Nitrogen-doped magnetic porous carbon nanospheres derived from dual templates-induced mesoporous polydopamine coated Fe3O4 for efficient extraction and sensitive determination of volatile nitrosamines by gas chromatography-mass spectroscopy.

N-nitrosamines (NAs) are highly carcinogenic compounds commonly found in food, beverages, and consumer products. Due to their wide polarity range, it is challenging to find a suitable carbon adsorbent that can simultaneously adsorb and enrich both polar and nonpolar NAs with good recovery. In this study, nitrogen-doped magnetic mesoporous carbon nanospheres (M-MCN) were prepared and employed as an adsorbent for magnetic solid-phase extraction (MSPE) to extract and concentrate four NAs. The introduction of nitrogen functional groups enhanced the hydrophilicity of the carbon material, allowing M-MCN to achieve a balance between hydrophilicity and hydrophobicity, resulting in good recovery for both polar and nonpolar NAs. A method combining MSPE with gas chromatography-mass spectrometry (GC-MS) was developed for the determination of NAs in processed meat and alcoholic beverages. The method exhibited a good linear range (1-100 ng g-1, r2 > 0.9967) and trace-level detection (0.53-6.6 ng g-1). The recovery rates for the four NAs ranged between 85.7 and 110.7 %, with intra-day precision expressed as relative standard deviation (RSD) between 4.1 and 10.7 %, and inter-day precision between 4.8 and 12.9 %. The results demonstrated not only good accuracy and precision but also provided a new adsorbent for the enrichment of trace-level NAs in processed meat and alcoholic beverage samples.

Facile construction of a stable core-shell spherically magnetic polyimide covalent organic framework for efficient extraction of phenylurea herbicides.

Efficient enrichment is crucial for the highly sensitive monitoring of phenylurea herbicides (PUHs) in various environmental waters. In this work, a stable core-shell spherically magnetic polyimide covalent organic framework (COF) was synthesized via a simple template-mediated precipitation polymerization method under mild conditions using tri(4-aminophenyl)amine (TAPA) and 3,3',4,4'-biphenyltetracarboxylic dianhydride (BPDA) as the building units (denoted as Fe3O4@TAPA-BPDA). The Fe3O4@TAPA-BPDA exhibits remarkable adsorption performance for PUHs with an optimized adsorption time of only 10 min. The adsorption of PUHs by Fe3O4@TAPA-BPDA followed the pseudo-second-order kinetic model and the Langmuir model. Furthermore, hydrogen bonding, halogen bonding, hydrophobic interaction, electro donor-acceptor interaction and π-π interactions are identified as the dominant mechanisms contributing to excellent adsorption performance. It was demonstrated that halogen bonds play an important role in the adsorption of substances containing chlorine atoms. The Fe3O4@TAPA-BPDA is easy to operate and highly regenerable. A simple magnetic solid-phase extraction (MSPE) method based on the Fe3O4@TAPA-BPDA was then developed for the rapid extraction of five PUHs in real samples, coupled with high-performance liquid chromatography (HPLC) determination. The analytical method developed has a linear range of 0.5-50 ng/mL, and the limit of detection (LOD) ranges from 0.06 to 0.10 ng/mL. The method exhibits good accuracy with recoveries ranged from 74.5 % to 111.4 %. The analytical method was successfully applied to the highly sensitive detection of PUHs in environmental water samples, which highlighting the potential application of the Fe3O4@TAPA-BPDA in the sample pretreatment.

Diaphragm ultrasonography as a monitor in assessing antagonistic effect of sugammadex on rocuronium in patients with Child-Pugh grades A and B.

