Bioorganic Chemistry最新文献

{"title":"Design, synthesis and biological evaluation of hydroxybenzothiazole-linked benzothiazole/benzoxazole conjugates as potent dual α-amylase and α-glucosidase inhibitors.","authors":"Rafaqat Hussain, Hina Sarfraz, Umair Khurshid, Noor Alqurashi, Ayaz Ali Khan, Nawal H Siddig, Nawal Al-Hoshani, Hayam A Alwabsi","doi":"10.1016/j.bioorg.2026.110437","DOIUrl":"10.1016/j.bioorg.2026.110437","url":null,"abstract":"<p><p>The current study focuses on the synthesis and evaluation of novel Hydroxybenzothiazole-Linked Benzothiazole/Benzoxazole Conjugates to target Diabetes Mellitus (DM) by inhibiting α-amylase and α-glucosidase. Spectroscopic methods, including ¹H and ¹³C NMR spectroscopy, were employed to confirm the structures of newly synthesized conjugates. The findings of in-vitro analysis displayed that the synthesized derivatives inhibited α-amylase and α-glucosidase enzymes with IC₅₀ values ranging from 3.65 ± 0.20 μM to 32.15 ± 3.20 μM on α-amylase and 5.92 ± 0.80 μM to 35.60 ± 3.40 μM on α-glucosidase, in contrast to the reference drug Acarbose (α-amylase IC₅₀ = 8.25 ± 0.80 μM; α-glucosidase IC₅₀ = 10.75 ± 1.10 μM). Among the series 9a-9f and 10a-10f, analogs 10 f, 10b, 9b, and 9e displayed superior anti-diabetic activity compared to the reference drug Acarbose. The inhibitory activity of these conjugates can be attributed to their favorable and stable interactions with critical amino acid residues of targeted enzymes, as revealed through molecular docking analysis. ADMET predictions and drug-likeness evaluations showed favorable pharmacokinetic features, while DFT investigations revealed electronic insights related to bioactivity. Experimental outcomes and in silico support display that these potent Hydroxybenzothiazole-Linked Benzothiazole/Benzoxazole Conjugates were comparable to an existing diabetic mellitus inhibitor while conserving an acceptable safety profile, specifying potential for further therapeutic development and optimization against diabetic Mellitus.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"181 ","pages":"110437"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148860262","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 novel Quinazoline-chalcone hybrids as dual VEGFR-2/P-gp inhibitors to reverse cisplatin resistance in cervical Cancer.","authors":"Tong Yan, Mutewaer Muhebuli, Mourboul Ablise, Shulipan Mulati, Wutiekuer Wumaier, Yi Nan Wang, Nuerkaiweisaier Yalikun, Wei Yi Zhang, Zheng Yang","doi":"10.1016/j.bioorg.2026.110411","DOIUrl":"10.1016/j.bioorg.2026.110411","url":null,"abstract":"<p><p>To address the clinical challenge of cisplatin resistance in cervical cancer, a series of 25 novel quinazoline-chalcone derivatives (5a-5w and 10a-10b) was designed and synthesized using a dual-target strategy. Among them, lead compound 5n displayed potent antiproliferative activity against HeLa and cisplatin-resistant HeLa/DDP cells (IC₅₀ = 1.21 μM and 1.88 μM, respectively), achieving a remarkably low resistance index (RI = 1.55) and a high selectivity index (SI = 53.0) over normal H8 cells. Mechanistic studies revealed that 5n strongly inhibited VEGFR-2 kinase (IC₅₀ = 126.4 nM), suppressed its phosphorylation, and effectively reduced HUVEC tube formation. Furthermore, at a non-cytotoxic concentration (0.3 μM), 5n directly blocked the efflux function of P-glycoprotein (P-gp) without altering its expression levels. Notably, co-administration of 5n significantly restored HeLa/DDP cell sensitivity to cisplatin, reducing the RI of cisplatin from 6.07 to 1.49, outperforming the classical inhibitor, verapamil. Molecular dynamics simulations demonstrated that the conformational flexibility of 5n enables stable binding to the distinct active sites of VEGFR-2 and P-gp. In silico ADMET prediction revealed favorable drug-like properties. Coupled with a favorable safety profile in a zebrafish toxicity model, these findings highlight 5n as a promising dual-target lead compound for overcoming cisplatin-resistant cervical cancer.