A novel PARP-ATR dual inhibitor exhibits anti-triple-negative breast cancer activity by inducing excessive DNA damage in the mitotic phase.

Triple-negative breast cancer (TNBC), a particularly aggressive breast carcinoma subtype, exhibits poor clinical outcomes and elevated mortality rates. The therapeutic response to PARP inhibitors (PARPi) is significantly improved in TNBC patients harboring breast cancer susceptibility gene 1/2 (BRCA1/2) mutations compared to naïve patients. Preclinical studies suggested that combination therapy using PARPi and ATR inhibitor (ATRi), which synergistically blocks DNA repair and compromises cell cycle progression, showed promising activity in different cancer models, including TNBC.

Liquid chromatography-tandem mass spectrometry methods for clinical quantitation of antibiotics.

The accurate quantification of antibiotics in biological matrices is pivotal for supporting individualized medication, optimizing antibiotics therapy and addressing the global crisis of antimicrobial resistance (AMR). LC-MS/MS has emerged as the gold standard for clinical antibiotic quantification, particularly valued for its accuracy, multiplexing efficiency, and compatibility with complex sample types. This review provides a comprehensive overview of the principles, methodologies, and clinical applications of LC-MS/MS in antibiotic quantification, with a focus on its role in therapeutic drug monitoring (TDM), pharmacokinetics (PK), and epidemiological studies.

Relationship between serum uric acid levels and metabolism associated fatty liver disease in postmenopausal women based on NHANES 2017-2020.

Studies have shown that postmenopausal women have more metabolic abnormalities than premenopausal women. No consensus exists on how serum uric acid (sUA) affects metabolism-associated fatty liver disease (MAFLD) in postmenopausal women.This prospective observational study examined this link using National Health and Nutrition Examination Survey (NHANES) 2017 to 2020 data.

Physiological state recognition model of small silkworm based on improved YOLOv5.

Silkworm breeding, as a pivotal economic activity across various regions of China, plays a crucial role in promoting rural revitalization. Notably, the early stage of silkworm development, during which the larvae are most vulnerable and environmentally sensitive, poses significant challenges due to their high pathogenicity and mortality rates. To enhance the efficiency of silkworm breeding, it is imperative to accurately and rapidly identify the physiological state of these small silkworms, ensuring timely feedback to farmers.

Oxidation/Alkylation of Amino Acids with α-Bromo Carbonyls Catalyzed by Copper and Quick Access to HDAC Inhibitor.

A facile and efficient method was reported for Cu-catalyzed selective α-alkylation processes of amino acids/peptides and α-bromo esters/ketones through a radical-radical coupling pathway. The reaction displays an excellent functional group tolerance and broad substrate scope, allowing access to desired products in moderate to excellent yields. Notably, this method is distinguished by site-specificity and exhibits total selectivity for aryl glycine motifs over other amino acid units.

Dandelion polysaccharide treatment protects against dextran sodium sulfate-induced colitis by suppressing NF-κB/NLRP3 inflammasome-mediated inflammation and activating Nrf2 in mouse colon.

The treatment of ulcerative colitis (UC) is still an intractable medical problem. Polysaccharides are promising candidates for the treatment of UC and have received widespread attention in recent years. The objective of this study was to explore the protective effect and underlying mechanism of dandelion polysaccharide (DP) on dextran sulfate sodium (DSS)-induced colitis in mice.

Design, Synthesis and Biological Evaluation of Histone Deacetylase Inhibitors Based on Pyrrolo[2,3-d]pyrimidine and Pyrrolo[2,3-b]pyridine Scaffolds.

Histone deacetylases (HDACs) are validated targets for the development of anticancer drugs in epigenetics. We have designed and synthesized a series of novel HDAC inhibitors based on pyrrolo[2,3-d]pyrimidine and pyrrolo[2,3-b]pyridine scaffolds. Compound B3 {(E)-3-(4-(((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide} exhibits potent inhibitory activity against HDACs 1, 2, 3, 6, and 8 with IC values of 5.

Design, synthesis and biological evaluation of novel histone deacetylase (HDAC) inhibitors derived from -elemene scaffold.

