Bioorganic Chemistry最新文献

{"title":"Quercetin inhibits gastric cancer growth and enhances T cells immunity by modulating the PI3K-AKT signaling pathway.","authors":"Yali Liu, Xiaojuan Kang, Jiaxuan Wang, Xinyang Zhou, Wushuang Tan, Tingting Kang, Wengui Shi, Dekui Zhang","doi":"10.1016/j.bioorg.2026.110420","DOIUrl":"10.1016/j.bioorg.2026.110420","url":null,"abstract":"<p><strong>Background: </strong>Quercetin, a flavonoid derived from astragalus and other medicinal plants, exhibits anti-cancer activity; however, its mechanisms in gastric cancer, especially regarding tumor immunity, remain incompletely understood. The aim of this study is to elucidate the mechanism of quercetin against gastric cancer.</p><p><strong>Methods: </strong>Quercetin was evaluated in vitro for the effects on proliferation, apoptosis, cell cycle, mitochondrial potential, and morphology in MKN-45, AGS and normal GES-1 cells. Its efficacy and safety were assessed in vivo using a xenograft model. A \"gastric cancer cells + T cells\" co-culture system was established to examine quercetin's influence on T cell function. Target prediction employed network pharmacology, molecular docking, and molecular dynamics simulations, with validation via PD-L1 knockdown and PI3K overexpression rescue.</p><p><strong>Results: </strong>Quercetin significantly inhibited MKN-45 proliferation, induced G0/G1 arrest, and promoted apoptosis, accompanied by mitochondrial damage, loss of membrane potential, downregulation of BCL-2, and upregulation of BAX, CytC, cleaved Caspase-9, and cleaved Caspase-3. In vivo, quercetin reduced tumor growth, decreased Ki-67, increased tumor apoptosis and peripheral CD8⁺ T cells, with no apparent organ toxicity. In co-culture, quercetin enhanced CD8⁺ T cell cytotoxicity, increasing granzyme B, perforin, IL-2, and IFN-γ. Mechanistically, quercetin bound PD-L1, reduced its protein expression without affecting mRNA, and suppressed the PI3K-AKT signaling pathway.</p><p><strong>Conclusion: </strong>Quercetin exhibited a dual mechanism: it directly suppressed gastric cancer cell proliferation and induced mitochondria-mediated apoptosis, while also enhancing CD8⁺ T cell cytotoxicity. Its anti-cancer mechanism involved modulation of PD-L1 protein expression and suppression of the PI3K-AKT signaling pathway. These findings supported the feasibility of quercetin as a potential therapeutic candidate for gastric cancer.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"181 ","pages":"110420"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel [1,2,4]triazolo[1,5-a]pyrimidine derivatives as promising antioxidant and antimicrobial agents: Synthesis, antibiofilm, DFT calculations, molecular docking, ADMET analysis, and MD simulations.","authors":"Farid M Sroor, Ahmed F El-Sayed","doi":"10.1016/j.bioorg.2026.110392","DOIUrl":"10.1016/j.bioorg.2026.110392","url":null,"abstract":"<p><p>The escalating threat of antimicrobial resistance necessitates the discovery of novel therapeutic scaffolds with distinct mechanisms of action. A novel series of [1,2,4]triazolo[1,5-a]pyrimidine derivatives (FNT01-12) featuring various aromatic substitutions at positions 5 and 7 was designed, synthesized, and evaluated as antioxidant and antimicrobial agents. The reaction of 1H-1,2,4-triazol-5-amine with freshly synthesized chalcones (5-16) yielded the targeted [1,2,4]triazolo[1,5-a]pyrimidine derivatives (FNT01-12) in excellent yields. The chemical structures of these compounds were confirmed using spectral data and elemental analyses. The in vitro antimicrobial screening revealed a high degree of structure-dependent selectivity. Compound FNT09 emerged as a potent broad-spectrum agent, exhibiting significant efficacy against both Gram-positive and Gram-negative pathogens, including an MIC of 5.00 μg/mL against P. aeruginosa. Conversely, FNT11 and FNT12 demonstrated exceptional, narrow-spectrum potency exclusively against P. aeruginosa (MIC = 5.00 μg/mL), substantially outperforming Ciprofloxacin. Furthermore, FNT11 and FNT12 exhibited profound antibiofilm capabilities, disrupting established P. aeruginosa biofilms by 40.21 and 44.32%, respectively. DFT optimization showed that FNT11 had