Bioorganic Chemistry最新文献_第2页

Repurposing tavaborole to combat resistant bacterial infections through competitive inhibition of KPC-2 and metabolic disruption

IF 4.5 2区医学

Bioorganic Chemistry Pub Date : 2025-03-26 DOI: 10.1016/j.bioorg.2025.108421

Minda Liu , Tianqi Fang , Shanshan Wang , Hongxia Ma , Lingcong Kong , Xuming Deng , Zihao Teng , Jianfeng Wang , Peng Zhang , Lei Xu

{"title":"Repurposing tavaborole to combat resistant bacterial infections through competitive inhibition of KPC-2 and metabolic disruption","authors":"Minda Liu , Tianqi Fang , Shanshan Wang , Hongxia Ma , Lingcong Kong , Xuming Deng , Zihao Teng , Jianfeng Wang , Peng Zhang , Lei Xu","doi":"10.1016/j.bioorg.2025.108421","DOIUrl":"10.1016/j.bioorg.2025.108421","url":null,"abstract":"<div><div>The rise of carbapenem-resistant <em>Enterobacteriaceae</em> (CRE) strains has emerged as an increasing threat to global public health. The development of antibiotic adjuvants presents an economical and promising approach to address this crisis. Through a high-throughput screen of the FDA-approved compound library, we identified tavaborole (AN2690) as a broad-spectrum β-lactamase inhibitor. The mechanistic study revealed that tavaborole formed a reversible binding with the active serine of KPC-2, showing effective competitive inhibition. Its electron-deficient boron atom formed a borate ester bond with hydroxyl group of the serine residue at the active site of KPC-2, transitioning to an sp3-hybridized state that mimicked the tetrahedral intermediate during KPC-2 catalytic. Moreover, transcriptomic analysis and bacterial metabolism assays further unveiled tavaborole addition can inhibit tricarboxylic acid (TCA) cycle, coupled with downregulation of intracellular ATP levels, indicating that tavaborole compromised the bacterial metabolic homeostasis and exerted synergistic antibacterial activity. Notably, the combination treatment further suppressed the development of meropenem resistance. In mouse intraperitoneal infection models, tavaborole effectively restored the efficacy of meropenem against CRE bacteria. These findings elucidate the synergistic mechanisms of tavaborole, expand its potential applications in anti-infection therapeutics, and provide a promising strategy for addressing CRE infections.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108421"},"PeriodicalIF":4.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143761052","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}

引用次数: 0

Synthesis of mPEG-functionalized betulin-based maleic derivatives and unraveling the effect of PEGylation on dental restorative resins

IF 4.5 2区医学

Bioorganic Chemistry Pub Date : 2025-03-26 DOI: 10.1016/j.bioorg.2025.108415

Zhiyuan Ma, Yifan Chen, Wei Sun, Ruili Wang

{"title":"Synthesis of mPEG-functionalized betulin-based maleic derivatives and unraveling the effect of PEGylation on dental restorative resins","authors":"Zhiyuan Ma, Yifan Chen, Wei Sun, Ruili Wang","doi":"10.1016/j.bioorg.2025.108415","DOIUrl":"10.1016/j.bioorg.2025.108415","url":null,"abstract":"<div><div>As a derivative of bisphenol A (BPA), bisphenol A glycidyl dimethacrylate (Bis-GMA) is questioned regarding its endocrine-disrupting properties. We previously reported a plant-derived monomer, betulin-based maleic diester derivative (MABet), as a substitute for Bis-GMA, but its yellow powdery appearance greatly affected the viscosity and aesthetics of dental resins. Herein, we synthesized three novel types of mPEG-functionalized MABet (P<sub>n</sub>MABet) by leveraging the active carboxylic acid groups of MABet to undergo a DCC coupling reaction with mPEG variants with diverse repeating ethylene glycol units (<em>n</em> = 7, 12, and 16). Their chemical structures were validated using <sup>1</sup>H and <sup>13</sup>C NMR spectroscopy, FT-IR spectroscopy, and HR-MS. Afterwards, the P<sub>n</sub>MABet were incorporated into Bis-GMA-based resins at 10, 30, and 50 wt%. The mechanical performance was firstly evaluated to determine the optimal monomer content. The results showed that all P<sub>n</sub>MABet monomers were light-yellow liquids. Increasing their concentration from 10, 30, to 50 wt% and the number of repeating units of mPEG from 7, 12, to 16 significantly reduced the mechanical property of resins. Of all groups, 10 wt% addition of P<sub>7</sub>MABet endowed the resulting 1P<sub>7</sub>M4B5T resin with the highest flexural and compressive strength (123.2 ± 10.3 MPa; 296.6 ± 27.5 MPa) than the 5B5T control (70.0 ± 6.4 MPa; 230.5 ± 22.5 MPa). This resin also exhibited comparable viscosity, polymerization conversion, cytotoxicity to 5B5T without antibacterial activity. The developed P<sub>n</sub>MABet have the potential to modulate resin viscosity. Exploring the structure-property relationship is beneficial to realize monomer design and regulate resin properties.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108415"},"PeriodicalIF":4.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143725432","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}