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"181 ","pages":"110411"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786384","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 biological evaluation of selective HDAC6 inhibitors featuring an N-benzyl-2-(aryl/heteroaryl)acetamide cap.","authors":"Tingting Li, Lingfang Wei, He Shi, Wenying Yan, Yujie Sun, Yusha Zhang, Yiteng Wang, Xiangyu Lu, Yan Fu, Zhaobo Liu, Pingfan Yuan, Jie Liu, Yang Zhang, Qingzhong Jia, Xuedong Li","doi":"10.1016/j.bioorg.2026.110427","DOIUrl":"10.1016/j.bioorg.2026.110427","url":null,"abstract":"<p><p>Histone deacetylase 6 (HDAC6) is predominantly localized in the cytoplasm with nucleocytoplasmic shuttling capability. Featuring two tandem catalytic domains and a C-terminal ubiquitin-binding domain, it primarily deacetylates non-histone substrates such as α-tubulin and HSP90. This distinct subcellular localization and substrate profile endow HDAC6 with the unique capacity to orchestrate pivotal roles in cytoskeletal regulation, the cellular stress response, protein degradation, and cell migration, thereby positioning it as a highly attractive target for anti-tumor drug development. Utilizing the previously identified hit compound Hit-063 as a starting point and guided by the classic HDAC inhibitor pharmacophore model, a series of novel compounds incorporating an N-benzyl-2-(aryl/heteroaryl)acetamide fragment were rationally designed and synthesized. Among these analogs, compound 27 (Cmpd_27) was identified as the most promising lead, exhibiting potent nanomolar inhibition against HDAC6 with an IC₅₀ value of 4.29 ± 0.12 nM. Notably, Cmpd_27 demonstrated superior isoform selectivity, with selectivity indices exceeding 150-fold over HDAC1 and HDAC3, as further validated by Western blot analysis. At the cellular level, Cmpd_27 triggered G2/M phase arrest and induced apoptosis in HCT-116 cells, leading to a significant suppression of cell proliferation (IC₅₀ = 0.69 ± 0.04 μM). Moreover, insights derived from quantum chemical analysis of frontier molecular orbitals and molecular dynamics (MD) simulations provide a robust theoretical foundation for the rational design and structural optimization of next-generation selective HDAC6 inhibitors.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"181 ","pages":"110427"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148838682","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":"Glycosylation switches spiramycin from an antibiotic to a hepatoprotective agent by targeting GSTP1.","authors":"Hai-Zhu Jia, Zheng-Shuang Zhu, Li-Li Hong, Ru Lin, Hua Sun, Wei-Qing He, Jian-Qiang Kong","doi":"10.1016/j.bioorg.2026.110448","DOIUrl":"10.1016/j.bioorg.2026.110448","url":null,"abstract":"<p><p>Glycosylation commonly inactivates macrolide antibiotics, and the resulting glycosides are largely dismissed as inactive waste products. Whether such molecules retain hidden therapeutic potential remains underexplored. Here, we address this question using spiramycin I 2'-O-glucopyranoside as a proof-of-concept model. The glycoside was enzymatically synthesized via OleD and structurally confirmed by NMR and HR-ESI-MS. Activity evaluation showed that glycosylation at the 2'-OH position abolished antibacterial activity, adding a new example to glycosylation-mediated antibiotic inactivation. To explore whether this inactivated glycoside harbors alternative functions, we performed in silico target fishing and reverse docking. These approaches identified glutathione S-transferase P (GSTP1) as a high-confidence target, a prediction further supported by molecular dynamics simulations and MM/PBSA calculations. Guided by this hypothesis, we evaluated the glycoside in an acetaminophen (APAP)-induced HepG2 hepatocyte injury model and found that it significantly attenuated cell death, whereas the parent antibiotic exacerbated cytotoxicity. Moreover, glycosylation led to a markedly higher solubility. These findings demonstrate that antibacterially inert glycosides can retain valuable non-antibiotic activities, exemplified here by hepatoprotection via GSTP1 engagement. Beyond this specific case, our study establishes a paradigm for repurposing inactivated antibiotic glycosides as a previously overlooked source of bioactive molecules, advocating for broader re-evaluation of such \"waste\" metabolites in drug discovery.