Background: Although diaphragm ultrasound can be used for detecting residual neuromuscular blockade post-surgery, there exists notable dearth in contemporary research exploring the correlation between preoperative Child-Pugh classification and the effectiveness of sugammadex in reversing rocuronium-induced blockade as evaluated by diaphragmatic ultrasonography. Methods: This was a prospective, double-blind, non-randomized controlled clinical trial conducted on patients scheduled for laparoscopic liver resection surgery. The participants were categorized into two groups, A and B, based on their preoperative Child-Pugh classification. Prior to anesthesia induction, baseline diaphragm thickness was evaluated using ultrasonography. Throughout the surgical procedure, a deep neuromuscular blockade was maintained with rocuronium. Post-surgery, sugammadex (2 mg/kg) was intravenously administered to patients in both groups upon reaching a train-of-four ratio of 0.2. Diaphragm thickness was assessed at 0, 10, and 30 min, as well as 2 h after extubation, to analyze thickening fractioning (TF) and thickness recovery fractioning (TRF). Results: No significant differences in TF or TRF were observed between the two groups at 0, 10, and 30 min, as well as 2 h after extubation. Furthermore, there were no significant variances in hemodynamic stability following sugammadex administration. However, patients in the Child-Pugh B group experienced a significantly prolonged time from sugammadex administration to tracheal extubation (19 ± 8.0 min vs. 11 ± 6.1 min) and an extended post-anesthesia care unit stay (123 ± 28.3 min vs. 103 ± 26.0 min) compared to those in the Child-Pugh A group. Conclusion: The preoperative Child-Pugh grades may not exhibit a significant association with the reversal effect of sugammadex on rocuronium, as evaluated through diaphragmatic ultrasonography. Clinical trial registration: Registered in the ClinicalTrials.gov (NCT05028088) on July 18, 2021.

Maternal RNA transcription in Dlk1-Dio3 domain is critical for proper development of the mouse placental vasculature.

The placenta is a unique organ for ensuring normal embryonic growth in the uterine. Here, we found that maternal RNA transcription in Dlk1-Dio3 imprinted domain is essential for placentation. PolyA signals were inserted into Gtl2 to establish a mouse model to prevent the expression of maternal RNAs in the domain. The maternal allele knock-in (MKI) and homozygous (HOMO) placentas showed an expanded junctional zone, reduced labyrinth and poor vasculature impacting both fetal and maternal blood spaces. The MKI and HOMO models displayed dysregulated gene expression in the Dlk1-Dio3 domain. In situ hybridization detected Dlk1, Gtl2, Rtl1, miR-127 and Rian dysregulated in the labyrinth vasculature. MKI and HOMO induced Dlk1 to lose imprinting, and DNA methylation changes of IG-DMR and Gtl2-DMR, leading to abnormal gene expression, while the above changes didn't occur in paternal allele knock-in placentas. These findings demonstrate that maternal RNAs in the Dlk1-Dio3 domain are involved in placental vasculature, regulating gene expression, imprinting status and DNA methylation.

Leveraging Predictions of Task-Related Latents for Interactive Visual Navigation.

Interactive visual navigation (IVN) involves tasks where embodied agents learn to interact with the objects in the environment to reach the goals. Current approaches exploit visual features to train a reinforcement learning (RL) navigation control policy network. However, RL-based methods continue to struggle at the IVN tasks as they are inefficient in learning a good representation of the unknown environment in partially observable settings. In this work, we introduce predictions of task-related latents (PTRLs), a flexible self-supervised RL framework for IVN tasks. PTRL learns the latent structured information about environment dynamics and leverages multistep representations of the sequential observations. Specifically, PTRL trains its representation by explicitly predicting the next pose of the agent conditioned on the actions. Moreover, an attention and memory module is employed to associate the learned representation to each action and exploit spatiotemporal dependencies. Furthermore, a state value boost module is introduced to adapt the model to previously unseen environments by leveraging input perturbations and regularizing the value function. Sample efficiency in the training of RL networks is enhanced by modular training and hierarchical decomposition. Extensive evaluations have proved the superiority of the proposed method in increasing the accuracy and generalization capacity.