-Elemene is the major active ingredient of TCM anticancer drug elemene extracts. To further improve its antitumor activity and poor solubility, a polar HDACi pharmacophore was incorporated its scaffold. Systematic SAR studies led to the discovery of compounds and , which exhibited potent inhibitory activity against HDACs (HDAC1: IC = 22 and 9 nM; HDAC6: 8 and 14 nM, respectively).

Dysregulation of PD-L1 by UFMylation imparts tumor immune evasion and identified as a potential therapeutic target.

Immunotherapy of PD-L1/PD-1 blockage elicited impressive clinical benefits for cancer treatment. However, the relative low response and therapy resistance highlight the need to better understand the molecular regulation of PD-L1 in tumors. Here, we report that PD-L1 is a target of UFMylation.

Recent advances of novel fourth generation EGFR inhibitors in overcoming C797S mutation of lung cancer therapy.

Lung cancer is the second place among the global cancer population in term of the morbidity and mortality, while non-small cell lung cancer (NSCLC) accounts for the largest proportion of all lung cancer patient. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are commonly used in the treatment of NSCLC. Despite of the success in coping with EGFR kinase resistance lung cancer using the first three generations of EGFR-TK inhibitors (EGFR-TKIs), the new problem of resistance to Osimertinib occurred due to the newly developed EGFR mutation.

Design, synthesis and antitumor efficacy evaluation of a series of novel β-elemene-based macrocycles.

β-Elemene is the major constituent of the antitumor drugs elemene extract approved in China. By incorporating macrocyclization strategy into the β-elemene skeleton, we designed a series of novel macrocycles retaining three key carbon-carbon double bonds. Four different methods have been successfully developed for these challenging ring systems.

Discovery of small-molecule compounds and natural products against Parkinson's disease: Pathological mechanism and structural modification.

Parkinson's disease (PD) is the second common neurodegenerative disease characterized by movement disorder. The symptoms of PD harm both the physical and mental health of patients. However, the current treatment strategies for PD only alleviate the symptoms but cannot recover the degenerative process of dopaminergic neurons.

Drug discovery of histone lysine demethylases (KDMs) inhibitors (progress from 2018 to present).

Post-translational modifications (PTMs) of histone by histone demethylases (KDMs) play an important role in the regulation of gene expression, which implicates the development of various human cancers and other diseases. Discovering and developing inhibitors targeting KDMs have become an active and fast-growing research area over the past decades. In this review, the latest emerging small-molecule inhibitors of KDMs were surveyed with the emphasis on the literature since 2018, including lysine specific demethylases (LSD or KDM1) inhibitors and JmjC family N-methyl lysine demethylases (JmjC KDMs, i.

Two phenanthroimidazole turn-on probes for the rapid detection of selenocysteine and its application in living cells imaging.

Detection of selenocysteine (Sec) content in cells by fluorescence probe is of great significance for the identification of human related diseases. To achieve fast and sensitive detection of Sec, two isomers A4 and B4 as turn-on fluorescent probes to detect Sec were designed and synthesized. Both A4 and B4 display fast turn-on response, high selectivity and sensitivity toward Sec, which can be applied for fluorescence imaging of Sec in living cells.

Medicinal chemistry updates of novel HDACs inhibitors (2020 to present).

Epigentic enzymes histone deacetylases (HDACs) catalyze the removal of acetyl groups from the ε-N-acetylated lysine residues of various protein substrates including both histone and non-histone proteins. Different HDACs have distinct biological functions and are recruited to specific regions of the genome. Due to their important biological functions, HDACs have been validated in clinics for anticancer therapy, and are being explored for potential treatment of several other diseases such as Alzheimer disease (AD), metabolic disease, viral infection, and multiple sclerosis, etc.

β-Elemene derivatives produced from SeO-mediated oxidation reaction.

Herein, we report the first access of β-elemene derivatives through the SeO-mediated oxidation reaction. Several new compounds were isolated through such a one-step reaction, and their structures were elucidated using various 2D-NMR techniques. This method provides easy access to multiple oxidative β-elemene derivatives in one single step and represents the first modifications on cyclohexyl ring of β-elemene.

4-Hydroxy-3-methylbenzofuran-2-carbohydrazones as novel LSD1 inhibitors.