the highest stability (lowest energy: -1388.7095 Eh). FNT10 was the strongest electron donor (HOMO = -4.7870 eV), while FNT11 exhibited the narrowest HOMO-LUMO gap (2.338 eV) and highest nucleophilicity (4.677 eV), indicating high reactivity and electron-donating ability. Molecular docking and Dynamics (MD) simulations confirmed that the most active derivatives form highly stable, thermodynamically favorable complexes with critical bacterial targets: dihydropteroate synthase (DHPS), DNA gyrase, LasR, and Penicillin-Binding Protein 4 (PBP4). Trajectory analyses (RMSD, RMSF, PCA) and MM-GBSA binding free energy calculations indicated that robust van der Waals interactions primarily drive stability. Finally, predictive ADMET profiling confirmed that these lead candidates possess favorable pharmacokinetic properties and comply with Lipinski's Rule of Five, establishing FNT09, FNT10, FNT11, and FNT12 as promising scaffolds for the targeted treatment of recalcitrant bacterial infections.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"181 ","pages":"110392"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of rigid linker-based CDK4/6 PROTACs for the treatment of breast cancer.","authors":"Guoyong Pan, You Li, Jinke Tan, Yuanyuan Chen, Weijiao Chen, Huanaoyu Yang, Xujie Zhuang, Linhu Shen, Ziyu Zong, Yiming Fan, Jiadong Gao, Liping Wang, Xiao-Yu Zhang, Peng Yang, Kai Yuan","doi":"10.1016/j.bioorg.2026.110368","DOIUrl":"10.1016/j.bioorg.2026.110368","url":null,"abstract":"<p><p>Selective cyclin-dependent kinase (CDK) 4/6 inhibitors play a leading role in the treatment of breast cancer; however, their efficacy is often limited by acquired resistance. Proteolysis-targeting chimera (PROTAC) technology has recently emerged as a promising therapeutic strategy to overcome drug resistance. In this study, we designed and synthesized a series of novel CDK4/6 PROTACs based on dalpiciclib incorporating rigid linkers. The optimal compound P11 exhibited potent and selective CDK4/6 degradation activity mediated by the ubiquitin-proteasome system. Binding model analysis demonstrated that P11 is capable of forming a stable CDK6-CRBN-P11 ternary complex. P11 significantly inhibited proliferation and colony formation, and induced cell cycle arrest in breast cancer cell lines. Furthermore, P11 effectively suppressed tumor growth in an MCF-7 xenograft model, demonstrating stronger anti-breast cancer activity than dalpiciclib both in vitro and in vivo. Importantly, P11 showed potential to overcome acquired resistance to CDK4/6 inhibitors. Therefore, P11 could be a promising preclinical candidate for further development.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"181 ","pages":"110368"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioorganic strategies for quorum sensing inhibition: disrupting biofilms and virulence in drug-resistant pathogens.","authors":"Mo Ahamad Khan, Lechen Zhu, Xinyu Zhu, Hu Zhu","doi":"10.1016/j.bioorg.2026.110423","DOIUrl":"10.1016/j.bioorg.2026.110423","url":null,"abstract":"<p><p>The escalating global crisis of antimicrobial resistance (AMR) poses a severe threat to public health, with bacterial biofilms and virulence factors exacerbating treatment failures in drug-resistant pathogens. Quorum sensing (QS), a density-dependent communication system, orchestrates biofilm formation, virulence expression, and resistance mechanisms in clinically relevant bacteria, including Pseudomonas aeruginosa, Staphylococcus aureus, and other pathogenic bacteria. Unlike conventional antibiotics, which exert selective pressure that can lead to resistance, QS inhibition offers a promising anti-virulence strategy by attenuating pathogenicity without directly killing bacteria. This review focuses on bioorganic approaches to QS disruption, encompassing natural products, synthetic analogues, hybrid phytocompound-nanoparticle conjugates, and metal-organic frameworks (MOFs). Key sections explore QS systems in Gram-negative and Gram-positive pathogens; molecular mechanisms of inhibition, including autoinducer synthesis blockade, receptor antagonism, and enzymatic degradation; structure-activity relationships (SAR), with emphasis on pharmacophores