Simultaneous enrichment and sequential elution of cis-diol containing molecules and deoxyribonucleotides with bifunctional boronate and titanium (â £) ion modified-magnetic nanoparticles prior to quantitation by high performance liquid chromatography.

Some diseases can cause abnormal concentrations of catecholamines (CAs), nucleosides (NSs) and nucleotides (NTs) in patients. Previous studies normally focused on the detection of the three types of substances separately. In this work, a bifunctional boronate and titanium (Ⅳ) ion affinity magnetic adsorbent with high-capacity was prepared. The adsorbent can simultaneously enrich CAs, NSs and NTs in a single extraction process, and the adsorbed analytes can be sequentially eluted by 1.0% trifluoroacetic acid and 20.0 mmol L-1 Na3PO4. An analytical method of the analytes has been established by coupling the adsorbent with RP-HPLC. The method has low detection limits (0.039-0.708 ng mL-1) and good reproducibility (inter- and intra-day of assay RSDs less than 15.0%). Serum sample from healthy volunteer was successfully quantified for two CAs, four NSs and five NTs. Compared with the reported methods, the proposed method is simpler to operate, consume less samples, and has enough accurate and sensitivity to obtain comprehensive information on the concentrations of analytes in a single extraction process.

Multivariate covalent organic frameworks guided carboxyl functionalized magnetic adsorbent for enrichment of fluoroquinolones in milk prior to high performance liquid chromatographic analysis.

Herein, we prepared a carboxyl functionalized magnetic covalent organic framework (Fe3O4@iCOF-COOH) by combining multivariate synthetic strategy with post-synthetic modification. It was used as an adsorbent for magnetic solid phase extraction (MSPE) of six fluoroquinolones (FQs), and showed good absorption performance at neutral pH. Carboxyl groups are found to be crucial for the adsorption of fluoroquinolones. The adsorption mechanism was primarily attributed to strong hydrogen bonding, π-π interaction as well as potential hydrophobic effect. The optimal extraction conditions are sample pH at 6.0, adsorbent dosage of 3 mg, eluent of 1.0 mL methanol solution containing 7.5% ammonia, and extraction/desorption time of 30 min. Under the optimized conditions, the Fe3O4@iCOF-COOH was used as an adsorbent for MSPE of FQs in milk, an analytical method was established by combining with high-performance liquid chromatography-ultraviolet detection (HPLC-UV). The limits of detection (LODs) and limit of quantification (LOQs) were 1.24-4.58 ng⋅mL-1 and 4.12-15.3 ng⋅mL-1, respectively. The recoveries of target FQs in spiked milk were 68.4-105%. This work provides a new way to prepare covalent organic framework based adsorbents for solid phase extraction, and can be readily extended to other type of adsorbents.

Boosting the C2H2/CO2 Separation Performance of Metal-Organic Frameworks through Fluorine Substitution.

A pair of metal-organic frameworks (MOFs) of JXNU-15 (formulated as [Co6(µ3-OH)6(BTB)2(BPY)3]n, BTB3- = benzene-1,3,5-tribenzoate and BPY = 4,4'-bipyridine) and its fluorinated JXNU-15(F) ([Co6(µ3-OH)6(SFBTB)2(BPY)3]n) based on the fluorous 1,3,5-tri(3,5-bifluoro-4-carboxyphenyl)benzene (SFBTB3-) ligands were presented. The detailed comparisons of the acetylene/carbon dioxide (C2H2/CO2) separation abilities between the isostructural JXNU-15(F) and JXNU-15 were presented. In comparison with the parent JXNU-15, the higher C2H2 uptake, larger adsorption selectivity of the C2H2/CO2 (50/50) mixture, and enhanced C2H2/CO2 separation performance endow JXNU-15(F) with highly efficient C2H2/CO2 separation performance, which is demonstrated by singe-component gas adsorptions and dynamic gas mixture breakthrough experiments. The fluorine substituents exert the crucial effects on the enhanced C2H2/CO2 separation ability of JXNU-15(F) and play the dominant role in the C2H2-framework interactions, as uncovered by computational simulations. This work illustrates a powerful fluorine substitution strategy for boosting C2H2/CO2 separation ability for MOFs.

