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关键词： In vitro activity   In vivo activity   Molecular docking   SYK inhibitors   Structural optimization  

摘要： Spleen tyrosine kinase (SYK) has emerged as a promising therapeutic target for cancer treatment. In this study, based on the lead compound Lanraplenib, a series of novel imidazo[1,2-a]pyrazine derivatives were designed and synthesized through structure-based optimization focusing on modifications at the solvent-exposed C-8 position. The synthesized compounds were evaluated for their in vitro SYK inhibitory activity, and most of them exhibited improved potency. Among them, compound B13 showed the highest activity with an IC₅₀ value of 10.9 nM, comparable to Lanraplenib. In vitro studies demonstrated that B13 displayed significant anti-proliferative effects against SKOV3, MDA-MB-231 and HepG2 cells, and effectively inhibited colony formation. Mechanistic studies revealed that B13 induced S phase cell cycle arrest and promoted apoptosis in a dose-dependent manner. Molecular docking suggested that the enhanced activity of B13 may be attributed to enhanced hydrophobic interactions and additional hydrogen bonding within the SYK binding pocket. Furthermore, B13 exhibited moderate metabolic stability in liver microsomes. In vivo studies using a SKOV3 xenograft model demonstrated that B13 significantly inhibited tumor growth in a dose-dependent manner, with tumor inhibition rates of 58.62% and 66.97% at 30 and 60 mg/kg, respectively, better than Lanraplenib, while showing no obvious toxicity. Collectively, these findings identify B13 as a promising SYK inhibitor and provide valuable insights for the further development of SYK targeted therapeutics for solid tumors.

关键词： 1,2,3-triazole   Alzheimer disease   hCA I   hCA II   Indole   Thiosemicarbazone  

摘要： In this study, we report the synthesis, characterization, and enzyme inhibition effects of new thiosemicarbazone-indole-1,2,3-triazole-acetamide derivatives. All compounds were characterized by using NMR and FTIR spectroscopic and elemental analysis techniques. All new thiosemicarbazone-indole-1,2,3-triazole-acetamide derivatives (12a-q) were examined as potential inhibitors against acetylcholinesterase (AChE) and two key human carbonic anhydrases (hCA I and II), which are important in the treatment of Alzheimer’s disease. Enzymatic evaluations showed that all new compounds were more potent than the standard inhibitor tacrine against AChE, and most were more potent than the standard drug acetazolamide against carbonic anhydrases. Specifically, the best compound against AChE (12f) was 93.2-fold more potent than tacrine, while the best compounds against hCA I (12l) and hCA II (12m) were 2.4-fold and 2.3-fold more potent than acetazolamide, respectively. By molecular modeling study, compounds 12f, 12l, and 12m were placed into the active sites of AChE, hCA I, and hCAII, and the docking data agreed with the in vitro findings. Furthermore, molecular dynamics simulations demonstrated that compound 12f formed a stable complex with AChE.

摘要： The authors wish to address an unintentional error identified in the published article. In the original version of this article an administrative error occurred during the figure preparation process, sub-figures "B" and "C" of Figure 9 were the same, which were intended to show cellular uptake for different formulations.Komal Rao: Writing – original draft, Methodology. Nimra Naz Siddiqui: Writing – original draft, Methodology. Muhammad Abdullah: Writing – original draft. Salim Saifullah: Investigation. Humera Jahan: Supervision. Muhammad Raza Shah: Supervision.The authors declare no conflicts of interest. The corrected version of Figure 9 is provided below and accurately reflects cellular uptake for different formulations. This correction does not affect the results or conclusions of the study.Fig. 9Morphological analysis of HepG2 cells. A: Untreated;B: treated with CUR;and C: treated with HBP-CUR-NPs after 24 h of treatment. The confluency, cell size, and cellular networking appeared to be reduced in treated cells, as compared to the control. Three independent experiments had shown similar morphology of HepG2 cells.Fig. 9 dummy alt text © 2026 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： IL-17   RORγt inverse agonists   autoimmune diseases   ethylsulfonyl derivatives   psoriasis  

摘要： RORγt, a member of the nuclear receptor family, plays a central role in directing Th17 cell differentiation and pro-inflammatory function. Dysregulation of this transcription factor contributes significantly to autoimmune conditions such as psoriasis, rheumatoid arthritis, and multiple sclerosis. Consequently, inhibition of RORγt has attracted considerable interest as a therapeutic approach for these disorders. In this study, we designed and synthesized a series of aryl sulfonyl derivatives as RORγt inhibitors. Selected compounds were functionally characterized as inverse agonists, with compound 7 as the initial lead. Through a scaffold-hopping strategy and systematic structure–activity relationship (SAR) studies of key substituents, we identified potent RORγt inhibitors with favorable oral bioavailability. Compound 8v emerged as the most promising candidate. In vivo pharmacokinetic studies demonstrated that 8v possessed good oral absorption. In addition, 8v showed moderate metabolic stability in human and mouse liver microsomes (t₁_/₂ = 45 min and 151 min, respectively). Furthermore, in a mouse model of LPS-induced systemic inflammation—where IL-17 elevation is mediated by T-cell activation—and in an IMQ-induced psoriasis-like dermatitis model, 8v significantly inhibited IL-17 secretion and ameliorated disease-related symptoms. Collectively, these results support the therapeutic potential of small-molecule RORγt modulators for the treatment of inflammatory and autoimmune diseases.