Histone lysine specific demethylase 1 (LSD1 or KDM1A) is a potential therapeutic target in oncology due to its overexpression in various human tumors. We report herein a new class of benzofuran acylhydrazones as potent LSD1 inhibitors. Among the 31 compounds prepared, 14 compounds exhibited excellent LSD1 inhibitory activity with IC values ranging from 7.

Novel Selective Histone Deacetylase 6 (HDAC6) Inhibitors: A Patent Review (2016-2019).

Background: Many human diseases are associated with dysregulation of HDACs. HDAC6 exhibits deacetylase activity not only to histone protein but also to non-histone proteins such as α- tubulin, HSP90, cortactin, and peroxiredoxin. These unique functions of HDAC6 have gained significant attention in the medicinal chemistry community in recent years.

Identification and characterization of the first cytokinin glycosyltransferase from rice.

Background: Cytokinins are one of the five major hormones families in plants and are important for their normal growth and environmental adaptability. In plants, cytokinins are mostly present as glycosides in plants, and their glycosylation modifications are catalyzed by family 1 glycosyltransferases. Current research on cytokinin glycosylation has focused on the biochemical identification of enzymes and the analysis of metabolites in Arabidopsis.

Selective Tyk2 inhibitors as potential therapeutic agents: a patent review (2015-2018).

Introduction: Tyrosine kinase 2 (Tyk2) is a non-receptor tyrosine-protein kinase, an enzyme that in humans is encoded by the TYK2 gene. Tyk2, together with three other family subtypes, namely, Jak1, Jak2, and Jak3, belong to the JAK family. Before 2014, far more publications and patents appeared in public domain attributing to the development of selective Jak2 and Jak3 inhibitors than those for selective Tyk2 and Jak1 inhibitors.

Diversity-Oriented Synthesis of Natural-Product-like Libraries Containing a 3-Methylbenzofuran Moiety for the Discovery of New Chemical Elicitors.

Natural products are a major source of biological molecules. The 3-methylfuran scaffold is found in a variety of plant secondary metabolite chemical elicitors that confer host-plant resistance against insect pests. Herein, the diversity-oriented synthesis of a natural-product-like library is reported, in which the 3-methylfuran core is fused in an angular attachment to six common natural product scaffolds-coumarin, chalcone, flavone, flavonol, isoflavone and isoquinolinone.

Finding new elicitors that induce resistance in rice to the white-backed planthopper Sogatella furcifera.

Herein we report a new way to identify chemical elicitors that induce resistance in rice to herbivores. Using this method, by quantifying the induction of chemicals for GUS activity in a specific screening system that we established previously, 5 candidate elicitors were selected from the 29 designed and synthesized phenoxyalkanoic acid derivatives. Bioassays confirmed that these candidate elicitors could induce plant defense and then repel feeding of white-backed planthopper Sogatella furcifera.

3-(2,5-Di-methyl-phen-yl)-8-meth-oxy-2-oxo-1-aza-spiro-[4.5]dec-3-en-4-yl 3-(2-bromo-4-fluoro-phen-yl)acrylate.

In the title compound, C27H27BrFNO4, which is an inhibitor of acetyl-CoA carboxyl-ase, the cyclo-hexane ring displays a chair comformation with the spiro-C and meth-oxy-bearing C atoms deviating by 0.681 (7) and -0.655 (1) Å, resppectively, from the mean plane formed by the other four C atoms of the spiro-C6 ring.

(1'S,4'S)-5-(2,5-Dimethyl-phen-yl)-4'-meth-oxy-6-oxa-3-aza-spiro-[bicyclo-[3.1.0]hexane-2,1'-cyclo-hexa-n]-4-one.

In the title compound, C18H23NO3, the cyclo-hexane ring has a chair conformation. The oxirane plane (OCC) makes a dihedral angle of 76.15 (13)° with that of the pyrrolidine ring to which it is fused.

Metabolism-based synthesis, biological evaluation and structure-activity relationship analysis of spirotetramat analogues as potential lipid biosynthesis inhibitors.

Background: In previous studies, scientists found that, when spirotetramat was introduced into plants or animals, it was mainly metabolised at positions C-4 and C-8. That is to say, these two functional positions potentially played an important role in spirotetramat's bioactivities. In order to develop novel insecticides or miticides, the present authors designed and synthesised 35 spirotetramat analogues based on metabolite structures.