An engineered cascade-sensitized red-emitting upconversion nanoplatform with a tandem hydrophobic hydration-shell and metal-phenolic network decoration for single 808 nm triggered simultaneous tumor PDT and PTT enhanced CDT.

Near-infrared light (NIR) driven lanthanide-doped upconversion nanoparticle (UCNP) based photo-dynamic therapy (PDT) holds a great promise for the non-invasive treatment of deep-seated tumors. However, it has also been highly hindered by the low upconversion luminescence (UCL) efficiency, hypoxia nature of solid tumors, and low therapeutic efficiency using single modality. Herein, we present a novel Nd3+ → Yb3+ → Tm3+ → Er3+ cascade-sensitized red-emitting UCNP with tandem hydrophobic hydration-shell (HHS) and metal-phenolic network (Fe-tannic acid, Fe-TA) decoration (UCNP@HHS@Fe-TA, denoted as UCFS@Fe-TA) for single 808 nm triggered simultaneous tumor PDT and photothermal therapy (PTT) enhanced chemo-dynamic therapy (CDT). The UCNP can supply intense red emission under high tissue penetrating/minimized tissue overheating 808 nm excitation, and their HHS coating with perfluorocarbon/photosensitizer Ce6 co-doping can not only realize UCL-based PDT, but also strengthen PDT of as-formed UCFS via O2-carrying/UCL protection capacity of the HHS. Fe-TA coating can supply 808 nm triggered PTT, and the rise in temperature during PTT leads to enhanced Fenton catalytic activity of Fe-TA and faster ˙OH production rate of CDT to match with the real-timely released 1O2 in PDT. The as-designed UCFS@Fe-TA thus can achieve a single 808 nm triggered simultaneous PDT and PTT enhanced CDT, leading to a PTT-assisted reactive oxygen species storm for efficient tumor suppression. Such a design also renders the nanoplatform lower cell dark toxicity. In addition, the single excitation-triggered multimodal therapy mode might address the excitation wavelength mismatch issue in dual laser-triggered PTT/PDT mode. This study has therefore presented an efficient nanotherapeutic platform enabling synergistic multimodal tumor therapies with high biocompatibility.

Advances in Drug Therapy for Gastrointestinal Stromal Tumour.

Gastrointestinal stromal tumour (GIST) is a common gastrointestinal sarcoma located in the stromal cells of the digestive tract, and molecular studies have revealed the pathogenesis of mutations in KIT and PDGFRA genes. Since imatinib opened the era of targeted therapy for GIST, tyrosine kinase inhibitors (TKIs) that can treat GIST have been developed successively. However, the lack of new drugs with satisfactory therapeutic standards has made addressing resistance a significant challenge for TKIs in the face of the resistance to first-line and second-line drugs. Therefore, we need to find as many drugs and new treatments that block mutated genes as possible. METHODS: We conducted a comprehensive collection of literature using databases, integrated and analysed the selected literature based on keywords and the comprehensive nature of the articles, and finally wrote articles based on the content of the studies. RESULTS: In this article, we first briefly explained the relationship between GIST and KIT/ PDGFRα and then introduced the related drug treatment. The research progress of TKIs was analyzed according to the resistance of the drugs. CONCLUSION: This article describes the research progress of some TKIs and provides a brief introduction to the currently approved TKIs and some drugs under investigation that may have better therapeutic effects, hoping to provide clues to the research of new drugs.

Polymer brush grafted immobilized metal ion affinity adsorbent based on polydopamine/polyethyleneimine-coated magnetic graphene oxide for selective enrichment of cytokinins in plants.

