Chemoselectivity Strategy Based on B-Label Integrated with Tailored COF for Targeted Metabolomic Analysis of Short-Chain Fatty Acids by UHPLC-MS/MS.

Chemoselective extraction strategy is an emerging and powerful means for targeted metabolomics analysis, which allows for the selective identification of biomarkers. Short-chain fatty acids (SCFAs) as functional metabolites for many diseases pose challenges in qualitative and quantitative analyses due to their high polarity and uneven abundance. In our study, we proposed the B-labeled method for the derivatization of SCFAs using easily available 3-aminobenzeneboronic acid as the derivatization reagent, which enables the introduction of recognition unit (boric acid groups). To analyze the B-labeled targeted metabolites accurately, cis-diol-based covalent organic framework (COF) was designed to specifically capture and release target compounds by pH-response borate affinity principle. The COF synthesized by the one-step Schiff base reaction possessed a large surface area (215.77 m2/g), excellent adsorption capacity (774.9 µmol/g), good selectivity, and strong regeneration ability (20 times). Combined with ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis, our results indicated that the detection sensitivities of SCFAs increased by 1.2-2500 folds compared with unlabeled method, and the retention time and isomer separation were improved. Using this strategy, we determined twenty-six SCFAs in the serum and urine of rats in four groups about osteoporosis and identified important biomarkers related to the tricarboxylic acid cycle and fatty acid metabolism pathways. In summary, UHPLC-MS/MS based on B-labeled derivatization with tailored COF strategy shows its high selectivity, excellent sensitivity, and good chromatographic behavior and has remarkable application prospect in targeted metabolomics study of biospecimens.

Exploration of 4-(1H-indol-3-yl)cyclohex-3-en-1-amine analogues as HDAC inhibitors: Design, synthesis, biological evaluation and modelling studies.

Epigenetics regulate the gene expression and chromatin organization associated with the development and occurrence of cancer. Histone deacetylase inhibitors (HDACis) have been proved to be an effective epigenetic targeting drug for cancer treatment. The structures of most HDACis were divided into four parts, including cap group, connection unit, linker region and zinc binding group. We designed a series of compounds containing the structure of phenoxyacetate for the linker region and cyclohexene for connection unit as a novel type of inhibitors. Representative compound YZ1 exhibited obvious antiproliferative activity against four different cell lines and potent enzymatic inhibitory activities to class I HDACs, which IC50 of HDAC1-3 were 1.6 nM, 1.9 nM and 3.8 nM respectively. In addition, YZ1 concentration-dependently inhibited cell proliferation, induced apoptosis and cycle arrest at G2/M phase in HCT116 cells. With biological activity assessment and docking studies, these results indicate YZ1 has the potential to be a lead compound for further optimization as HDAC inhibitors.

Design, synthesis, and biological evaluation of ß-carboline 1,3,4-oxadiazole based hybrids as HDAC inhibitors with potential antitumor effects.

A series of novel ß-carboline 1,3,4-oxadiazole based hybrids were designed, synthesized, and tested for cytotoxicity and HDAC inhibition. Among the target compounds, compound ZDLT-1 displayed high inhibitory activity for class I HDACs 1, 2, and 3, and potent anti-proliferative activity against HCT116 cells with an IC50 value of 0.173 ± 0.018 µM, it also exhibited better inhibitory activity with an IC50 value of 6 nM for HDAC6 than SAHA (IC50 = 15 nM). Furthermore, the pharmacological experiment of Hoechst staining, colony formation, cell apoptosis assay, and wound healing scratch assay indicated that compound ZDLT-1 was a potent cytotoxic agent against HCT116 cells with cell apoptosis induction. Further, in silico prediction of physicochemical properties, drug-likeness, and ADME parameters suggested that compound ZDLT-1 is a promising anticancer agent. Taken together, the high potency cytotoxicity and class I HDACs inhibitory activity of compound ZDLT-1, which with the ß-carboline 1,3,4-oxadiazole based hybrids as potent anticancer agents could be nominated for further modification and optimization.

Discovery of novel benzofuro[3,2-b]quinoline derivatives as dual CDK2/Topo I inhibitors.

Uncontrolled cell proliferation is a hallmark of cancer. The major regulator of the cell cycle, cyclin dependent kinase 2 (CDK2), has become a mature target for cancer treatment. Herein, we describe our efforts toward the discovery of a series of benzofuro[3,2-b]quinoline alkaloid derivatives as CDK2 inhibitors through a scaffold hopping strategy. Compound ZLHQ-5f has topoisomerase I (Topo I) inhibitory activity due to the unique structure of benzofurano[3,2-b]quinoline. Resultantly, ZLHQ-5f exhibited promising anti-proliferative and CDK2 inhibitory activities. It also arrests the cell cycle in S-phase, triggers apoptosis in HCT116 cells, and has a good safety profile in vivo. There has yet to be a report on dual CDK2/Topo I inhibitor, thus this will be a novel attempt.

