neat example of building structure- and property-specific MOFs guided by reticular chemistry.

A Zirconium-Organic Framework Constructed from Saddle-Shaped Tetratopic Carboxylate for High-Rate and -Efficiency Iodine Capture.

Metal-organic frameworks (MOFs) exhibit strong potential for applications in molecular adsorption and separation because of their highly tunable structures and large specific surface areas and have also been used for iodine capture. However, most works on MOF-based iodine capture focus on the adsorption capacity while taking little consideration of the capture rate and efficiency. Herein, we report the design of a saddle-shaped tetratopic carboxylic acid containing four thiophene groups (H4COTTBA) and the synthesis of a 4,8-connected flu-type zirconium MOF (HIAM-4014) using this linker. HIAM-4014 exhibits highly efficient iodine capture. The large cagelike pore structure, OH- groups on the unsaturated Zr6 clusters, electron-rich nature of the thiophene group in the linker, and high surface area are all attributed to the tetrahedral geometry of H4COTTBA, which endows HIAM-4014 with a relatively high iodine adsorption capacity of 2.50 g/g within 2 h and an equilibrium adsorption capacity of 2.68 g/g after 5 h. Coupled with a high elution ratio and great recyclability, HIAM-4014 is a good candidate for the efficient removal of waste iodine.

Amino group induced structural diversity and near-infrared emission of yttrium-tetracarboxylate frameworks.

Near-infrared (NIR)-emitting materials have been extensively studied due to their important applications in biosensing and bioimaging. Luminescent metal-organic frameworks (LMOFs) are a new class of highly emissive materials with strong potential for utilization in biomedical related fields because of their nearly unlimited structural and compositional tunability. However, very little work has been reported on organic linker-based NIR-MOFs and their emission properties. In the present work, a series of yttrium-tetracarboxylate-based LMOFs (HIAM-390X) are prepared via judicious linker design to achieve NIR emission with diverse structures. The introduction of an amino group not only offers the remarkable emission bathochromic shift from 521 nm, 665 nm to 689 nm for the resultant MOFs, but also influences the linker conformations, leading to the topology evolution from (4,12)-c ftw, (4,8)-c scu, which is rarely reported in rare earth element-based MOFs, to an unprecedented topology hlx for HIAM-3901 (without an amino group), HIAM-3905 (with one amino group) and HIAM-3906 (with two amino groups). Among these MOFs, HIAM-3907 shows an emission maximum at ∼790 nm, with the emission tail close to 1000 nm. The NIR emission may be attributed to the combination of the strongly electron-donating amino group and the strongly electron-withdrawing acceptor naphtho[2,3-c][1,2,5]selenadiazole. This work sheds light on the rational design of organic linker-based LMOFs with controlled structures and NIR emission, and inspires future interest in biosensing and bioimaging related applications of NIR-MOFs.

Building an emission library of donor-acceptor-donor type linker-based luminescent metal-organic frameworks.

Luminescent metal-organic frameworks (LMOFs) have been extensively studied for their potential applications in lighting, sensing and biomedicine-related areas due to their high porosity, unlimited structure and composition tunability. However, methodical development in systematically tuning the emission properties of fluorescent organic linker-based LMOFs to facilitate the rational design and synthesis of target-specific materials has remained challenging. Herein we attempt to build an emission library by customized synthesis of LMOFs with targeted absorption and emission properties using donor-acceptor-donor type organic linkers. By tuning the acceptor groups (i.e. 2,1,3-benzothiadiazole and its derivatives), donor groups (including modification of original donors and use of donors with different metal-linker connections) and bridging units between acceptor and donor groups, an emission library is developed for LMOFs with their emissions covering the entire visible light range as well as the near-infrared region. This work may offer insight into well controlled design of organic linkers for the synthesis of LMOFs with specified functionality.

Customized Synthesis: Solvent- and Acid-Assisted Topology Evolution in Zirconium-Tetracarboxylate Frameworks.

