Site-Selective Electrophilic Trifluoromethylthiolation for the Synthesis of C5- or C7-SCF-Substituted Indolines.

We report herein an efficient and site-selective electrophilic trifluoromethylthiolation of indolines. In the absence of any catalyst or additive, C5-selective trifluoromethylthiolation could proceed at room temperature. With palladium used as the catalyst, the selectivity was reversed completely, giving C7-selecive trifluoromethylthiolated products.

PDCdb: the biological activity and pharmaceutical information of peptide-drug conjugate (PDC).

Peptide-drug conjugates (PDCs) have emerged as a promising class of targeted therapeutics with substantial pharmaceutical advantages and market potentials, which is a combination of a peptide (selective to the disease-relevant target), a linker (stable in circulation but cleavable at target site) and a cytotoxic/radioactive drug (efficacious/traceable for disease). Among existing PDCs, those based on radiopharmaceuticals (a.k.

Discovery of Potent Selective HDAC6 Inhibitors with 5-Phenyl-1-indole Fragment: Virtual Screening, Rational Design, and Biological Evaluation.

Among the HDACs family, histone deacetylase 6 (HDAC6) has attracted extensive attention due to its unique structure and biological functions. Numerous studies have shown that compared with broad-spectrum HDACs inhibitors, selective HDAC6 inhibitors exert ideal efficacy in tumor treatment with insignificant toxic and side effects, demonstrating promising clinical application prospect. Herein, we carried out rational drug design by integrating a deep learning model, molecular docking, and molecular dynamics simulation technology to construct a virtual screening process.

[Advances on cyclopeptides of plants].

Cyclopeptides isolated from a variety of plants are a class of cyclic nitrogen-containing compounds, and they are primarily formed by peptide bonds between amino acids, generally containing 2 to 37 L-configuration encoded or non-encoded amino acid residues. Cyclopeptides have significant values in scientific research as natural small-molecule metabolites produced by plants. The available studies have revealed that such natural products are ubiquitous in plants, which mainly include cyclic dipeptides, cyclic tetrapeptides, cyclic pentapeptides, cyclic hexapeptides, cyclic heptapeptides, cyclic octapeptides, cyclic nonapeptides, and cyclic decapeptides.

A new methodology to reveal potential nucleic acid modifications associated with the risk of endometrial cancer through dispersive solid-phase extraction coupled with UHPLC-QE-Orbitrap-MS/MS and HPLC-UV.

Nucleic acid modifications have attracted increasing attention in recent years since they have been found to be related to a number of diseases including cancer. Previous studies have shown that the early development of endometrial cancer (EC) is often accompanied by changes in methylation levels of related genes, and the expression of related proteins that regulate reactive oxygen species (ROS) shows significant differences in EC cells and tissues. However, it has not been reported whether nucleic acid modifications related to methylation or ROS can serve as biomarkers for EC.

INTEDE 2.0: the metabolic roadmap of drugs.

The metabolic roadmap of drugs (MRD) is a comprehensive atlas for understanding the stepwise and sequential metabolism of certain drug in living organisms. It plays a vital role in lead optimization, personalized medication, and ADMET research. The MRD consists of three main components: (i) the sequential catalyses of drug and its metabolites by different drug-metabolizing enzymes (DMEs), (ii) a comprehensive collection of metabolic reactions along the entire MRD and (iii) a systematic description on efficacy & toxicity for all metabolites of a studied drug.

High Hepcidin Levels Promote Abnormal Iron Metabolism and Ferroptosis in Chronic Atrophic Gastritis.

Background: Chronic atrophic gastritis (CAG) is a chronic inflammatory disease and premalignant lesion of gastric cancer. As an antimicrobial peptide, hepcidin can maintain iron metabolic balance and is susceptible to inflammation.

Objectives: The objective of this study was to clarify whether hepcidin is involved in abnormal iron metabolism and ferroptosis during CAG pathogenesis.

Discovery of selective HDAC6 inhibitors based on a multi-layer virtual screening strategy.

