Bioorganic Chemistry最新文献

{"title":"Selectively and efficiently eliciting a ROS-dependent energy crisis within cancer cells through a mitochondria-targeted catechol-based diphenylhextriene","authors":"Xia-Zhen Bao ,&nbsp;Xiao-Rong Ren ,&nbsp;Wei Tang ,&nbsp;Yu Zhang ,&nbsp;Zheng-Kai Deng ,&nbsp;Fang Dai ,&nbsp;Bo Zhou","doi":"10.1016/j.bioorg.2026.109505","DOIUrl":"10.1016/j.bioorg.2026.109505","url":null,"abstract":"<div><div>To effectively trigger an energy crisis within cancer cells, we devised and synthesized mitochondria-targeted catechol-based diphenylpolyenes by coupling them with a triphenylphosphonium unit <em>via</em> a modular synthetic approach. The exploration of structure-activity relationships in terms of cytotoxicity discloses that Mito-DHH, a catechol-type diphenylhextriene that specifically targets mitochondria, is the most potent molecule among those tested, manifesting its preferential elimination of A549 cells (IC₅₀ = 0.25 μM) as opposed to normal L02 cells (IC₅₀ = 2.8 μM). In this regard, it outperforms doxorubicin and 5-fluorouracil, the commonly employed chemotherapy drugs. Mechanistic investigation affirms that the rapid accumulation of Mito-DHH within mitochondria of A549 cells enables its efficient auto-oxidation by leveraging the alkaline mitochondrial matrix to effectively and selectively generate reactive oxygen species (ROS). Through the generation of ROS, Mito-DHH initiates a ROS-dependent reduction of ATP levels within A549 cells in a dual-effect inhibitory pattern against both mitochondrial and glycolytic metabolisms, and the ultimate and selective apoptosis of A549 cells. This study takes Mito-DHH as an example to emphasize the universality of a ROS-generating strategy by targeting mitochondria in effectively inducing an energy crisis within cancer cells.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109505"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974455","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":"Design, synthesis, and antidiabetic evaluation of triazolopyrimidine thioacetamides as potent and selective α-glucosidase inhibitors","authors":"Fariba Peytam ,&nbsp;Maryam Norouzbahari ,&nbsp;Bahareh Bayati ,&nbsp;Hayrettin Ozan Gülcan ,&nbsp;Vahid Sheibani ,&nbsp;Maliheh Barazandeh Tehrani ,&nbsp;Somayeh Mojtabavi ,&nbsp;Mohammad Ali Faramarzi ,&nbsp;Fahimeh Ghasemi ,&nbsp;Mohammadreza Torabi ,&nbsp;Meghdad Payab ,&nbsp;Fatemeh Safari ,&nbsp;Loghman Firoozpour ,&nbsp;Alireza Foroumadi","doi":"10.1016/j.bioorg.2026.109482","DOIUrl":"10.1016/j.bioorg.2026.109482","url":null,"abstract":"<div><div>Diabetes mellitus is a global health challenge characterized by chronic hyperglycemia. <em>α</em>-Glucosidase inhibitors, like acarbose, are pivotal in managing postprandial blood glucose levels but are often associated with gastrointestinal side effects. This study aimed to rationally design and synthesize a library of 2-((6-amino-5,7-diaryl-[1,2,4]triazolo[1,5-<em>a</em>]pyrimidin-2-yl)thio)-<em>N</em>-arylacetamide derivatives (<strong>15a-15ae</strong>) as potent and selective <em>α</em>-glucosidase inhibitors. All 31 target compounds exhibited inhibitory activity (IC₅₀ ranging from 7.09 μM to 245.57 μM) under assay conditions where the reference drug, acarbose, exhibited an IC₅₀ value of 750.67 μM. The most potent compound, <strong>15o</strong> (IC₅₀ = 7.09 ± 0.2 μM), demonstrated approximately 106-fold higher potency than acarbose under the identical assay conditions. Kinetic analysis indicated that <strong>15o</strong> acted as a competitive inhibitor (Kᵢ = 6.9 μM). Moreover, this compound did not show <em>α</em>-amylase inhibitory activity and cytotoxicity at concentration of 100 μM, showing preliminary indications of favorable safety and selectivity. Spectroscopic studies (CD, fluorescence) and computational analyses (model performance and augmentation, docking, and MD simulations) confirmed the strong binding affinity and stabilization of compound <strong>15o</strong> within the enzyme's active site. <em>In vivo</em> evaluation in a diabetic rat model demonstrated that <strong>15o</strong> (30 mg/kg BW) significantly reduced fasting blood glucose, improved glucose tolerance in OGTT, reduced HbA₁c levels to near-normal ranges, and restored hepatic and pancreatic histology, with effects better than those observed with acarbose in this model. Compound <strong>15o</strong> also exhibited acceptable acute toxicity profiles. These findings introduced compound <strong>15o</strong> as a promising lead candidate for further structural development of anti-diabetic agents.