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"181 ","pages":"110448"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148860229","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":"Aggregation-induced BODIPY photosensitizers for synergistic type I/II photodynamic antibacterial therapy.","authors":"De-Chao Yang, Hang Zhu, Chanying Wu, Yangbin Zhuang, Xingye Lai, Yuchang Kang, Siqiao Huang, Jian-Yong Liu, Jianmin Chen, Liyang Du","doi":"10.1016/j.bioorg.2026.110438","DOIUrl":"10.1016/j.bioorg.2026.110438","url":null,"abstract":"<p><p>This study designed two heavy-atom-free boron dipyrromethene (BODIPY) photosensitizers with aggregation-induced emission (AIE) to overcome the aggregation-caused quenching (ACQ) and alleviate heavy-atom toxicity, aiming to enhance the antimicrobial photodynamic therapy (aPDT) of conventional BODIPY. The resulting photosensitizers, TPA-BDP and TPE-BDP, were efficiently synthesized via a one-pot strategy by incorporating triphenylamine or tetraphenylethylene electron donors at the meso-position of the BODIPY core. Upon 525 nm light irradiation, these compounds generate substantial reactive oxygen species (ROS) in the aggregated state without requiring heavy atom substitution. The ROS produced by TPA-BDP and TPE-BDP were identified as singlet oxygen (¹O₂) and superoxide anion (O₂^•-), enabling combined Type I/Type II photodynamic mechanisms that improved antibacterial activity. Antibacterial activity was evaluated against Gram-positive Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA) under irradiation using the plate counting method, with both photosensitizers exhibiting minimum inhibitory concentration below 6 μM. In vivo anti-MRSA efficacy, topical application of these photosensitizers followed by irradiation significantly accelerated wound healing while maintaining excellent biosafety, with the wound healing rate reaching over 90%. Collectively, these heavy-atom-free BODIPY photosensitizers integrate AIE, Type I/II aPDT activity, and in vivo wound-healing performance against MRSA, thus successfully addressing the major limitations of conventional BODIPY photosensitizers.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"181 ","pages":"110438"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148856770","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, anti-oomycete, and anti-fungal activities of novel paeonol derivatives containing carbamate moiety.","authors":"Zimeng Fan, Yihao Guo, Jiaxuan He, Huan Liu, Genqiang Chen, Xiaobo Huang, Yuee Tian, Lin Zhou, Zhiping Che","doi":"10.1016/j.bioorg.2026.110404","DOIUrl":"10.1016/j.bioorg.2026.110404","url":null,"abstract":"<p><p>Paeonol is the main active ingredient in the Chinese medicinal herb peony root bark. In order to discover new compounds with high efficiency and broad-spectrum pesticide biological activity, twenty novel paeonol carbamate derivatives (1a-c, 2a-c, 3a-c, 4a-c, 5a-c, and 1-5dd') were designed and synthesized by ingeniously introducing carbamate pharmacophores, and their structures were well characterized by ¹H NMR, ¹³C NMR, and HRMS. The stereochemical configurations of two target compounds 2c and 3c were unambiguously subjected to single-crystal X-ray diffraction. Moreover, we evaluated the bioactivities of these target compounds as anti-oomycete and anti-fungal agents against two serious agricultural pathogens, Phytophthora capsici and Fusarium graminearum. Amongst evaluated compounds, (1) Seven target compounds 2a, 2b, 3b, 4b, 5a, 5b, and 5dd' exhibited good anti-oomycete against the plant pathogen P. capsici. (2) Three target compounds 5b, 5c, and 5d,d' displayed good anti-fungal against the plant pathogen F. graminearum. (3) When X = Y = Br and R¹ = R² = Et, the corresponding compound 5b exhibits the best anti-oomycete and anti-fungal activity, with EC₅₀ values of 79.03 mg/L and 42.59 mg/L, respectively. Moreover, some interesting results of structure-activity relationships were also observed. This study provides valuable design ideas and theoretical data for further exploring the preparation and pesticide biological activity of paeonol carbamate derivatives.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"181 ","pages":"110404"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786267","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":"Curcumin exerts distinct anti-tumor effects mediated by NRF1α from NRF2 via metabolic reprogramming in hepatocellular carcinoma (HepG2).","authors":"Reziyamu Wufuer, Jing Feng, Shaofan Hu, Meng Wang, Keli Liu, Yiguo Zhang","doi":"10.1016/j.bioorg.2026.110405","DOIUrl":"10.1016/j.bioorg.2026.110405","url":null,"abstract":"<p><p>NRF1α and NRF2, two CNC-bZIP transcription factors, regulate redox homeostasis and metabolic stability, forming a precisely coordinated regulatory