Bioorganic Chemistry最新文献

{"title":"Simultaneous visualization of lipid droplets and tracking of the endogenous hypochlorous acid in psoriatic mice models with a novel fluorescent probe in a wash-free fashion.","authors":"Xuan Zhao, Xiaoxue Hu, Longxuan Li, Yuanping Liu, Boshuang Song, Yuzhi Li, Zhixing Cao, Houcheng Zhou, Cheng Peng, Yun Deng, Yuyu Fang","doi":"10.1016/j.bioorg.2024.107967","DOIUrl":"10.1016/j.bioorg.2024.107967","url":null,"abstract":"<p><p>Psoriasis is an autoimmune inflammation-related disease accompanied by a variety of complications. Reactive oxygen species (ROS) are modulators of inflammation, and their excessive production caused by oxidative/anti-oxidative imbalance has been observed in psoriatic patients. Hypochlorous acid (HOCl) is a ROS produced by myeloperoxidase (MPO) from chloride ions (Cl^-) and hydrogen peroxide (H₂O₂). Endogenous HOCl has recently been studied as a potential biomarker of psoriasis underlying the necessity for the development of efficient analytical tools for its detection and real time monitoring. Herein, we designed a novel highly sensitive and selective coumarin-based fluorescent probe for HOCl detection, named CN₂-CF₃-S. The probe itself featured negligible fluorescence because of the heavy atom effect of the thiocarbonyl group. However, upon responding to HOCl a conversion to sulfur-free derivative CN₂-CF₃-O occurs, resulting in a dramatical fluorescent enhancement setting the detection limit for HOCl of 3.2 nM. The HOCl-recognition mechanism could be ascribed to the HOCl-triggered oxidative desulfurization process that agrees with liquid chromatography-mass spectrometry (LC-MS) analysis and density functional theory (DFT) computations. The probe's design incorporated a synergistic combination of two structural features for efficient lipid droplets (LDs)-targeting imaging. An efficient push-pull system reinforced by the presence of two strongly electron-donating dimethylamino groups equipped CN₂-CF₃-O with pronounced solvatochromism realized through the enhanced blue-shifted emission in non-polar media. Meanwhile, the presence of trifluormethylphenyl moiety at the acceptor side led to an increased lipophilicity. The CN₂-CF₃-S probe has been successfully utilized to track the endogenous HOCl in cells and on skin of the psoriatic mice in a wash-free manner. As a result, we have demonstrated that the concentration of HOCl in skin might correlate positively with the degree of inflammation in psoriasis. Thus, CN₂-CF₃-S constitutes the first example of LDs-imaging fluorescent probe for detecting the psoriasis-linked HOCl, offering a convenient tool for further in-depth investigation of psoriasis pathophysiology.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107967"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692205","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":"Enabling oral novel Taxanes-based Chemotherapy with Lipophilic prodrug Self-nanoemulsifying drug delivery system.","authors":"Yifan Miao, Jinrui Liu, Hongying Xiao, Jia Deng, Wenqian Xu, Can Zhao, Qian Lu, Zhonggui He, Bingjun Sun, Chutong Tian, Jin Sun","doi":"10.1016/j.bioorg.2024.107902","DOIUrl":"10.1016/j.bioorg.2024.107902","url":null,"abstract":"<p><p>Larotaxel (LTX) and SB-T-1214 (SBT), two new synthetic experimental toxoids, have shown broad-spectrum antitumor activity, especially against tumors that are resistant to other drugs. However, their poor solubility, membrane permeability, and first-pass effect limits their use in oral administration. We designed and synthesized two long-chain triglyceride-mimic prodrugs of LTX (LTXSSTG) and SBT (SBTSSTG), which are bridged by disulfide bonds and efficiently incorporated them into Self-nanoemulsifying drug delivery system (SNEDDS). These prodrugs can bypass hepatic metabolism by entering the blood through intestinal lymphatic transport, following a similar oral absorption pathway to dietary lipids. It was found that LTXSSTG and SBTSSTG significantly improved oral bioavailability (about 4.5-fold for LTX and 3.4-fold for SBT) compared to their solution forms. Moreover, with LTXSSTG and SBTSSTG incorporating reduction stimulus-responsive spacer were much more effective in suppressing tumor growth in vivo with eliminated adverse effects than solution form. To sum up, this strategy provides a new avenue to enhance oral delivery of new toxoids.