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109482"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145923488","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":"Characterization of bridged guaiane-type sesquiterpenoids from Stellera chamaejasme and their antifungal activities against phytopathogenic fungi","authors":"Sheng-Yun Wei ,&nbsp;Yan Huang ,&nbsp;Jiao Yao ,&nbsp;Ping Zhao ,&nbsp;Jun-Cheng Su ,&nbsp;Luo-Sheng Wan ,&nbsp;Guo-Lei Zhu","doi":"10.1016/j.bioorg.2026.109475","DOIUrl":"10.1016/j.bioorg.2026.109475","url":null,"abstract":"<div><div>Plant pathogenic fungi pose a serious threat to global agricultural productivity, driving the need for novel and eco-friendly antifungal agents. An investigation into the antifungal constituents from the roots of <em>Stellera chamaejasme</em> led to the isolation of nine new guaiane-type sesquiterpenoids, named stelleroids D–L (<strong>1–3</strong> and <strong>8–13</strong>), along with eight known analogues. Their structures, featuring extensively modified bridged scaffolds and diverse oxidative patterns, were elucidated by comprehensive spectroscopic analysis and X-ray crystallography. Antifungal evaluation against five agriculturally significant phytopathogenic fungi identified compound <strong>11</strong> as the most potent and broad-spectrum agent, exhibiting exceptional activity against <em>Phytophthora infestans</em> (MIC = 3.1 μg/mL). Subsequent mechanistic studies revealed that compound <strong>11</strong> disrupted the cell membrane integrity of <em>P. infestans</em>, leading to increased permeability, leakage of cellular contents, and severe ultrastructural damage. Molecular docking simulations suggested that <strong>11</strong> could effectively bind to the putative targets CYP51 and SDH. Importantly, <em>in vivo</em> experiments on tomato fruits confirmed the significant protective and curative efficacy of <strong>11</strong> against late blight. This work not only expands the structural diversity of bioactive sesquiterpenoids but also provides a highly promising natural lead compound (<strong>11</strong>) with validated in planta efficacy for further development as a new antifungal agrochemical.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109475"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145923487","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":"Targeting the phosphoinositide 3-kinase signaling pathway and epidermal growth factor receptor: The potential of dimethylcardamonin-derived amino acids in triple-negative breast cancer therapy","authors":"Pornthip Chawapun ,&nbsp;Nopawit Khamto ,&nbsp;Yazdaniyar Fajri Halimi ,&nbsp;Kraikrit Utama ,&nbsp;Sadanon Siriphong ,&nbsp;Atchara Janthong ,&nbsp;Nathupakorn Dechsupa ,&nbsp;Jiraporn Kantapan ,&nbsp;Nawee Kungwan ,&nbsp;Thanyada Rungrotmongkol ,&nbsp;Puttinan Meepowpan ,&nbsp;Padchanee Sangthong","doi":"10.1016/j.bioorg.2026.109483","DOIUrl":"10.1016/j.bioorg.2026.109483","url":null,"abstract":"<div><div>Targeting the phosphoinositide 3-kinase (PI3K) signaling pathway, along with the epidermal growth factor receptor (EGFR), presents a promising strategy for breast cancer treatment. Here, dimethylcardamonin (DMC, <strong>1</strong>), isolated from <em>Syzygium nervosum</em> seeds, was modified by attaching amino acids such as serine (<strong>2</strong><strong>h</strong>), tryptophan (<strong>2i</strong>), and tyrosine (<strong>2j</strong>) to produce new compounds. Compounds <strong>2</strong><strong>h</strong>–<strong>2j</strong> demonstrated most excellent inhibitory effectiveness against breast cancer cells, with IC₅₀ values of 4.59 ± 0.06, 5.33 ± 0.59, and 6.89 ± 0.85 μM, respectively, in MDA-MB-231 cells. These DMC derivatives not only induced DNA damage but also triggered morphological changes in breast cancer cells. Notably, compound <strong>2j</strong> increased sub-G0/G1 cell cycle accumulation and through the G2/M phase arrest, significantly inducing