引用次数: 0

Design and synthesis of a highly polarity-sensitive fluorescent probe and its application in tumor cell imaging

IF 4.5 2区医学

Bioorganic Chemistry Pub Date : 2025-03-26 DOI: 10.1016/j.bioorg.2025.108399

Lumen Chao , Gerile Aodeng , Lu Ga , Jun Ai

{"title":"Design and synthesis of a highly polarity-sensitive fluorescent probe and its application in tumor cell imaging","authors":"Lumen Chao , Gerile Aodeng , Lu Ga , Jun Ai","doi":"10.1016/j.bioorg.2025.108399","DOIUrl":"10.1016/j.bioorg.2025.108399","url":null,"abstract":"<div><div>Among cancer patients, those in advanced stages generally face higher mortality rates, highlighting the importance of early diagnosis in improving cure rates and survival outcomes. Compared to normal cells, tumor cells exhibit a lower polarity in their microenvironment, providing a promising avenue for early cancer detection. It is feasible to distinguish tumor cells from normal cells by leveraging the fluorescence response of probes to polarity. In this study, we designed a fluorescence probe, PCC, with high sensitivity to polarity for early cancer diagnosis. The probe demonstrated a remarkable fluorescence intensity increase of 100-fold in a low-polarity solvent (1,4-dioxane) compared to a high-polarity solvent (water). Additionally, PCC exhibited excellent tumor-targeting ability, large Stokes shift, strong anti-interference capability, and high photostability. When applied to tumor cells (HeLa and CT26、SGC-7901) and normal cells (RAW 264.7、HUVEC、L-02), the probe produced a fluorescence intensity difference exceeding fourfold. These findings indicate that PCC, as a polarity-sensitive fluorescence probe, holds significant promise for early cancer diagnosis.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108399"},"PeriodicalIF":4.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734581","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}

引用次数: 0

Antibody-drug conjugates and radioconjugates targeting carbonic anhydrase IX and XII in hypoxic tumors: Bench to clinical applications

IF 4.5 2区医学

Bioorganic Chemistry Pub Date : 2025-03-25 DOI: 10.1016/j.bioorg.2025.108408

Sridhar Goud Nerella , Mahammad Ghouse Shaik , Priti Singh , Mohammed Arifuddin , Qasim Ullah , Claudiu T. Supuran

{"title":"Antibody-drug conjugates and radioconjugates targeting carbonic anhydrase IX and XII in hypoxic tumors: Bench to clinical applications","authors":"Sridhar Goud Nerella , Mahammad Ghouse Shaik , Priti Singh , Mohammed Arifuddin , Qasim Ullah , Claudiu T. Supuran","doi":"10.1016/j.bioorg.2025.108408","DOIUrl":"10.1016/j.bioorg.2025.108408","url":null,"abstract":"<div><div>Treating hypoxic tumors is challenging due to their aggressive nature, resistance to standard treatments, often leading to poor outcomes. Hypoxic tumors create a unique environment that reduces the effectiveness of traditional treatments such as chemotherapy and radiotherapy. Human carbonic anhydrases (hCA IX and hCA XII) are involved in tumors survival and metabolism by regulating pH homeostasis, ferroptosis, metastatization, and other processes. Developing drugs that specifically target these enzymes has been demonstrated to disrupt the tumor survival mechanisms, leading to significant antitumor effects. This review discusses recent developments on antibody-drug conjugates (ADCs) and radioconjugates targeting hCA IX and hCA XII in hypoxic tumors. New approaches based on small molecule inhibitors and monoclonal antibodies such as girentuximab provided encouraging results in preclinical research and clinical trials. These advances highlight the potential of hCA-targeted therapies to improve cancer treatment for hypoxic tumors.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108408"},"PeriodicalIF":4.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143704562","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}

