Discovery of 3-amide-pyrimidine-based derivatives as potential fms-like tyrosine receptor kinase 3 (FLT3) inhibitors for treating acute myelogenous leukemia.

FLT3-ITD and TKD mutants play a central role in acute myeloid leukemia (AML), making FLT3 an attractive target for AML treatment. To discover next-generation FLT3 inhibitors and gather additional structure-activity relationship (SAR) information, we performed structural modifications of G-749 (denfivontinib) utilizing structure simplification and scaffold hopping strategies. Among these derivatives, MY-10 exhibited the most potent and selective inhibition of MV4-11 cell proliferation, demonstrating potent inhibitory activity against FLT3-ITD (IC = 6.

Double-Layer Distributed and Integrated Fault Detection Strategy for Non-Gaussian Dynamic Industrial Systems.

Currently, with the increasing scale of industrial systems, multisensor monitoring data exhibit large-scale dynamic Gaussian and non-Gaussian concurrent complex characteristics. However, the traditional principal component analysis method is based on Gaussian distribution and uncorrelated assumptions, which are greatly limited in practice. Therefore, developing a new fault detection method for large-scale Gaussian and non-Gaussian concurrent dynamic systems is one of the urgent challenges to be addressed.

Discovery of Novel p53-MDM2 Inhibitor (RG7388)-Conjugated Platinum Complexes as Potent Antitumor Agents.

While a number of p53-MDM2 inhibitors have progressed into clinical trials for the treatment of cancer, their progression has been hampered by a variety of problems, including acquired drug resistance, dose-dependent toxicity, and limited clinical efficiency. To make more progress, we integrated the advantages of MDM2 inhibitors and platinum drugs to construct novel Pt-RG7388 (a selective MDM2 inhibitor) complexes. Most complexes, especially and , displayed greatly improved antiproliferative activity against both wild-type and mutated p53 cancer cells.

Discovery of Platinum-Artesunate Multiaction Prodrugs as Potent Antitumor and Antimalarial Agents.

Recently, artemisinin and derivatives have been revealed to possess encouraging antitumor activity. Herein, we integrated the antitumor advantages of artesunate and platinum drugs to construct novel Pt-artesunate dual-action and triple-action complexes. Most derivatives, especially , displayed broad-spectrum and potent antitumor activities against a number of cancer cell lines.

Inspired by bis-β-carboline alkaloids: Construction and antitumor evaluation of a novel bis-β-carboline scaffold as potent antitumor agents.

Bis-β-carboline alkaloids are widely distributed in natural products and represent a promising drug-like scaffold for discovering drugs and bioactive molecules. In this study, we utilized the structural simplification strategy to construct a novel bis-β-carboline scaffold via "one-pot" condensation-Mannich reaction. The simplified bis-β-carboline derivatives were obtained in good yield.

Discovery of potent tubulin inhibitors targeting the colchicine binding site via structure-based lead optimization and antitumor evaluation.

The colchicine binding site of tubulin is a promising target for discovering novel antitumour agents. Previously, we identified 2-aryl-4-amide-quinoline derivatives displayed moderate tubulin polymerisation inhibitory activity and broad-spectrum antitumour activity. In this study, structure based rational design and systematic structural optimisation were performed to obtain analogues bearing diverse substituents and scaffolds.

Laparoscopic placement of left renal vein extravascular stenting in treatment of nutcracker syndrome: Techniques and long-term outcomes.

Objectives: We aimed to assess the feasibility and efficacy of laparoscopic extravascular stent in treatment of nutcracker syndrome by transperitoneal or retroperitoneal approach.

Methods: Seventy-six patients with nutcracker syndrome were retrospectively enrolled from a tertiary referral center, and underwent transperitoneal (63 patients) or retroperitoneal (13 patients) laparoscopic extravascular stent from March 2011 to December 2020. Surgical parameters, complications, imaging and clinical outcomes were collected and analyzed.

Fall Detection for Shipboard Seafarers Based on Optimized BlazePose and LSTM.

Aiming to avoid personal injury caused by the failure of timely medical assistance following a fall by seafarer members working on ships, research on the detection of seafarer's falls and timely warnings to safety officers can reduce the loss and severe consequences of falls to seafarers. To improve the detection accuracy and real-time performance of the seafarer fall detection algorithm, a seafarer fall detection algorithm based on BlazePose-LSTM is proposed. This algorithm can automatically extract the human body key point information from the video image obtained by the vision sensor, analyze its internal data correlation characteristics, and realize the process from RGB camera image processing to seafarer fall detection.

Discovery of novel tubulin inhibitors targeting the colchicine binding site via virtual screening, structural optimization and antitumor evaluation.

The colchicine binding site of tubulin is a promising target for discovering novel antitumor agents which exert the antiangiogenic effect and are not susceptible to multidrug resistance. For identifying novel tubulin inhibitors, structure-based virtual screening was applied to identify hit 9 which displayed moderate tubulin polymerization inhibition and broad-spectrum in vitro antitumor activity. Structural optimization was performed, and biological assay revealed analog E27 displayed the best antitumor activity with IC values ranging from 7.