both early and late apoptosis. It also effectively reduced mitochondrial membrane potential alterations at higher concentrations. Furthermore, the compound <strong>2j</strong> upregulated the expression of genes like <em>Bax</em>, <em>BRCA1</em>, <em>Caspase-3</em>, <em>CDKN1A</em>, <em>Mcl-1</em>, and <em>PIK3CA</em>, potentially influencing apoptosis <em>via</em> the PI3K/AKT pathway. The compound 2j significantly inhibited the MDA-MB-231 cells proliferation by downregulation of EGFR, p-EGFR, and p-AKT protein expression levels. Molecular docking studies revealed that compound <strong>2j</strong> had a strong binding affinity and interacted closely with key catalytic residues of EGFR, outperforming erlotinib, a known EGFR inhibitor, suggesting its potential as an anti-breast cancer drug candidate.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109483"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974493","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":"Insights into red sea bream iridovirus pathogenesis: Unveiling host-pathogen interactions using membrane yeast two-hybrid and molecular dynamics","authors":"Weichao Chen,&nbsp;Jialong Yu,&nbsp;Meijia He,&nbsp;Hailian Wu,&nbsp;Dekui Qiu,&nbsp;Chao Zhao","doi":"10.1016/j.bioorg.2026.109547","DOIUrl":"10.1016/j.bioorg.2026.109547","url":null,"abstract":"<div><div>Red sea bream iridovirus (RSIV), a member of the genus Megalocytivirus, poses a substantial threat to global aquaculture through its infection of marine fish species. The major capsid protein (MCP) represents the principal immunogenic component of RSIV, yet the mechanisms governing its pathogenicity is unclear. Here, we employed a comprehensive approach combining protein interaction screening with artificial intelligence-based structural prediction to elucidate the interface between RSIV and its host. In brief, by constructing a yeast cDNA library of membrane protein in red snapper and using a membrane yeast two hybrid system, a cDNA library targeting RSIV-MCP was screened, and 53 different host interaction partners were identified from the preliminary screening of 96 positive clones. Reverse validation confirmed robust protein-protein interactions for all candidates, including heat shock proteins Hsc70, HSP90β, and HSC71-like protein. Leveraging AlphaFold3 for structural prediction, we generated high-confidence models of MCP and HSC70, enabling molecular docking and dynamics simulations. The resulting complex demonstrated structural stability within 100 ns, as reflected by convergence of root-mean-square deviation and radius of gyration values. Computational analyses revealed an extensive hydrogen-bond network at the binding interface. This finding is further supported by a calculated binding free energy of −318.45 kJ/mol, indicating a potentially strong interaction between MCP and HSC70. Mutational analysis identified key residues 646ILE and 452ILE as critical mediators of complex formation, with hydrogen bonding and van der Waals interactions serving as primary stabilizing forces. These results provide insights into RSIV-host protein interactions, establishing a foundation for understanding viral pathogenesis and developing targeted therapeutic strategies against this economically significant aquatic pathogen.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109547"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073895","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":"Effect of apatinib on albendazole metabolism in vitro and in vivo","authors":"Hailun Xia ,&nbsp;Haoxin Fu ,&nbsp;Lu Cao ,&nbsp;Ruibin Li ,&nbsp;Jun Wu ,&nbsp;Peiqi Wang ,&nbsp;Ren-ai Xu ,&nbsp;Weihong Lin","doi":"10.1016/j.bioorg.2026.109550","DOIUrl":"10.1016/j.bioorg.2026.109550","url":null,"abstract":"<div><div>Albendazole is a broad-spectrum antiparasitic benzimidazole and has potential for the treatment of tumors. The aim of this study was to investigate the potential inhibitory effects of 77 drugs on the metabolism of albendazole, and further to elaborate the inhibitory mechanism of apatinib on albendazole metabolism <em>in vitro</em> and <em>in vivo</em>, where the concentrations of albendazole and its metabolites were detected using an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay. <em>In