引用次数: 0

Emerging fluorescent probes for bioimaging of drug-induced liver injury biomarkers: Recent advances

IF 4.5 2区医学

Bioorganic Chemistry Pub Date : 2025-03-24 DOI: 10.1016/j.bioorg.2025.108407

Qingqing Jiang , Ran Chen , Meng Li , Tianyu Zhang , Ziyuzhu Kong , Kaifu Ma , Chao Ye , Xiaohan Sun , Wei Shu

{"title":"Emerging fluorescent probes for bioimaging of drug-induced liver injury biomarkers: Recent advances","authors":"Qingqing Jiang , Ran Chen , Meng Li , Tianyu Zhang , Ziyuzhu Kong , Kaifu Ma , Chao Ye , Xiaohan Sun , Wei Shu","doi":"10.1016/j.bioorg.2025.108407","DOIUrl":"10.1016/j.bioorg.2025.108407","url":null,"abstract":"<div><div>Drug-induced liver injury (DILI) has emerged as a significant concern in clinical settings, being one of the leading causes of acute liver failure. However, the specific pathogenesis of DILI remains unclear, and there is currently a lack of effective targeted therapies. Numerous studies have demonstrated that the occurrence and progression of DILI involve complex pathological processes, closely linked with various cellular substrates and microenvironments. Thus, developing non-invasive, highly sensitive, specific, and reliable methods to detect changes in biomarkers and microenvironments <em>in situ</em> would greatly aid in the precise diagnosis of DILI and help guide therapeutic interventions. Fortunately, fluorescence imaging technology has shown great promise in detecting biological species, microenvironments, and diagnosing DILI due to its superior detection capabilities. In this context, this review described the design strategies, working principles, and practical applications of small molecule fluorescent probes for monitoring biological species and microenvironments in DILI. Importantly, this review highlighted current limitations and future development directions, which may help uncover the underlying relationships between biological species, microenvironments, and DILI. This understanding could lead to potential diagnostic protocols and establish a platform for evaluating treatments and drug efficacy in DILI.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108407"},"PeriodicalIF":4.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715881","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}

引用次数: 0

Discovery of 6-amino pyridine clubbed heterocycles as potent dual GSK-3β/CK-1δ inhibitors for the treatment of Alzheimer's disease

IF 4.5 2区医学

Bioorganic Chemistry Pub Date : 2025-03-24 DOI: 10.1016/j.bioorg.2025.108409

Vinita Sharma , Jurnal Reang , Vivek Yadav , Prabodh Chander Sharma , Jaseela Majeed , Kalicharan Sharma

{"title":"Discovery of 6-amino pyridine clubbed heterocycles as potent dual GSK-3β/CK-1δ inhibitors for the treatment of Alzheimer's disease","authors":"Vinita Sharma , Jurnal Reang , Vivek Yadav , Prabodh Chander Sharma , Jaseela Majeed , Kalicharan Sharma","doi":"10.1016/j.bioorg.2025.108409","DOIUrl":"10.1016/j.bioorg.2025.108409","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a progressive and chronic neurodegenerative disorder progression through various kinases. Glycogen synthase kinase 3<em>β</em> (GSK-3<em>β</em>) and Casein Kinase-1<em>δ</em> (CK-1<em>δ</em>) have gained a lot of attention for its role in tau pathology. Utilizing a multitarget strategy, a series of 6-amino pyridine derivatives were developed as promising dual GSK-3<em>β</em>/CK-1<em>δ</em> inhibitors for the treatment of AD. This study involved the design, synthesis, and evaluation of novel 6-amino pyridine derivatives as dual GSK-3<em>β</em>/CK-1<em>δ</em> inhibitors exhibiting excellent biological activities. The <em>in-vitro</em> results indicated that most of compounds displayed promising activity against GSK-3<em>β</em>/CK-1<em>δ</em>. Among the tested compounds, <strong>8d</strong> exhibited strong inhibitory activity against GSK-3<em>β</em> and CK-1<em>δ</em>, with IC₅₀ values of 0.77 ± 0.01 μM and 0.57 ± 0.12 μM, respectively. Notably, compound <strong>8d</strong> significantly reduced tau hyperphosphorylated aggregates while demonstrating safety in SH-SY5Y neuroblastoma cell lines. ADME prediction results indicated that compound <strong>8d</strong> adhered to Lipinski's rule of five and exhibited potential to permeate the blood-brain barrier (BBB). Molecular docking analysis revealed that this compound fits well within the ATP binding site, forming hydrogen bonds between its 6-amino pyridine ring with key amino acids, including Asp133 and Val135 in the hinge region of GSK-3<em>β</em>, as well as Leu85 of CK-1<em>δ</em>. These findings indicate that 6-amino pyridine derivatives have the potential to be effective dual-target candidates for AD.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108409"},"PeriodicalIF":4.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143704560","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}