such as hydroxyl groups and α,β-unsaturated carbonyls; and evidence of biofilm and virulence attenuation in drug-resistant strains from in vitro, ex vivo, and in vivo studies. Synergistic effects with sub-MIC antibiotics are also highlighted, alongside challenges related to bioavailability, toxicity, and regulatory hurdles. Prospects include bioorthogonal probes for QS tracking, machine learning-aided design of next-generation inhibitors, nanoparticle-mediated targeted delivery, and emerging preclinical candidates. By leveraging advances in bioorganic chemistry, QS inhibition holds substantial translational potential for the management of AMR-driven infections and may redefine future therapeutic paradigms in infectious disease control.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"181 ","pages":"110423"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148838651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"D2AAK1 derivatives as neuroprotective agents: Synthesis and structural and pharmacological evaluation.","authors":"Michał K Jastrzębski, Piotr Wójcik, Diana Pietrzak-Mitura, Agata Bartyzel, Katarzyna M Targowska-Duda, Tadeusz Karcz, Olga Wronikowska-Denysiuk, Agnieszka Olejarz-Maciej, Agnieszka Michalak, Agata Sumara, Piotr Drączkowski, Emilia Fornal, Tomasz M Wróbel, Agnieszka A Kaczor","doi":"10.1016/j.bioorg.2026.110417","DOIUrl":"10.1016/j.bioorg.2026.110417","url":null,"abstract":"<p><p>This study describes 14 novel D2AAK1 derivatives exhibiting enhanced neuroprotective properties. These derivatives were tested for their inhibitory effects on AChE and MAO-B, as well as their effect on cell viability under normal conditions and under oxidative stress. D2AAK1 derivatives show strong cytoprotective effects, increasing cell viability by up to 80% under normal conditions and up to 60% under oxidative stress. These effects may involve modulation of MAPK p38 and Nrf2 pathway interactions, known to promote antioxidant and anti-apoptotic responses. In vivo studies indicated a beneficial effect of the tested derivative on memory processes in the novel object recognition test. These findings identify D2AAK1 derivatives as promising lead compounds for further development as potential treatments of memory deficits.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"181 ","pages":"110417"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148856852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of anti-inflammatory β-acids featuring an unusual 5/7/5 tricyclic skeleton via targeting the TLR4/MyD88 signaling pathway.","authors":"Kang Ding, Fu-Lin Zhou, Yan-Jing Shi, Zi-Hao Sha, Li-Jie Wang, Jia Zhang, Mao-Li Bai, Zhou-Zi-Qi Li, Jie-Kun Xu, Jun He, Wei-Ku Zhang","doi":"10.1016/j.bioorg.2026.110415","DOIUrl":"10.1016/j.bioorg.2026.110415","url":null,"abstract":"<p><p>Five pairs of previously undescribed β-acid enantiomers, (±)-humulunes A-E (1-5), were isolated from Humulus lupulus L. These compounds feature an unusual 5/7/5 tricyclic ring skeleton bearing multiple stereocenters. Their structures were elucidated through comprehensive spectroscopic analysis, including calculated NMR and electronic circular dichroism (ECD), as well as single-crystal X-ray diffraction. Among them, compounds (+)-3, (-)-3, and (+)-4 exhibited significant anti-inflammatory activity in LPS-induced RAW 264.7 cells. Furthermore, compound (-)-3 was found to inhibit cell apoptosis and reactive oxygen species (ROS) production, modulate macrophage polarization, and suppress the TLR4/MyD88 signaling pathway. Molecular docking, molecular dynamics simulation, and cellular thermal shift assay (CETSA) confirmed the direct and stable binding of (-)-3 to TLR4 protein, which may exert anti-inflammatory effects by blocking the activation of the TLR4/MyD88 signaling pathway, providing a reference for the development of anti-inflammatory therapeutics.