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107902"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491809","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":"The RIP3 activator C8 regulates the autophagy flux mediated by p62 and promotes the immunogenic form of cell death in human gastric cancer cells.","authors":"Xiaojie Liu, Yubin Jin, Mengli Zhang, Yanhe Jin, Jie Cao, Hangqi Dong, Xiangjing Fu, Cheng-Yun Jin","doi":"10.1016/j.bioorg.2024.107937","DOIUrl":"10.1016/j.bioorg.2024.107937","url":null,"abstract":"<p><p>There has been growing interest in investigating anti-tumor drugs that not only kill cancer cells but also stimulate the immune system, among them, necroptosis is a classical immunogenic form of cell death. In our study, we discovered that by targeting RIP3, Jaspine B derivative C8 induces necroptosis and initiates cell death, and this effect can be reversed by knockout of RIP3. Furthermore, RIP3 initiates autophagy and binds to p62 to inhibit autophagic flux. Additionally, the autophagy process mediated by RIP3 activates the Nrf2 signaling pathway via the formation of the p62/Keap1 complex. Early autophagy inhibitors enhance necroptosis by impending the accumulation of p62 and restraining the activation of Nrf2, whereas late autophagy inhibitors partially prevent C8-induced necroptosis. Notably, the immunogenic form of cell death induced by C8 did not affect tumor immunity. Overall, C8 functions as a RIP3 activator to suppress the development of gastric cancer. Upon activation, RIP3 regulates p62-mediated autophagic flux and the Nrf2 signaling pathway through the RIP3/p62/Keap1 axis.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107937"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613408","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 novel (E)-2-cyano-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl) derivatives as potent STAT3-targeting anticolorectal cancer agents.","authors":"Weiqing Jiang, Pingxian Liu, Zhangxun Zhao, Dongmei Fan, Xinlian He, Yunhan Jiang, Tao Yang","doi":"10.1016/j.bioorg.2024.107955","DOIUrl":"10.1016/j.bioorg.2024.107955","url":null,"abstract":"<p><p>Dysregulation of signal transducer and activator of transcription 3 (STAT3) is implicated in the pathogenesis of various cancers, underscoring its potential as a cancer therapeutic target. In this work, we designed and synthesized a novel series of (E)-2-cyano-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl) derivatives and evaluated their anti-proliferative effects on tumour cells. Among these derivatives, NW16 exhibited remarkable antiproliferative activity against HCT116 cells, with an IC₅₀ value of 0.28 μM, and exhibited dose- and time-dependent inhibition of the JAK/STAT3 signalling pathway. In addition, NW16 induced reactive oxygen species (ROS) production, which subsequently suppressed the ROS-dependent PI3K/AKT pathway and enhanced its antitumour efficacy. In vivo studies confirmed significant tumour-suppressive effects upon oral administration of NW16 along with favourable tolerability in a colorectal cancer xenograft model. These results indicate that NW16 could be a promising candidate for developing targeted therapy for colorectal cancer because of its multifaceted mechanism.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107955"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692202","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":"Naphthyl-functionalized acetamide derivatives: Promising agents for cholinesterase inhibition and antioxidant therapy in Alzheimer's disease.","authors":"Lorena Camargo-Ayala, Luis Prent-Peñaloza, Edison Osorio, Paola Andrea Camargo-Ayala, Claudio A Jimenez, Felipe Zúñiga-Arbalti, Iván Brito, Gerzon E Delgado, Margarita Gutiérrez, Efraín Polo-Cuadrado","doi":"10.1016/j.bioorg.2024.107896","DOIUrl":"10.1016/j.bioorg.2024.107896","url":null,"abstract":"<p><p>This study presents the synthesis and characterization of a series of 13 novel acetamides. These were subjected to Ellman's assay to determine the efficacy of the AChE and BChE inhibitors. Finally, we report their antioxidant activity as an alternative approach for the search for drugs to treat AD. These studies revealed that compounds 1a-1k and 2l-2m were obtained in moderate yield. Four amides (1h, 1j, 1k, and 2l) were selective for one of the enzymes (BChE); thus, those that inhibited BChE were more active than the positive control (galantamine) and showed better IC₅₀ values (3.30-5.03 µM). The theoretical free binding energies calculated by MM-GBSA indicated that all inhibitors were more stable than rivastigmine, and the inhibition mechanisms involved the entire active site: peripheral anionic site, oxyanion hole, acyl-binding pockets, and catalytic site. We examined the cytotoxicity of compounds 1h, 1j, 1k, and 2l in human dermal cells and found that they did not exhibit any toxic effects under the tested conditions. Additionally, these compounds, which also inhibited BChE, displayed mixed inhibition and did not exhibit hemolytic effects on human erythrocytes. Furthermore, the ABTS and DPPH assays indicated that, although none of the compounds showed activity in the DPPH assay, the EC₅₀ values for radical trapping by the ABTS method showed that compounds 1a, 1d, 1e, and 1g had EC₅₀ values lower than 10 µg/mL, indicating their strong radical scavenging capacity. We also report the crystal structures of compounds 1c, 1d, 1f, and 1g, which are found in monoclinic crystal systems.