关键词： Allosteric inhibitor   Antioxidant   Cerebral ischemia-reperfusion injury   Ferroptosis   IKKβ   Synthesis  

摘要： Antioxidant therapy represents a promising intervention for ischemic stroke, yet no targeted drug has successfully entered clinical application. While IKKβ is a known target in inflammatory and oncological diseases, its potential as an antioxidant target in stroke remains underexplored, and no IKKβ inhibitor has been approved clinically. Starting from the lead compound EF24, an IKKβ inhibitor with undefined mechanism, we first optimized its scaffold to obtain the safer derivative JH, then developed more potent analogs. A Random Forest-based QSAR model (R² = 0.9098) highlighted molecular charge distribution, topology, and lipophilicity as key activity determinants. The optimized compound JHB-17 showed ∼70-fold higher potency than EF24 and acted as a non-ATP competitive inhibitor, targeting a novel allosteric site on IKKβ. In an H₂O₂-induced SH-SY5Y cell injury model, JHB-17 demonstrated significant dual antioxidant cytoprotective effects, and IKKβ overexpression reversed the protective effect of JHB-17. H₂O₂ exposure induced IKKβ phosphorylation. Conversely, silencing IKKβ exerts antioxidant cytoprotective effects by upregulating heme oxygenase-1 (HO-1). JHB-17 markedly inhibited IKKβ phosphorylation, promoted Nrf2 nuclear translocation, subsequently upregulated HO-1, and concurrently elevated the ferroptosis suppressor SLC7A11 and glutathione. In a rat MCAO/R model, JHB-17 reduced cerebral infarct volume and improved neurobehavioral outcomes. JHB-17 exhibits favorable pharmacokinetic parameters, and the comet assay and acute toxicity test demonstrate its good safety profile. This study preliminarily reveals a novel allosteric site on IKKβ, identifies JHB-17 as a novel IKKβ allosteric inhibitor with dual antioxidant activity, proposes IKKβ as a novel antioxidant target for cerebral ischemia-reperfusion injury, and reveals a novel mechanism

关键词： Ammonia detoxification   Hepatic encephalopathy   L-ornithine liposomal nanoparticle   Proline cycle   Δ(1)-pyrroline-5-carboxylate dehydrogenase  

摘要： Hepatic encephalopathy (HE), a neuropsychiatric condition linked to liver malfunction and hyperammonemia. This study aims to investigate the therapeutic efficacy of L-ornithine liposomal nanoparticles in a rat model of HE, focusing on their capacity to inhibit Δ¹-pyrroline-5-carboxylate dehydrogenase (∆¹P5CDH) in HE rat model. Ten experimental groups were formed: G1–G4 acted as negative controls, G5 served as the untreated HE- control, and G6–G10 received treatments with L-ornithine, L-ornithine liposomal nanoparticles, or LOLA, either individually or in combination. A variety of assessments were performed, encompassing body weight monitoring, behavioral analysis, oxidative stress markers, inflammatory gene expression, (IL-1β, NF-κβ, IL-6, IL-10, TNFα, iNOS, TGF-β), protein expression for target ∆¹P5CDH and histological evaluation. The untreated HE group displayed notable abnormalities, such as augmented liver and brain weights, cognitive deficits, hyperammonemia, oxidative stress, and neuroinflammation. Treatment with L-ornithine, LOLA, and particularly L-ornithine liposomal nanoparticles resulted in significant enhancements by diminishing ammonia toxicity, re-establishing neurotransmitter equilibrium, decreasing oxidative stress, downregulating pro-inflammatory cytokine expression, and suppressing target protein ∆¹P5CDH, a key enzyme in proline metabolism. Histological features showed a reduction in hepatocellular degeneration and stored the nervous tissue function in the treatment groups compared with the HE untreated group. Thus, our findings elucidated that L-ornithine liposomal nanoparticles could serve as a potent therapeutic agent for HE therapy.

关键词： Dual-target ligand   Focal adhesion kinase   Pyrazolo[3,4-b]pyridine chemotype   Structure-activity relationship   Triple-negative breast cancer  

摘要： Triple-negative breast cancer (TNBC) remains difficult to treat because of the lack of effective therapeutic targets and limited treatment options. Dual targeting of Focal adhesion kinase 1 (FAK1) and 2 (FAK2) has emerged as a promising strategy, yet current dual-targeted ligands are still limited in structural diversity and binding mode. In this study, a pyrazolo[3,4-b]pyridine scaffold was identified through virtual screening and optimized to generate 16 derivatives. Among them, compound 8a showed the strongest binding affinity for both FAK1 and FAK2, with K_D values of 2.9 μM and 2.5 μM, respectively, and exhibited the best selectivity toward TNBC cells. Intracellular target engagement studies indicated that 8a protected specific peptides within the kinase domains of FAK1 and FAK2 in cells. Functionally, 8a induced G₂/M-phase arrest and activated DNA damage-related signaling, accompanied by decreased phosphorylation of CDK1. The antiproliferative activity of 8a was markedly attenuated by FAK1/FAK2 knockdown but significantly enhanced in combined treatment with doxorubicin. In addition, 8a inhibited 4 T1 tumor growth in vivo without significant body weight loss. These findings identify pyrazolo[3,4-b]pyridine as a new chemotype for dual FAK1/FAK2 targeting and support 8a as a target-dependent lead compound for anti-TNBC development.