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"181 ","pages":"110415"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148856855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Synthesis of chalcones derived from 1-naphthylacetophenone and evaluation of their cytotoxic and apoptotic effects in acute leukemia cell lines\" [Bioorganic Chem. 116 (2021) 105315].","authors":"Amanda Virtuoso Jacques, Natália Marcéli Stefanes, Laura Otto Walter, Daiane Mari Perondi, Fernanda da Luz Efe, Luiz Felipe Schmitz de Souza, Larissa Sens, Stephanie Milis Syracuse, Ana Carolina Rabello de Moraes, Aldo Sena de Oliveira, Carolina Teixeira Martins, Luma Godoy Magalhaes, Adriano Defini Andricopulo, Lisandra de Oliveira Silva, Ricardo José Nunes, Maria Cláudia Santos-Silva","doi":"10.1016/j.bioorg.2026.110575","DOIUrl":"https://doi.org/10.1016/j.bioorg.2026.110575","url":null,"abstract":"","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":" ","pages":"110575"},"PeriodicalIF":5.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Design, synthesis, and biological evaluation of cathepsin B cleavage albumin-binding SN38 prodrug in breast cancer\" [Bioorg. Chem. 147 (2024) 107370].","authors":"Yingxin Lu, Ying Huang, Jiyu Jin, Jiahui Yu, Wei Lu, Shulei Zhu","doi":"10.1016/j.bioorg.2026.110573","DOIUrl":"https://doi.org/10.1016/j.bioorg.2026.110573","url":null,"abstract":"","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":" ","pages":"110573"},"PeriodicalIF":5.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum \"Synthesis of novel dibenzoxanthene derivatives and observation of apoptosis in human hepatocellular cancer cells\" [Bioorg. Chem. 72 (2017) 333-344].","authors":"Hui-Hui Yang, Yun-Jun Liu, Xiu-Zhen Wang","doi":"10.1016/j.bioorg.2026.110014","DOIUrl":"10.1016/j.bioorg.2026.110014","url":null,"abstract":"","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":" ","pages":"110014"},"PeriodicalIF":5.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148154585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tetrazolo[1,5-c]quinazolines as anti-Klebsiella pneumoniae scaffolds: Bridging in vitro activity and multi-target docking prediction.","authors":"Lyudmyla Antypenko, Oleksii Antypenko, Lyudmyla Lyashko, Alina Fominichenko, Valentyna Kozyrieva, Serhii Kovalenko, Mieko Arisawa","doi":"10.1016/j.bioorg.2026.110155","DOIUrl":"10.1016/j.bioorg.2026.110155","url":null,"abstract":"<p><p>The emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) represents a significant challenge in antimicrobial chemotherapy, with mortality rates reaching 50% in bloodstream infections. Building on prior disk diffusion evidence of K. pneumoniae inhibition by N-acetamide tetrazoloquinazoline compounds and a cross-series analysis of >60 published derivatives across seven structural subclasses, this study presents the first MIC-quantified antibacterial evaluation against a clinically isolated, multidrug-resistant K. pneumoniae strain. Twenty-one synthetic tetrazolo[1,5-c]quinazoline derivatives were evaluated, with molecular docking performed against five bacterial enzyme targets: FabI (fatty acid synthesis), MurA (cell wall biosynthesis), DNA gyrase (DNA replication), KPC-2 (β-lactam resistance), and LpxC (lipopolysaccharide synthesis). Two compounds demonstrated antibacterial activity, both with MIC values of 64 mg/L: the thiol derivative 63sh (315 μM) and 2-chlorobenzyl acetamide 102 (166 μM). No inhibition was observed against Escherichia coli or Staphylococcus aureus at concentrations up to 512 mg/L. Computational docking against five bacterial enzyme targets revealed FabI enoyl-ACP reductase as the most favorable binding target. Under conventional medicinal chemistry criteria, MIC values of 64 mg/L correspond to hit-level rather than lead-level potency; substantial structural optimization is required before preclinical consideration. In silico ADMET profiling (admetSAR3.0) indicates that the computationally favored but experimentally inactive/weak compounds (96, 97, 109, 112) possess lower predicted membrane permeability (Caco-2: -5.07 to -5.41 vs. -4.36 to -4.98 log nm/s) and higher P-glycoprotein inhibition probabilities (0.741-0.795), consistent with impaired membrane permeation as the primary mechanistic explanation for this discordance.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"180 ","pages":"110155"},"PeriodicalIF":5.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148366356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}