Metal-organic frameworks (MOFs) demonstrate strong potential for various important applications due to their well tunable structures and compositions through metal and organic linker engineering. As an effective approach, topology evolution by controlling linker conformation has received considerable attention, where solvents and acids have crucial effects on structural formation. However, a systematic study of such effects remains under investigated. Herein, we carried out a methodical study on the topology evolution in Zr-MOFs directed by solvothermal conditions with various combinations of three common solvents and six different acids. As a result, three Zr-MOFs with different topologies, scu (HIAM-4007), scp (HIAM-4008), and csq (HIAM-4009), were obtained using the same Zr6-cluster and tetratopic carboxylate linker, in which structure diversity shows significant influence on their corresponding photoluminescence quantum yields. Further experiments revealed that the acidity of acids and the basicity of solvents strongly influenced the linker conformation in the resultant MOFs, leading to the topology evolution. Such a solvent- and acid-assisted topology evolution represents a general approach that can be used with other tetratopic carboxylate linkers to realize structural diversity. The present work demonstrates an effective structure designing strategy by controlling synthetic conditions, which may prove to be powerful for customized synthesis of MOFs with specific structure and functionality.

A Microporous Metal-Organic Framework Incorporating Both Primary and Secondary Building Units for Splitting Alkane Isomers.

We demonstrate the assembly of a mononuclear metal center, a hexanuclear cluster, and a V-shaped, trapezoidal tetracarboxylate linker into a microporous metal-organic framework featuring an unprecedented 3-nodal (4,4,8)-c lyu topology. The compound, HIAM-302, represents the first example that incorporates both a primary building unit and a hexanuclear secondary building unit in one structure, which should be attributed to the desymmetrized geometry of the organic linker. HIAM-302 possesses optimal pore dimensions and can separate monobranched and dibranched alkanes through selective molecular sieving, which is of significant value in the petrochemical industry.

Full-Color Emission in Multicomponent Metal-Organic Frameworks via Linker Installation.

Herein, we demonstrate that linker installation (LI) through postsynthesis is an effective strategy to insert emissive second linkers into single-linker-based metal-organic frameworks (MOFs) to tune the emission properties of multicomponent MOFs. Full-color emission, including white-light emission, can be achieved via such a LI process.

Tuning and Directing Energy Transfer in the Whole Visible Spectrum through Linker Installation in Metal-Organic Frameworks.

While limited choice of emissive organic linkers with systematic emission tunability presents a great challenge to investigate energy transfer (ET) over the whole visible light range with designable directions, luminescent metal-organic frameworks (LMOFs) may serve as an ideal platform for such study due to their tunable structure and composition. Herein, five Zr6 cluster-based LMOFs, HIAM-400X (X=0, 1, 2, 3, 4) are prepared using 2,1,3-benzothiadiazole and its derivative-based tetratopic carboxylic acids as organic linkers. The accessible unsaturated metal sites confer HIAM-400X as a pristine scaffold for linker installation. Six full-color emissive 2,1,3-benzothiadiazole and its derivative-based dicarboxylic acids (L) were successfully installed into HIAM-400X matrix to form HIAM-400X-L, in which the ET can be facilely tuned by controlling its direction, either from the inserted linkers to pristine MOFs or from the pristine MOFs to inserted linkers, and over the whole range of visible light. The combination of the pristine MOFs and the second linkers via linker installation creates a powerful two-dimensional space in tuning the emission via ET in LMOFs.

In Situ Characterization of Dehydration during Ion Transport in Polymeric Nanochannels.

The transport of hydrated ions across nanochannels is central to biological systems and membrane-based applications, yet little is known about their hydrated structure during transport due to the absence of in situ characterization techniques. Herein, we report experimentally resolved ion dehydration during transmembrane transport using modified in situ liquid ToF-SIMS in combination with MD simulations for a mechanistic reasoning. Notably, complete dehydration was not necessary for transport to occur across membranes with sub-nanometer pores. Partial shedding of water molecules from ion solvation shells, observed as a decrease in the average hydration number, allowed the alkali-metal ions studied here (lithium, sodium, and potassium) to permeate membranes with pores smaller than their solvated size. We find that ions generally cannot hold more than two water molecules during this sterically limited transport. In nanopores larger than the size of the solvation shell, we show that ionic mobility governs the ion hydration number distribution. Viscous effects, such as interactions with carboxyl groups inside the membrane, preferentially hinder the transport of the mono- and dihydrates. Our novel technique for studying ion solvation in situ represents a significant technological leap for the nanofluidics field and may enable important advances in ion separation, biosensing, and battery applications.