vitro</em> results showed that 10 drugs inhibited albendazole metabolism by more than 80%, with the half-maximal inhibitory concentrations (IC₅₀) of apatinib in rat liver microsomes (RLM), human liver microsomes (HLM) and recombinant human CYP3A4 (rCYP3A4) being 0.47, 5.53 and 2.01 μM, respectively. Moreover, the inhibition of albendazole by apatinib was non-time-dependent. In addition, the inhibitory mechanisms were mixed consisting of non-competitive and un-competitive for RLM, and competitive and non-competitive for HLM and rCYP3A4. Pharmacokinetic parameters in Sprague-Dawley rats showed that apatinib caused significant increases in AUC_(0-t), AUC_(0-∞), C_max, T_max and t_1/2, while a significant decrease in CL_z/F for albendazole. For the metabolites albendazole sulfoxide and hydroxyalbendazole, apatinib caused significant increases in AUC_(0-t), AUC_(0-∞), and T_max, while a significant decrease in CL_z/F. In summary, apatinib could inhibit the metabolism of albendazole <em>in vitro</em> and <em>in vivo</em>, so albendazole should be closely monitored for adverse effects when used in combination with apatinib and discontinued if necessary.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109550"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073983","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":"Vicinal dithiol proteins-triggered prodrug activation: A novel strategy for Cancer-specific imaging and therapy","authors":"Suntao Shi ,&nbsp;Ruipeng Shen ,&nbsp;Yating Chen,&nbsp;Mengzhao Zhang,&nbsp;Jingyi Liu,&nbsp;Chunlin Sun,&nbsp;Haijuan Zhang,&nbsp;Baoxin Zhang","doi":"10.1016/j.bioorg.2026.109552","DOIUrl":"10.1016/j.bioorg.2026.109552","url":null,"abstract":"<div><div>Theranostic platforms have garnered considerable attention as a promising strategy to enhance the precision and efficacy of cancer treatment. Vicinal dithiol proteins (VDPs) are critical for maintaining cellular redox balance, and their dysregulation is associated with various pathological conditions, such as cancer, stroke and neurodegenerative diseases. Herein, we design a novel VDPs-activated theranostic prodrug, <strong>Lena-green</strong>, which incorporates an α, β-unsaturated acrylamide group as a recognition site for the first time. Upon exposure to VDPs, <strong>Lena-green</strong> conjugates the fluorophore to VDPs while releasing lenalidomide (<strong>Lena</strong>), a clinically established anticancer drug, enabling fluorescence-based tracking and achieving high drug release efficiency in vitro. In murine models of subcutaneous breast cancer, <strong>Lena-green</strong> exhibited significantly enhanced therapeutic efficacy. This innovative design provides a promising strategy for real-time monitoring of drug release, thereby improving the precision and effectiveness of cancer treatment.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109552"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146058365","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":"Development of STING inhibitors with indole and pyrazine derivatives linked through amide bond as potent anti-inflammatory agents","authors":"Peng Zhou ,&nbsp;Tingting Zhang ,&nbsp;Yaya Peng ,&nbsp;Gen Yang ,&nbsp;Jiayin Yan ,&nbsp;Xiangxiang Cao ,&nbsp;Jinliang Ma ,&nbsp;Wenpei Dong ,&nbsp;Chang-Po Chen","doi":"10.1016/j.bioorg.2025.109462","DOIUrl":"10.1016/j.bioorg.2025.109462","url":null,"abstract":"<div><div>The essential role of STING-mediated signaling in autoimmune and inflammatory disorders makes it a compelling therapeutic target, driving the development of novel small-molecule STING inhibitors. Based on the lead STING inhibitor <strong>H151</strong>, herein we designed and prepared a series of novel STING inhibitors composed of amino indole and pyrazine derivatives linked with amide bond. Structure activity relationship investigation demonstrated that compound <strong>QQ21</strong> showed significant improved STING inhibition activity in mouse RAW-Lucia™ ISG cells with an IC₅₀ value of 86 nM, which is 8-fold of the efficacy of <strong>H151</strong>. <strong>QQ21</strong> effectively inhibited the activity of STING agonist CMA in mouse. In cisplatin-induced acute kidney injury (AKI) mouse model, <strong>QQ21</strong> significantly prevented kidney function damage and inflammation.