network in HCC characterized by functional complementarity and directional antagonism. Although curcumin (CUR), a dietary polyphenol, exerts pleiotropic anti-cancer effects, its clinical application is limited by low bioavailability and undefined molecular targets. This study hypothesized that CUR acts through differential regulation of NRF1α/NRF2-mediated signaling, with NRF1α as the primary effector in HCC. Firstly, we confirmed direct CUR-NRF1α interaction, and CUR stabilizes NRF1α through suppressing proteasomal degradation. Subsequently experiments, using a panel of isogenic HepG2 cell lines (wild-type, NRF1α^-∕-, NRF2^-∕-) and xenograft models, we characterized the dose-dependent effects of CUR on NRF1α expression and systematically compared its downstream pathways involved in oxidative stress resistance and metabolic regulation. CUR exhibited genotype-dependent biphasic effects: it synergistically activated both NRF1α and NRF2 in WT cells, but paradoxically inhibited hyperactive NRF2 in NRF1α-deficient cells. NRF1α mediated the core tumor-suppressive functions via metabolic reprogramming and alleviation of oxidative stress, whereas NRF2 contributed to residual protective effects in the absence of NRF1α. Notably, the anti-tumor efficacy of CUR was largely dependent on intact NRF1α signaling. In xenograft models, CUR showed modest single-agent activity but induced synthetic lethality in NRF1α-deficient tumors by inhibiting NRF2. Collectively, NRF1α acts as the primary effector of CUR in HCC, offering new mechanistic insights. These findings support the development of NRF1α-selective CUR derivatives and highlight NRF1 expression as a candidate predictive biomarker.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"181 ","pages":"110405"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786273","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 iodo-phenanthroimidazole derivatives as potential HDAC1 inhibitors inducing mitophagy to suppress glioblastoma progression.","authors":"Xiaomei Shi, Jiangbo Liang, Zhuoyan Wu, Mengjiao She, Yan Liu, Chunguang Zhu, Ling Fang, Ranxi Dong, Qiong Wu, Wenjie Mei","doi":"10.1016/j.bioorg.2026.110370","DOIUrl":"10.1016/j.bioorg.2026.110370","url":null,"abstract":"<p><p>Glioblastoma, the most prevalent and highly aggressive primary brain tumor, is characterized by high clinical recurrence rates and significant resistance to conventional therapies, highlighting the need for innovative targeted agents to address current treatment limitations. This study employed an integrated computational and experimental strategy to identify novel iodo-phenanthroimidazole derivatives (compounds 1-3). Compound 3 was identified as a lead candidate that inhibits HDAC1 and may trigger autophagy, thereby suppressing glioblastoma progression. Molecular docking and molecular dynamics simulations indicated stable interactions between compound 3 and the HDAC1 catalytic site (estimated binding energies of -7.75 and - 7.74 kcal/mol), with a notable halogen bond between the iodine atom and Asp104. The phenanthroimidazole scaffold was proposed as a potential zinc-binding group (ZBG) for HDAC1 inhibition. Biophysical validation using isothermal titration calorimetry (ITC) confirmed submicromolar binding affinity (Kd = 1.04 × 10^-7 M, ΔH = -91.24 kJ·mol^-1). In vitro evaluation demonstrated potent inhibition of U87-MG glioblastoma cell proliferation (IC₅₀ = 0.23 μM), and flow cytometric analysis indicated concomitant cell cycle arrest at both G2/M and S phases. Transmission electron microscopy revealed autophagic vacuoles containing damaged mitochondria, and immunofluorescence showed an increased LC3-II/LC3-I ratio. Together with the observed loss of mitochondrial membrane potential and ATP depletion, these findings are consistent with the induction of a mitophagy-like process. Using an in vivo zebrafish orthotopic glioblastoma model, the lead compound demonstrated blood-brain barrier penetration and effectively suppressed tumor growth and U87-MG cell metastasis. This work highlights the potential of iodo-phenanthroimidazole derivatives as a novel therapeutic strategy for glioblastoma. The data support a model in which HDAC1 inhibition is associated with mitochondrial dysfunction and mitophagy, contributing to tumor suppression.