引用次数: 0

Recent advance in macrolactams: Structure, bioactivity, and biosynthesis

IF 4.5 2区医学

Bioorganic Chemistry Pub Date : 2025-03-24 DOI: 10.1016/j.bioorg.2025.108406

Jiawei Qiu , Ruochang Qin , Shuai Zhi , Liwei Liu

{"title":"Recent advance in macrolactams: Structure, bioactivity, and biosynthesis","authors":"Jiawei Qiu , Ruochang Qin , Shuai Zhi , Liwei Liu","doi":"10.1016/j.bioorg.2025.108406","DOIUrl":"10.1016/j.bioorg.2025.108406","url":null,"abstract":"<div><div>Macrolactams have garnered significant attention in recent years due to their diverse structures and remarkable biological activities. Despite the increasing number of new members being reported, a systematic discussion of recent advancements in this family is still lacking, particularly in areas such as structure-activity relationship and newly identified biosynthetic pathways that deviate from the traditional collinear rule. To address this gap, we compiled 105 macrolactams reported between 2004 and 2023, produced by microbial strains isolated from diverse environments, including marine sediments, soil, plants, and animals. This review not only highlights the sources, structures, and biological activities of these macrolactams but also delves into 17 known biosynthetic pathways. We provide an in-depth analysis of the associated biosynthetic gene clusters, the mechanisms of key enzymes, and their roles in the biosynthesis process. By offering these insights, this review serves as a valuable reference for the discovery of novel macrolactams and their sustainable production using synthetic biology approaches in the future.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108406"},"PeriodicalIF":4.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143760934","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}

引用次数: 0

Capturing and releasing cucurbitacins with α, β-unsaturated group from Cucumis melo based on reversibility of thia-Michael addition reaction

IF 4.5 2区医学

Bioorganic Chemistry Pub Date : 2025-03-23 DOI: 10.1016/j.bioorg.2025.108404

Tianyu Zhu , Liangyong Hu , Hang Hu , Yujie Li , Jiangmin Zhu , Guanzhao Wu , Defeng Xu

{"title":"Capturing and releasing cucurbitacins with α, β-unsaturated group from Cucumis melo based on reversibility of thia-Michael addition reaction","authors":"Tianyu Zhu , Liangyong Hu , Hang Hu , Yujie Li , Jiangmin Zhu , Guanzhao Wu , Defeng Xu","doi":"10.1016/j.bioorg.2025.108404","DOIUrl":"10.1016/j.bioorg.2025.108404","url":null,"abstract":"<div><div>Molecules containing α, β<strong>-</strong>unsaturated carbonyl structure have gained constant attention because of their potential of interacting with nucleophilic amino acid residues and further protein function regulating. However, current methods for finding and isolating such compounds are challenged by lacking of convenience and orientation. Herein we introduce a new strategy for capturing and releasing natural products with α, β<strong>-</strong>unsaturated group by regulating the direction of thia-Michael addition reaction. Target molecules could be separated from various impurities by means of controlling the association and dissociation with hydrophilic small sulfhydryl molecules and consequently change of polarity and solubleness. Our strategy showed effectiveness that natural products containing α, β<strong>-</strong>unsaturated esters and ketones could be successfully released from the adducts with cysteine. Finally, nine cucurbitacins with target functional group from the extract of <em>Cucumis melo</em> were enriched and isolated with high selectivity. This strategy may thus help to isolate natural products with α, β<strong>-</strong>unsaturated group in complex samples.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108404"},"PeriodicalIF":4.5,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143687697","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}

引用次数: 0

Optimizing ST6GAL1 inhibition and selectivity using lithocholic acid-amino acid conjugates for antimetastatic and antiangiogenic agent development