The abnormal enhancement of histone deacetylase 6 (HDAC6) has been demonstrated to be closely related to the occurrence and development of various malignant tumors, attracting extensive attention as a promising target for cancer therapy. Currently, only limited selective HDAC6 inhibitors have entered clinical trials, making the rapid discovery of selective HDAC6 inhibitors with safety profiles particularly urgent. In this study, a multi-layer virtual screening workflow was established, and the representative compounds screened were biologically evaluated in combination with enzyme inhibitory and anti-tumor cell proliferation experiments.

Inhibition of Kv7/M Channel Currents by Fangchinoline.

Introduction: Voltage-gated Kv7/M potassium channels play an essential role in the control of membrane potential and neuronal excitability. Fangchinoline, a bisbenzylisoquinoline alkaloid, displays extensive biological activities including antitumor, anti-inflammatory, and antihypertension effects. In this study, we investigated the effects of fangchinoline on Kv7/M channels.

Liquiritin Protects Against Cardiac Fibrosis After Myocardial Infarction by Inhibiting CCL5 Expression and the NF-κB Signaling Pathway.

Purpose: Despite significant advances in interventional treatment, myocardial infarction (MI) and subsequent cardiac fibrosis remain major causes of high mortality worldwide. Liquiritin (LQ) is a flavonoid extract from licorice that possesses a variety of pharmacological properties. However, to our knowledge, the effects of LQ on myocardial fibrosis after MI have not been reported in detail.

Do biological activities of selective histone deacetylase 6 (HDAC6) inhibitors rely on the modification of cap group?

Nowadays, significant progress has been made in the development of selective histone deacetylase 6 (HDAC6) inhibitors, exerting great potential in the treatment of various malignant tumors and neurodegenerative diseases. Previously, selective inhibitory activities of HDAC inhibitors were generally considered sensitive to the interactions between the Cap group and the binding site of HDAC6, and a large number of selective HDAC6 inhibitors have been designed and synthesized based on the strategy. However, some inhibitors without Cap group could also exhibit excellent potency and selective inhibition towards HDAC6, and in this study, BRD9757 and compound 8, as capless selective HDAC6 inhibitors, were selected as molecular probes to explore the difference of their binding interactions in HDAC1&6.

Protective effects and possible mechanism of 6-gingerol against arsenic trioxide-induced nephrotoxicity based on network pharmacological analysis and experimental validation.

Background And Objective: Nephrotoxicity induced by the chemotherapeutic drug arsenic trioxide (ATO) is often overlooked, and the underlying mechanisms remain poorly understood. Based on network pharmacology and experimental validation, this study investigates the protection of 6-gingerol (6G) against ATO-induced nephrotoxicity and the potential mechanisms.

Methods: We screened and collected 6G and disease-related targets and then imported the interaction targets into a String database to construct protein-protein interaction (PPI) networks.

Design, Synthesis, and biological evaluation of HDAC6 inhibitors based on Cap modification strategy.

The abnormal biological functions of HDAC6 were closely related to the occurrence and development of various tumors, making HDAC6 gradually become promising therapeutic target for cancer treatment and inspiring researchers to explore and develop selective HDAC inhibitors. In this study, based on the classical pharmacophore model of HDAC inhibitors, 20 compounds were designed and synthesized by modifying the Cap group, and the biological activities of the target compounds were assessed through anti-proliferation and enzyme inhibition experiments. The title compounds exhibited varying degrees of inhibitory activities against the selected tumor cell lines, especially the compounds 9m, 9q, and 12c, which were further evaluated at the enzymatic level.

Protective Effects of 6-Gingerol on Cardiotoxicity Induced by Arsenic Trioxide Through AMPK/SIRT1/PGC-1α Signaling Pathway.

Arsenic trioxide (AsO) induced cardiotoxicity to limit the clinical applications of the effective anticancer agent. 6-Gingerol (6G) is the main active ingredient of ginger, a food with many health benefits. The present study aims to investigate the potential pharmacological mechanisms of 6G on AsO-induced myocardial injury.

Protective mechanisms of 10-gingerol against myocardial ischemia may involve activation of JAK2/STAT3 pathway and regulation of Ca homeostasis.