Recent Progress in the Discovery of Antifungal Agents Targeting the Cell Wall.

Due to the limit of available treatments and the emergence of drug resistance in the clinic, invasive fungal infections are an intractable problem with high morbidity and mortality. The cell wall, as a fungi-specific structure, is an appealing target for the discovery and development of novel and low-toxic antifungal agents. In an attempt to accelerate the discovery of novel cell wall targeted drugs, this Perspective will provide a comprehensive review of the progress made to date on the development of fungal cell wall inhibitors.

Resveratrol: Multi-Targets Mechanism on Neurodegenerative Diseases Based on Network Pharmacology.

Resveratrol is a natural polyphenol in lots of foods and traditional Chinese medicines, which has shown promising treatment for neurodegenerative diseases (NDs). However, the molecular mechanisms of its action have not been systematically studied yet. In order to elucidate the network pharmacological prospective effects of resveratrol on NDs, we assessed of pharmacokinetics (PK) properties of resveratrol, studied target prediction and network analysis, and discussed interacting pathways using a network pharmacology method.

Pretreatment elevated prognostic nutritional index predicts a favorable prognosis in patients with prostate cancer.

Background: The prognostic nutritional index (PNI), an immunity and nutrition based prognostic score, was correlated with clinical outcomes in different tumors. However, the prognostic significance of PNI has not been investigated in hormone sensitive prostate cancer (PCa). The objective of this study was to determine the prognostic significance of PNI in hormone sensitive PCa.

Progress in 11β-HSD1 inhibitors for the treatment of metabolic diseases: A comprehensive guide to their chemical structure diversity in drug development.

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a key metabolic enzyme that catalyzing the intracellular conversion of inactive glucocorticoids to physiologically active ones. Work over the past decade has demonstrated the aberrant overexpression of 11β-HSD1 contributed to the pathophysiological process of metabolic diseases like obesity, type 2 diabetes mellitus, and metabolic syndromes. The inhibition of 11β-HSD1 represented an attractive therapeutic strategy for the treatment of metabolic diseases.

Structural simplification: an efficient strategy in lead optimization.

The trend toward designing large hydrophobic molecules for lead optimization is often associated with poor drug-likeness and high attrition rates in drug discovery and development. Structural simplification is a powerful strategy for improving the efficiency and success rate of drug design by avoiding "molecular obesity". The structural simplification of large or complex lead compounds by truncating unnecessary groups can not only improve their synthetic accessibility but also improve their pharmacokinetic profiles, reduce side effects and so on.

Antifungal Activity of Crude Extract from the Rhizome and Root of A. Gray.

This study aimed to investigate the antifungal activity of hydroalcoholic extract from (SJA) against different fungi. The minimum inhibitory concentration (MIC) for SJA was determined by the broth microdilution method. The antifungal effects of SJA against were further confirmed by cell growth test and time-kill curve test.

Design, synthesis and biological evaluation of novel antitumor spirodihydrothiopyran-oxindole derivatives.

Sulfur containing spiroheterocyclic oxindoles are promising privileged scaffolds in medicinal chemistry and drug discovery. Previously, we identified a new class of spirodihydrothiopyran-oxindoles with good in vitro antitumor activity against A549 lung cancer cell line. Herein, various spirooxindole-dihydrothiopyrans with diverse substitutions were synthesized and assayed to investigate the structure-activity relationships.

Design, synthesis and evaluation of new classes of nonquaternary reactivators for acetylcholinesterase inhibited by organophosphates.

A new series of nonquaternary conjugates for reactivation of both nerve agents and pesticides inhibited hAChE were described in this paper. It was found that substituted salicylaldehydes conjugated to aminobenzamide through piperidine would produce efficient reactivators for sarin, VX and tabun inhibited hAChE, such as L6M1R3, L6M1R5 to L6M1R7, L4M1R3 and L4M1R5 to L4M1R7. The in vitro reactivation experiment for pesticides inhibited hAChE of these new synthesized oximes were conducted for the first time.

Synthesis of spiro-tetrahydrothiopyran-oxindoles by Michael-aldol cascade reactions: discovery of potential P53-MDM2 inhibitors with good antitumor activity.

Using proline as the catalyst, an organocatalytic Michael-aldol cascade reaction was developed for the synthesis of spiro-tetrahydrothiopyran oxindoles. The highly functionalized scaffold was assembled in moderate to good yields (51-78%) and excellent diastereoselectivities (>20 : 1 dr). Interestingly, the oxindoles displayed moderate to good in vitro antitumor activities and were validated as p53-MDM2 inhibitors, which represented promising lead compounds for antitumor drug discovery.

Design, synthesis and biological evaluation of novel antitumor spirotetrahydrothiopyran-oxindole derivatives as potent p53-MDM2 inhibitors.

p53-MDM2 protein-protein interaction is a promising target for novel antitumor drug development. Previously, we identified a new class of spirotetrahydrothiopyran-oxindole p53-MDM2 inhibitors by novel organocatalytic enantioselective cascade reactions. Herein, a series of new derivatives were designed, synthesized and assayed to investigate the structure-activity relationships.