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107896"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491810","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":"Interpret the potential role of zinc against oxidative stress in inflammation with a practical fluorescent assay.","authors":"Zengyan Lin, Lanlan Zhang, Daliang Li","doi":"10.1016/j.bioorg.2024.107886","DOIUrl":"10.1016/j.bioorg.2024.107886","url":null,"abstract":"<p><p>Zinc plays a critical role in inflammation and apoptosis, potentially offering new insights into health and disease beyond its established involvement in various biological processes. A fluorescent probe, SPI, has been designed and synthesized for the real-time detection of dynamic changes of zinc ions (Zn²⁺) in the potential resistance to oxidative stress, showing fluorescence enhancement at approximately 639 nm with a limit of detection of around 65 pM, which allowed it to identify even low concentrations of Zn²⁺ with intrinsic excellent biocompatibility. By establishing a cellular inflammation and apoptosis model using HT-DNA, hydrogen peroxide (H₂O₂), and dexamethasone (DXMS), the study effectively simulates conditions that can alter Zn²⁺ dynamics. Monitoring the fluorescence changes of SPI in response to these conditions allows researchers to observe how Zn²⁺ levels fluctuate in real-time, providing a clearer picture of its role in maintaining intracellular redox homeostasis. The findings indicate that SPI can be instrumental in elucidating the detailed molecular mechanisms through which Zn²⁺ influences immune responses and associates with cellular stress pathways. Overall, the development of SPI not only replenishes a potential assay into the toolbox to study Zn²⁺ in living cells but also opens new avenues for the further investigations into the therapeutic potential of modulating zinc levels in various pathological conditions.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107886"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566738","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 Macrocyclic small molecules Based on 2-Amino-4-thiazolylpyridineas selective EGFR inhibitors with high Blood-Brain barrier penetration for the treatment of glioblastoma.","authors":"Guowu Wu, Mingfeng Zhou, Fengqiu Guo, Yong Lin, Yongxin Chen, Yifan Kong, Jun Xiao, Shanhe Wan, Zhonghuang Li, Xiaoyun Wu, Tingting Zhang, Jiajie Zhang","doi":"10.1016/j.bioorg.2024.107905","DOIUrl":"10.1016/j.bioorg.2024.107905","url":null,"abstract":"<p><p>Because epidermal growth factor receptor (EGFR) is the most commonly mutated oncogene in glioblastoma (GBM), the development of EGFR inhibitors has become a promising direction for the treatment of GBM. However, due to factors such as limited blood-brain barrier (BBB) permeability and pathway compensation mechanisms, current EGFR inhibitors targeting GBM are not satisfactory. In the previous study, we obtained compound 10c with strong anti-cell proliferation activity. Since macrocyclization can effectively change the physical and chemical properties of molecules, and optimize their selectivity. Therefore, a series of 2-amino-4-thiazolyl pyridine scaffold macrocyclic derivatives were designed and synthesized using compound 10c as the lead compound in this study. Compound 3a, which inhibited the growth of glioblastoma cell lines U87MG and U87-EGFRVIII, had average IC₅₀ values of 4.69 µM and 4.98 µM, respectively. Compound 3a was highly selective to 9 kinases in the ErbB family, including ErbB2 and ErbB4. In addition, compound 3a demonstrated good blood-brain barrier permeability in mice, the blood-brain concentration of the drug remained above 20 % within 5-60 min following intravenous administration in mice. In conclusion, compound 3a is a promising candidate for novel EGFR inhibitors targeting GBM.