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"181 ","pages":"110370"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786344","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":"Sulfated fuco-oligosaccharides from Acaudina leucoprocta: Structural characterization and anticoagulant activity.","authors":"Zhengwei Ying, Haroon Khan, Li Peipei, Huicheng Yang, Lingyan Wang, Manman Chen, Chunyu Niu, Syed Shams Ul Hassan, Yan Chen, Leifang Zhang, Yin Chen, Yanlei Yu","doi":"10.1016/j.bioorg.2026.110307","DOIUrl":"10.1016/j.bioorg.2026.110307","url":null,"abstract":"<p><p>Sulfated fucans from sea cucumbers are potent anticoagulants, but their structural complexity has hindered understanding of their structure-activity relationship at the oligosaccharide level. Herein, we report the preparation, structural characterization, and anticoagulant evaluation of structurally defined sulfated fuco-oligosaccharides from the sea cucumber, Acaudina leucoprocta. Crude polysaccharides were fractionated by anion-exchange chromatography to obtain a fucan sulfate fraction (WS-0). Mild acid hydrolysis of WS-0 generated an oligosaccharide mixture, which was purified by sequential Bio-Gel P-2 and anion-exchange chromatography, yielding a series of oligosaccharide fractions with degrees of polymerization (DP) ranging from 1 to 9. Their structures were elucidated using ESI-MS, MS/MS, and 800 MHz NMR spectroscopy. Two structurally defined fuco-disaccharides were obtained: α-L-Fucp2S4S-(1 → 3)-α/β-L-Fucp (dWS0-4-0.14) and a mixture of α-L-Fucp2S-(1 → 3)-α/β-L-Fucp and α-L-Fucp4S-(1 → 3)-α/β-L-Fucp (dWS0-4-0.05). Among the oligosaccharide fractions, dWS0-3-1 (DP 3-6) exhibited the strongest anticoagulant activity, prolonging APTT to 47.4 ± 4.7 s and TT to 43.2 ± 1.0 s at 400 μg/mL, while showing minimal effect on PT. Comparative analysis revealed that both chain length and sulfation pattern co-determine anticoagulant potency, with 2,4-di-O-sulfation enabling shorter chains to inhibit thrombin. This study provided the first structural map of anticoagulant fuco-oligosaccharides from A. leucoprocta, identifying minimal structural motifs for activity and offering promising leads for developing novel antithrombotic agents.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"181 ","pages":"110307"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786353","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":"FRET-based hypoxia-responsive self-quenching BODIPY nanoparticles enhance lung cancer efficacy while avoiding skin toxicity.","authors":"Chen Guo, Shanshan Chen, Jia Li, Lili Su, Yangmei Xu, Jianyong Liu, Qinying Liu","doi":"10.1016/j.bioorg.2026.110416","DOIUrl":"10.1016/j.bioorg.2026.110416","url":null,"abstract":"<p><p>Photodynamic therapy is a promising antitumor modality with significant potential for clinical translation. Given phototoxicity, the development of photosensitizers that exhibit high tumor selectivity continues to be a critical research priority. To suppress the activity of photosensitizers in non-target tissues, a photosensitizer named BDP-Q was designed, comprising a pair of BODIPY derivatives that exhibit intramolecular fluorescence resonance energy transfer (FRET) effects, linked via an azobenzene bond to respond to azoreductase overexpressed in hypoxic tumor microenvironments. BDP-Q displayed nearly complete fluorescence quenching under normal conditions and reducing environment-responsive properties. Furthermore, polyethylene glycol-block-polycaprolactone (PEG-b-PCL) was used to encapsulate BDP-Q to enhance water solubility, thereby facilitating biological applications. BDP-Q nanoparticles (BDP-Q NPs) exhibited over 15.74-fold and 48.47-fold higher ROS production in hypoxic A549 and H226 cells, respectively, compared to normoxic cells, and this effect was inhibited by the azoreductase inhibitor diphenyleneiodonium chloride (DPI). Moreover, BDP-Q NPs demonstrated significant cytotoxicity against A549 cells, having an IC₅₀ of 0.5962 μM in vitro and a 97.6% tumor inhibition rate in vivo. Importantly, unlike conventional photosensitizers, BDP-Q NPs caused no skin damage even under laser irradiation. In summary, this study presents a safe and effective hypoxia-responsive BODIPY-based photosensitizer with significant potential for clinical application.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"181 ","pages":"110416"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786416","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}