Discovery of novel α-carboline derivatives as glycogen synthase kinase-3ß inhibitors for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease, characterized by irreversible cognitive impairment, memory loss, and behavioral disturbances, ultimately resulting in death. The critical roles of glycogen synthase kinase-3ß (GSK-3ß) in tau pathology have also received considerable attention. Based on molecular docking studies, a series of novel α-carboline derivatives were designed, synthesized, and evaluated as GSK-3ß inhibitors for their various biological activities. Among them, compound ZCH-9 showed the most potent inhibitory activity against GSK-3ß, with an IC50 value of 1.71 ± 0.09 µM. The cytotoxicity assay showed that ZCH-9 had low cytotoxicity toward the cell lines SH-SY5Y, HepG2, and HL-7702. Moreover, Western blot analysis indicated that ZCH-9 effectively inhibited hyperphosphorylation of the tau protein in okadaic acid-treated SH-SY5Y cells. The binding mode between ZCH-9 and GSK-3ß was analyzed and further clarified throughout the molecular dynamics simulations. In general, these results suggested that the α-carboline-based small-molecule compounds could serve as potential candidates targeting GSK-3ß for the treatment of AD.

A real-time computer-aided diagnosis method for hydatidiform mole recognition using deep neural network.

BACKGROUND AND OBJECTIVE: Hydatidiform mole (HM) is one of the most common gestational trophoblastic diseases with malignant potential. Histopathological examination is the primary method for diagnosing HM. However, due to the obscure and confusing pathology features of HM, significant observer variability exists among pathologists, leading to over- and misdiagnosis in clinical practice. Efficient feature extraction can significantly improve the accuracy and speed of the diagnostic process. Deep neural network (DNN) has been proven to have excellent feature extraction and segmentation capabilities, which is widely used in clinical practice for many other diseases. We constructed a deep learning-based CAD method to recognize HM hydrops lesions under the microscopic view in real-time. METHODS: To solve the challenge of lesion segmentation due to difficulties in extracting effective features from HM slide images, we proposed a hydrops lesion recognition module that employs DeepLabv3+ with our novel compound loss function and a stepwise training strategy to achieve great performance in recognizing hydrops lesions at both pixel and lesion level. Meanwhile, a Fourier transform-based image mosaic module and an edge extension module for image sequences were developed to make the recognition model more applicable to the case of moving slides in clinical practice. Such an approach also addresses the situation where the model has poor results for image edge recognition. RESULTS: We evaluated our method using widely adopted DNNs on an HM dataset and chose DeepLabv3+ with our compound loss function as the segmentation model. The comparison experiments show that the edge extension module is able to improve the model performance by at most 3.4% regarding pixel-level IoU and 9.0% regarding lesion-level IoU. As for the final result, our method is able to achieve a pixel-level IoU of 77.0%, a precision of 86.0%, and a lesion-level recall of 86.2% while having a response time of 82 ms per frame. Experiments show that our method is able to display the full microscopic view with accurately labeled HM hydrops lesions following the movement of slides in real-time. CONCLUSIONS: To the best of our knowledge, this is the first method to utilize deep neural networks in HM lesion recognition. This method provides a robust and accurate solution with powerful feature extraction and segmentation capabilities for auxiliary diagnosis of HM.

Hydrophilic molecularly imprinted membranes based on GO-loading for simultaneously selective recognition and detection of three amphenicols drugs in pork and milk.

It plays an important role to effective detection of amphenicols antibiotic residues in food and an important issue considering of possible impact on human health. In this work, the molecularly imprinted membranes (MIMs) were proposed to simultaneously recognize and detect thiamphenicol (TAP), florfenicol (FF) and chloramphenicol (CAP) in pork and milk samples. The synergistic effect of graphene oxide (GO), double functional monomer (methacrylate and acrylamide) and "click chemistry" strategy prompted the membranes to possess good surface hydrophilicity (48.6°), excellent selectivity and capacity to exclude macromolecules. The theoretical models of selectivity mechanism showed the selective recognition depended mainly on the hydrogen bond interaction and van der Waals interaction between the analytes and monomers. The limit of detection for 3 analytes were 0.04-0.28 µg kg-1, and showed a good correlation (r > 0.9949). Finally, this study established an effective MIMs-UHPLC-MS/MS method with great potential for the monitor of antibiotics residue in complicated matrices.

Development and structure-activity relationship of tacrine derivatives as highly potent CDK2/9 inhibitors for the treatment of cancer.

CDK2/9 are members of the CDKs family, which play key roles in the occurrence and development of many cancers by regulating cell cycle and transcriptional prolongation, respectively. To further optimize and discuss the structure-activity relationships (SARs), a series of tacrine-based compounds were designed and synthesized from the compound ZLWT-37, which was studied by our group previously but no detailed SARs study was conducted on CDK2/9. Among this series, compounds ZLMT-12 (35) exhibited the most potent antiproliferative activity (GI50 = 0.006 µM for HCT116) and superior CDK2/9 inhibitory properties (CDK2: IC50 = 0.011 µM, CDK9: IC50 = 0.002 µM). Meanwhile, ZLMT-12 showed a weak inhibitory effect on acetylcholinesterase (AChE, IC50 = 19.023 µM) and butyrylcholinesterase (BuChE, IC50 = 2.768 µM). In addition, ZLMT-12 can suppress colony formation and migration in HCT116 cells, as well as induce the apoptosis and arrest the cell cycle in the S phase and G2/M phase. In vivo investigations revealed that ZLMT-12 inhibits tumor growth in the HCT116 xenograft tumor model at a low dose of 10 mg/kg without causing hepatotoxicity. The acute toxicity test showed low toxicity with a median lethal dosage (LD50) of 104.417 mg/kg. These findings showed that ZLMT-12 might be used as a drug candidate by targeting CDK2/9.