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109462"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974492","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":"Structure-guided discovery of 6-aminopyridine derivatives for group II PAK4 inhibition","authors":"Eun Lee ,&nbsp;Jisoo Kim ,&nbsp;Hye-ji Yoon ,&nbsp;Jeong-Wook Yang ,&nbsp;Jong Soon Kang ,&nbsp;Raok Jeon","doi":"10.1016/j.bioorg.2026.109470","DOIUrl":"10.1016/j.bioorg.2026.109470","url":null,"abstract":"<div><div>p21-Activated kinase 4 (PAK4) is a Group II serine/threonine kinase implicated in tumor growth and immune evasion, and is therefore a promising target for anticancer therapy. Leveraging structure-guided design, we report a novel series of 6-aminopyridine derivatives that target a previously underexplored deep hydrophobic subpocket adjacent to Phe461, which extends from the floor pocket of PAK4. Even with a relatively concise compound set, the focused SAR study identified key substituent features required for deep-pocket engagement, and subsequent molecular docking and dynamics simulations supported an underexploited binding mode centered on the key residue Phe461. Among the synthesized compounds, <strong>17</strong> (PAK4 IC₅₀ 0.71 μM) and <strong>29</strong> (PAK4 IC₅₀ 1.88 μM) demonstrated comparable enzymatic potency, consistent with ATP-competitive inhibition, while compound <strong>29</strong> was effective in inhibiting cancer cell proliferation (HCT-116 GI₅₀ 23.0 μM; A549 GI₅₀ 11.3 μM). In conclusion, this study highlights the potential of targeting underexplored subpockets in PAK4 and provides new molecular insights for the discovery of PAK4 inhibitors.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109470"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145964886","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":"Engineering ruthenium(II)-based nanoparticles for synergistic sonodynamic therapy with multi-targeted redox catalysis","authors":"Jianing Chen ,&nbsp;Chaoyi Zhu ,&nbsp;Siqi Tang ,&nbsp;You Meng ,&nbsp;Xiuchong Yu ,&nbsp;Jianjiong Li ,&nbsp;Ting Fei ,&nbsp;Qi Liao ,&nbsp;Ning Xi ,&nbsp;Yang Xi ,&nbsp;Yang Lu ,&nbsp;Yufen Zhao","doi":"10.1016/j.bioorg.2026.109474","DOIUrl":"10.1016/j.bioorg.2026.109474","url":null,"abstract":"<div><div>Sonodynamic therapy (SDT) could effectively overcomes the wavelength and energy limitations inherent to photodynamic therapy (PDT). However, current strategies for sonosensitizer optimization predominantly focus on acceptor engineering through extensive π-extension, which inadvertently compromises biocompatibility. Here, we first proposed a donor-engineering strategy by engineering conventional <em>sp</em>³-hybridized amino groups with <em>sp</em>² counterparts, forming the [Ru(tpy)(Aze-phen)Cl](PF₆) (complex <strong>4</strong>). Complex <strong>4</strong> narrow the energy gap efficiently, achieving 1.6-fold higher NADH sonocatalytic oxidation efficiency than <em>sp</em>³-based analogues [Ru(tpy)(Meo-phen)Cl](PF₆) (complex <strong>1</strong>), [Ru(tpy)(pip-phen)Cl](PF₆) (complex <strong>2)</strong>, and [Ru(tpy)(pyr-phen)Cl](PF₆) (complex <strong>3</strong>). Self-assembly with DSPE-PEG2000 and complex <strong>4</strong> yields tumor-targeted nanoparticles, NanoRu, could be gathered in mitochondrion and cell nucleus. Functionally, NanoRu combinated SDT treatment exhibited synergized therapeutic effects on cancer cells with reduced growth of colongenic growth, increased ROS and lipid peroxidation, decreased GSH level. The irregulated ferroptosis, apoptosis, and DNA damage were indicated by altered protein expression of ACSL4 and GPX4, cleaved PARP and caspase 3, and γ-H2AX, respectively. Moreover, these nanoparticles under ultrasound irradiation induce significant regression of CT26 tumors with 83 % in mice. Together, our work establishes the first Ru(II)-based platform integrating donor engineering, multi-organelle targeting, and redox catalysis, overcoming chemoresistance while advancing precision sonodynamic-chemotherapy in colorectal cancer cells.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109474"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145923537","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}