IF 4.5 2区医学

Bioorganic Chemistry Pub Date : 2025-03-22 DOI: 10.1016/j.bioorg.2025.108401

Wei-Sheng Chen , Christian Angelo P. Concio , Tzu-Ting Chang , Chia-Ling Chen , Ser John Lynon P. Perez , Wen-Shan Li

{"title":"Optimizing ST6GAL1 inhibition and selectivity using lithocholic acid-amino acid conjugates for antimetastatic and antiangiogenic agent development","authors":"Wei-Sheng Chen , Christian Angelo P. Concio , Tzu-Ting Chang , Chia-Ling Chen , Ser John Lynon P. Perez , Wen-Shan Li","doi":"10.1016/j.bioorg.2025.108401","DOIUrl":"10.1016/j.bioorg.2025.108401","url":null,"abstract":"<div><div>A series of LCA-aromatic amino acid conjugates were synthesized and tested for their inhibitory effects on N-glycan specific ST6GAL1 and O-glycan specific ST3GAL1. The LCA-amino acid conjugates with phenyl and indole moieties showed enhanced inhibitory activity and selectivity towards the <em>N</em>-glycan-specific ST6GAL1, with the indole-containing compound <strong>4e</strong> exhibiting the highest activity (IC<sub>50</sub> = 20.0 ± 0.5 μM). In addition, compound <strong>4e</strong> exhibited the highest antimetastatic potential, effectively inhibiting MDA-MB-231 cell migration at non-cytotoxic concentrations. Compound <strong>4e</strong> also suppressed tumor growth and metastasis in vivo, attributing to its potential to disrupt integrins sialylation. The conjugate has also demonstrated excellent antiangiogenetic properties in vitro and ex vivo, owing to its ability to downregulate the VEGF/VEGFR2/Akt pathway. Taken together, these findings prove the practicality of employing LCA as a scaffold and aromatic amino acid conjugation in the discovery of novel, potent, and selective ST inhibitors necessary to address abnormal cell surface α-2,6-<em>N</em>-sialylation.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108401"},"PeriodicalIF":4.5,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747117","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}

引用次数: 0

Development of new genipin derivatives as potential NASH treatments: Design, synthesis and action mechanism

IF 4.5 2区医学

Bioorganic Chemistry Pub Date : 2025-03-22 DOI: 10.1016/j.bioorg.2025.108403

Zi-Tong Feng, Shi-Ying Fan, Xing-Yu Pan, Ling-Yi Kong, Jian-Guang Luo

{"title":"Development of new genipin derivatives as potential NASH treatments: Design, synthesis and action mechanism","authors":"Zi-Tong Feng, Shi-Ying Fan, Xing-Yu Pan, Ling-Yi Kong, Jian-Guang Luo","doi":"10.1016/j.bioorg.2025.108403","DOIUrl":"10.1016/j.bioorg.2025.108403","url":null,"abstract":"<div><div>Nonalcoholic steatohepatitis (NASH) is a multifaceted liver disease. Endoplasmic reticulum stress (ERS), a key driver in NASH pathogenesis, triggers metabolic irregularities, liver steatosis, and inflammation. Genipin, an iridoid from the traditional Chinese medicine <em>Gardenia jasminoides</em>, has demonstrated significant effects against ERS. In the current work, 33 new genipin derivatives were designed and synthesized to evaluate their potential to treat NASH. Notably, <strong>G15</strong> emerged as the most potent candidate, significantly attenuating lipid accumulation induced by free fatty acids (FFAs) in L-02 cells. Further investigation revealed that <strong>G15</strong>'s mitigation of ERS was primarily achieved by suppressing the levels of inositol-requiring enzyme 1 (IRE1). Western blot analysis confirmed that <strong>G15</strong> effectively down-regulated IRE1 protein expression and decreased the expression levels of its downstream X-box binding protein 1 (XBP1) and signal transducer and activator of transcription 3 (STAT3) proteins, thereby reducing cellular lipid accumulation. In addition, <strong>G15</strong> treatment inhibited FFA-induced nitric oxide (NO) production in a concentration-dependent manner and suppressed the secretion of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α. Collectively, these findings underscore that <strong>G15</strong> has the potential to be a leading candidate for the treatment of NASH by down-regulating the IRE1/XBP1/STAT3 signaling pathway.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108403"},"PeriodicalIF":4.5,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143704561","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}

引用次数: 0