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107905"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542469","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":"Structurally diverse phenylpropanoyl phloroglucinol derivatives from Mallotus philippensis and their anti-bacterial activities.","authors":"Yeqi Chen, Wenlin Zheng, Xun Song, Dabo Pan, Yue Zhuo, Zhenzhen Yang, Qi Wang, Yan Wu, Jihong Gu","doi":"10.1016/j.bioorg.2024.107918","DOIUrl":"10.1016/j.bioorg.2024.107918","url":null,"abstract":"<p><p>Fifteen undescribed phenylpropanoyl phloroglucinol derivatives featuring modified isoprenyl and/or geranyl units (1-15), in conjunction with thirteen known analogues (16-28), were obtained from the glandular hairs of the fruit of Mallotus philippensis. Meanwhile, fourteen pairs of new enantiomers [(±)-1-9, (±)-11-15] were further resolved by chiral purification. Their structures were determined by comprehensive spectroscopic analyses, single-crystal X-ray diffraction experiments and quantum chemical calculations. Bioactivity evaluation showed that compound 17 exhibited significant anti-bacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) with MIC of 6 μg/mL, while compounds 3, 4, 8 and 18 displayed moderate effects with MIC of 24, 12, 24, and 12 μg/mL, respectively. The KEGG enrichment analysis of 17 revealed that the phosphotransferase system (PTS) pathway was significantly enriched. In addition, compound 17 was found to affect the amino acids biosynthesis and amino acids/carbohydrate metabolism, and the qRT-PCR verified the accuracy of the transcriptome analysis.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107918"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556566","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":"A FRET probe based on flavonol-benzothiazole for the detection of viscosity and SO₂ derivatives.","authors":"Wei Xiao, Qing Zhang, Dong Hui You, Nian Bing Li, Guang Ming Zhou, Hong Qun Luo","doi":"10.1016/j.bioorg.2024.107913","DOIUrl":"10.1016/j.bioorg.2024.107913","url":null,"abstract":"<p><p>Sulfur dioxide (SO₂) and viscosity play important roles in living organisms, and abnormal levels of them are associated with many diseases. Hence, a bifunctional fluorescence probe (E)-3-(2-(4-(4-(4-(6-fluoro-3-hydroxy-4-oxo-4H-chromen-2-yl)benzoyl)piperazin-1-yl)styryl)benzo-[d]thiazol-3-ium-3-yl)propane-1-sulfonate (HFBT) with fluorescence resonance energy transfer (FRET) properties was successfully constructed by using 3-hydroxyflavonol as the energy donor and benzothiazole sulphonate derivatives as the energy acceptor, and it can be used for the detection of SO₂ derivatives (HSO₃^-/HSO₃^2-) and viscosity. HFBT exhibits a large Stokes shift (245 nm), high resonance energy transfer efficiency (95.56 %), and excellent selectivity, anti-interference and low limit of detection (LOD = 0.057 μM) for HSO₃^-. The fluorescence intensity of HFBT at 596 nm gradually increases with the increase of viscosity. Interestingly, a visual HSO₃^- detection platform was successfully constructed and applied to the quantitative detection of HSO₃^- in food. Additionally, HFBT was successfully applied to imaging endogenous and exogenous HSO₃^- in cells. The successful development of HFBT provides an effective tool for the detection and imaging of HSO₃^- in food and cells.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107913"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556565","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":"Towards antimicrobial agents: Design and antibacterial activity of a hybrid fluorophore where porphyrin and Rose Bengal moieties are linked through the hydroxyl group of a xanthene dye.","authors":"G Mamardashvili, E Kaigorodova, N Solomonova, N Mamardashvili","doi":"10.1016/j.bioorg.2024.107960","DOIUrl":"10.1016/j.bioorg.2024.107960","url":null,"abstract":"<p><p>The axial complex of Sn(IV)-tetra(4-sulfophenyl)porphyrin (SnP) with Rose Bengal (RB) was obtained where RB axial binding is realized through the hydroxyl groups of the xanthene dye [SnP(RB)₂]. The luminescent properties of the SnP(RB)₂ (fluorescence and ability to generate singlet oxygen at room temperature) in aqueous media with additives of surfactant cetylpyridinium chloride (CPC) and ε-poly-l-lysine (EPL) were studied. It was found that nature of the medium (surfactant additives of different concentrations) determines the effectiveness of the photoinduced energy transfer from the RB fragment to the SnP fragment of the hybrid fluorophore (HF). It has been established that the ability of the HF to generate singlet oxygen in D₂O and D₂O-micellar media is higher than that of its constituent fragments. The dark and photodynamic antibacterial activity of the HF against two microorganisms [Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus)] was determined and analyzed. It was shown how the antibacterial activity of the HF depends on the nature of the bacteria, the micellar environment and radiation dose.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107960"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666342","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}