10-Gingerol (10-Gin), an active ingredient extracted from ginger, has been reported to have beneficial effects on the cardiovascular system. However, its protective effects on myocardial ischemia (MI) and the underlying cellular mechanisms are still unclear. To investigate the protection conferred by 10-Gin against MI injury and its potential mechanisms in cardiomyocytes via patch-clamp and molecular biology techniques.

Multistage pH-responsive codelivery liposomal platform for synergistic cancer therapy.

Background: Small interfering RNA (siRNA) is utilized as a potent agent for cancer therapy through regulating the expression of genes associated with tumors. While the widely application of siRNAs in cancer treatment is severely limited by their insufficient biological stability and its poor ability to penetrate cell membranes. Targeted delivery systems hold great promise to selectively deliver loaded drug to tumor site and reduce toxic side effect.

Mechanisms Underlying Gastrodin Alleviating Vincristine-Induced Peripheral Neuropathic Pain.

Gastrodin (GAS) is the main bioactive ingredient of Gastrodia, a famous Chinese herbal medicine widely used as an analgesic, but the underlying analgesic mechanism is still unclear. In this study, we first observed the effects of GAS on the vincristine-induced peripheral neuropathic pain by alleviating the mechanical and thermal hyperalgesia. Further studies showed that GAS could inhibit the current density of Na1.

Comparison of the Inhibitory Binding Modes Between the Planar Fascaplysin and Its Nonplanar Tetrahydro-β-carboline Analogs in CDK4.

Fascaplysin is a natural marine product originating from sponges, attracting widespread attention due to its potential inhibitory activities against CDK4. However, its clinical application has been largely limited because of serious adverse effects caused by planar skeleton. To reduce the serious adverse effects, 18 tetrahydro-β-carboline analogs (compounds 6a-i and 7a-i) were designed and synthesized via breaking the planarity of fascaplysin, and the biological activities of the synthesized compounds were evaluated by MTT assay and CDK4/CycD3 enzyme inhibition assay.

Inhibition of the I and the activation of peak I contribute to the arrhythmogenic effects of aconitine and mesaconitine in guinea pigs.

Aconitine (ACO), a main active ingredient of Aconitum, is well-known for its cardiotoxicity. However, the mechanisms of toxic action of ACO remain unclear. In the current study, we investigated the cardiac effects of ACO and mesaconitine (MACO), a structurally related analog of ACO identified in Aconitum with undocumented cardiotoxicity in guinea pigs.

Synthesis and Biological Evaluation of HDAC Inhibitors With a Novel Zinc Binding Group.

Vorinostat (SAHA) with great therapeutic potential has been approved by the FDA for the treatment of cutaneous T-cell lymphoma as the first HDACs inhibitor, but the drawbacks associated with hydroxamic acid group (poor stability, easy metabolism, weak binding ability to class IIa isozymes, and poor selectivity) have been exposed during the continuous clinical application. Based on the pharmacophore of HDAC inhibitors, two series of compounds with novel zinc binding group (ZBG) were designed and synthesized, and the antitumor bioactivities were evaluated in four human cancer cell lines (A549, Hela, HepG2, and MCF-7). Among the synthesized compounds, compounds , , , , and exhibited promising inhibitory activities against the selected tumor cell lines, especially compounds and on Hela's cytostatic activity (: IC = 11.

A Complete Study of Farrerol Metabolites Produced in Vivo and in Vitro.

Although farrerol, a characteristically bioactive constituent of L., exhibits extensive biological and pharmacological activities (e.g.

Exploring in vivo metabolism and excretion of QO-58L using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry.

QO-58 lysine (QO-58L) as a new potassium channel opener, reported to have a potential activity to cure neuropathic pain. The aim of this research is to develop and validate a high-performance liquid chromatography with tandem spectrometry (LC-MS/MS) method for the quantification of QO-58L in rat urine, feces and bile. In addition, analyze and identify the metabolites in urine and bile.

Exogenous melatonin for sleep disorders in neurodegenerative diseases: a meta-analysis of randomized clinical trials.

The purpose of this work is to investigate the efficacy of exogenous melatonin in the treatment of sleep disorders in patients with neurodegenerative disease. We searched Pubmed, the Cochrane Library, and ClinicalTrials.gov, from inception to July 2015.