An immobilized metal affinity (IMAC) adsorbent was prepared for selective enrichment of adenine type CKs, via grafting polymer chain pendant with iminodiacetic acid (IDA) from polydopamine (PDA)/polyethyleneimine (PEI)-coated magnetic graphene oxide (magGO) via surface-initiated-atom transfer radical polymerization (SI-ATRP). The prepared IMAC sorbent exhibited remarkable adsorption performances and good selectivity for adenine-type CKs and was utilized as a sorbent of magnetic solid-phase extraction (MSPE) for effective enrichment of four adenine-type CKs in bean sprouts. Under the optimized extraction conditions, an analytical method for four adenine type CKs in bean sprouts was established by combining the MSPE combined with ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The recoveries of the analytes were between 80.4 ± 1.9% and 114.6 ± 1.5% (n = 3). The limits of detection (LODs) range from 0.63 to 2.30 pg⋅mL-1. The relative standard deviations of intra-day and inter-day were less than 12.6%. The established method was successfully applied to the selective extraction and sensitive detection of trace adenine-type CKs in plant samples.

Nitrogen and bromine co-doped carbon dots with red fluorescence for sensing of Ag+ and visual monitoring of glutathione in cells.

Carbon dots (CDs) with red fluorescence emission have excellent advantages in cell imaging. Herein, novel nitrogen and bromine doped CDs (N,Br-CDs) were prepared with 4-bromo-1,2-phenylenediamine as precursor. The N, Br-CDs present the optimal emission wavelength at 582 nm (λex = 510 nm) at pH 7.0 and 648 nm (λex = 580 nm) at pH 3.0 âˆ¼ 5.0, respectively. The fluorescence intensity of N,Br-CDs at 648 nm versus Ag+ concentration shows a good relationship from 0 to 60 µM with the limit of detection (LOD) of 0.14 µM. Furthermore, the fluorescence of N,Br-CDs/Ag+ is efficiently restored via the combination of glutathione (GSH) and Ag+ and linearly changes with GSH concentration from 0 âˆ¼ 6.0 µM with LOD of 49 nM. This method has been successfully employed to monitor intracellular Ag+ and GSH with fluorescence imaging. The results suggest that the N,Br-CDs has application potential in the sensing of Ag+ and visual monitoring of GSH in cells.

Application and SARs of Pyrazolo[1,5-a]pyrimidine as Antitumor Agents Scaffold.

Pyrazolo[1,5-a]pyrimidines are fused heterocycles that have spawned many biologically active antitumor drugs and are important privileged structures for drug development. Pyrazolo[1,5- a]pyrimidine derivatives have played an important role in the development of antitumor agents due to their structural diversity and good kinase inhibitory activity. In addition to their applications in traditional drug targets such as B-Raf, KDR, Lck, and Src kinase, some small molecule drugs with excellent activity against other kinases (Aurora, Trk, PI3K-γ, FLT-3, C-Met kinases, STING, TRPC) have emerged in recent years. Therefore, based on these antitumor drug targets, small molecule inhibitors containing pyrazolo[1,5-a]pyrimidine scaffold and their structure-activity relationships are summarized and discussed to provide more reference value for the application of this particular structure in antitumor drugs.

Dicopper(II) paddle-wheel metal-organic frameworks for high propyne storage under ambient conditions.

Fluorinated dicopper(II) metal-organic framework JXNU-16F with 1,3,5-tri(3,5-bifluoro-4-carboxyphenyl)benzene ligands and nonfluorinated JXNU-16 exhibit high propyne uptakes of 443 and 496 cm3 g-1 under ambient conditions, respectively. Their remarkable propyne uptakes result from suitable pore spaces and strong propyne⋯propyne interactions amongst the adsorbed propyne molecules, as revealed by computational simulations.

Research Progress on Small Molecules Inhibitors Targeting TRK Kinases.

BACKGROUND: Trk gene fusions are an important driver in the development of cancers, including secretory breast cancer and infantile congenital sarcoma. Since the first-generation of small molecule Trk inhibitors (Larotrectinib and Entrectinib) came to market, research on small molecule TRK inhibitors, especially second-generation inhibitors that break through the resistance problem, has developed rapidly. Therefore, this article focuses on the research progress of first-generation drugs and second-generation drugs that break through drug resistance. METHODS: We used the database to search for relevant and cutting-edge documents, and then filtered and selected them based on the content. The appropriate articles were analyzed and classified, and finally, the article was written according to the topics. RESULTS: The phenomenon of Trk protein fusion and its relation to tumors are described, followed by an explanation of the composition and signaling pathways of Trk kinases. The representative Trk inhibitors and the development of novel Trk inhibitors are classified according to whether they overcome drug resistance problems. CONCLUSION: This paper provides a theoretical reference for the development of novel inhibitors by introducing and summarizing the representative and novel Trk inhibitors that break through the drug resistance problem.

Carbon quantum dots with pH-responsive orange-/red-light emission for fluorescence imaging of intracellular pH.

N-doped carbon quantum dots (N-CDs) with polyaminobenzene hydrazine as precursor were prepared by solvothermal method for the monitoring of pH fluctuation in HeLa cells via fluorescence imaging. The N-CDs show two emission wavelengths at 582 and 640 nm under different pH with two excitation wavelengths. The fluorescence intensity at 640 nm (λex = 520 nm) and the ratio of F582/F640 (λex = 470 nm) linearly increase with pH in the range of 2.4 ~ 3.6 (R2 = 992) and 5.6 ~ 7.6 (R2 = 0.987), respectively. The sensor exhibits high sensitivity and reversibility and anti-interference capability, thus enabling sensing pH change in intracellular environment in real time, as demonstrated by successful monitoring of intracellular pH fluctuation during H2O2 stimulation in HeLa cells.

Enhancement of Propadiene/Propylene Separation Performance of Metal-Organic Frameworks by an Amine-Functionalized Strategy.

Here, a hexanuclear Co6(µ3-OH)6 cluster-based metal-organic framework (MOF), [Co6(µ3-OH)6(BTB)2(bpy)3]n (JXNU-15) (bpy = 4,4'-bipyridine), with the 1,3,5-tri(4-carboxyphenyl)benzene (BTB3-) ligand was synthesized for the challenging propadiene/propylene separation. The combination of a large pore volume and a suitable pore environment boosts the significantly high propadiene (C3H4) uptake (311 cm3 g-1 at 298 K and 100 kPa) for JXNU-15. An amine-functionalized MOF of JXNU-15(NH2) was further obtained with the 1,3,5-tri(4-carboxyphenyl)benzene analogue of 3,3″-diamino-5'-(3-amino-4-carboxyphenyl)-[1,1':3',1″-terphenyl]-4,4″-dicarboxylic ligand. The comparative studies of propadiene/propylene(C3H4/C3H6) separation performance between isostructural JXNU-15 and JXNU-15(NH2) are provided. JXNU-15(NH2) exhibits an impressive C3H4 capacity at low pressures with 69.1 cm3 g-1 at 10 kPa, which is twice that of JXNU-15 under the same conditions. Moreover, the separation selectivity of JXNU-15(NH2) is 1.3-fold higher as compared to JXNU-15. JXNU-15(NH2) with enhanced C3H4/C3H6 separation performance was elegantly illustrated by gas separation experiments and theoretical simulations. This work presents an amine-functionalized strategy for the enhancement of the C3H4/C3H6 separation performance of MOF.

MOF-coated upconversion nanoconstructs for synergetic photo-chemodynamic/oxygen-elevated photodynamic therapy.

Excessive production of intracellular reactive oxygen species (ROS) can induce apoptosis of cancer cells; however, it is often limited by severe triggering conditions and hypoxic microenvironments of solid tumors. To address these issues, herein, we have designed a MOF-coated upconversion nanoconstruct (UCTSCF, referring to UC@Ce6/TFS@mSiO2@MIL-100(Cu/Fe)) for synergetic photochemodynamic therapy (PCT)/oxygen-elevated photodynamic therapy (PDT). The MOF (MIL-100(Fe)) coating with Cu-doping was designed to catalyze H2O2 overexpression in cancer cells to generate the most cytotoxic ˙OH via chemodynamic therapy (CDT). It is noted that UC, representing 808 nm driven upconversion nanoparticles with high tissue penetration depth/low over-heating effects, was designed to provide intense blue light which can relieve the severe triggering conditions of CDT via PCT. Furthermore, the functional layer of the photosensitizer chlorin e6 (Ce6) and O2-carrying triethoxy(1H,1H,2H,2H-nonafluorohexyl)silane (TFS) co-doped mesoporous silicon (Ce6/TFS@mSiO2) can cause oxygen-elevated 1O2 production upon 671 nm light irradiation. In such a simple ROS generation nanoplatform, we heighten the antitumor effect via oxygen-elevated synergetic tumor PCT/PDT.

In situ reaction-based ratiometric fluorescent assay for alkaline phosphatase activity and bioimaging.

Alkaline phosphatase (ALP) is an important biomarker, it is of great significance to develop a sensitive and efficient analytical method for ALP. In this study, an in situ reaction based ratiometric fluorescence assay for ALP was proposed. l-ascorbic acid-2-phosphate (AA2P) was used as a substrate for ALP, and Cu2+/o-phenylenediamine (OPD) were involved in this system. Cu2+ can oxidize OPD to 2,3-diaminophenazine (OPDox) with an emission centered at 566 nm. The presence of ALP can catalyze the hydrolysis of AA2P to ascorbic acid (AA), which will inhibit the production of OPDox and reduce the corresponding fluorescence intensity, and AA will react with OPD to generate 3-(dihydroxyethyl)furan[3,4-b]quinoxalin-1-one (DFQ) with an emission peak at 447 nm. The fluorescence ratio of F447/F566 has a linear relationship with ALP activity. The proposed method is highly sensitive, finely selective, cost efficiency and easy to operate, it exhibits good linearity in the range of 0.5-22 and 22-40 mU·mL-1, with a detection limit as low as 0.06 mU·mL-1. The excellent applicability of this strategy in human serum samples and MCF-7 cells imaging suggests that this method has promising prospects for biomedical research.

Design, synthesis and biological evaluation of novel osimertinib derivatives as reversible EGFR kinase inhibitors.

A series of osimertinib derivatives without acrylamide groups were synthesized and their inhibitory rates against L858R/T790M/C797S mutated EGFR kinase and antiproliferation activities against non-small cell lung cancer cell lines (A549, H1975) were evaluated. The preferred compounds were selected and their in vitro inhibitory activities against various EGFR kinases (wild-type, L858R/T790M, L858R/T790M/C797S) and c-Met kinase were tested. Compound 9h showed remarkable inhibitory activity against the wild type (IC50 = 29 nM), L858R/T790M mutant type (IC50 = 10 nM) and L858R/T790M/C797S mutant type (IC50 = 242 nM) as reversible EGFR kinase inhibitor, which was selected to further perform the AO/EB staining assays, cell cycle distribution assays and wound-healing assays on A549 and/or H1975 cell lines. The results showed dose-dependent activities of the induction of cell apoptosis, G1/G0-phase arrestation and inhibition of migration. Compound 22a showed remarkable inhibitory activity against the L858R/T790M/C797S mutant EGFR kinase (IC50 = 137 nM), which was nearly three times compared to osimertinib (IC50 = 410 nM). It's worth noting that 22a exhibited excellent kinase selectivity against the L858R/T790M/C797S mutant EGFR kinase rather than the wild-type, which reached 5.4 times and far more than the 0.012 times of osimertinib. Additionally, molecular docking analyses were performed to explain the action modes between the compounds and the corresponding EGFR kinases. In conclusion, compounds 9h and 22a have been demonstrated as promising candidates and worth further study.