Bioorganic Chemistry最新文献

{"title":"Design and synthesis of JNK1-targeted PROTACs and research on the activity.","authors":"Yue Guo, Fengling Liu, Man Chi, Hewen Qian, Ye Zhang, Yaxia Yuan, Shurong Hou, Xiabin Chen, Lei Ma","doi":"10.1016/j.bioorg.2024.108044","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108044","url":null,"abstract":"<p><p>Kinase dysregulation is greatly associated with cell growth, proliferation, differentiation and apoptosis, which indicates their great potential as therapeutic targets for treatment of numerous progressive disorders, including inflammatory, metabolic and autoimmune disorders, organ fibrosis and cancer. The c‑Jun N‑Terminal Kinase (JNK), as a member of MAPK family, is proved to be a potential target for the treatment of pulmonary fibrosis, which is the most common progressive and fatal fibrotic lung disease. As a new strategy, small-molecule-mediated targeted protein degradation pathway has the advantages of catalytic properties, overcoming drug resistance and expanding target space, which can circumvent the limitations associated with kinase inhibitors. Proteolysis targeting chimeras (PROTAC) contains a linker to concatenate a ligand of E3 ubiquitin ligase and a ligand for a protein of interest (POI). We developed a total of 20 JNK1-targeted PROTACs that induce proteasomal degradation of JNK1 components. The most active PROTAC molecule PA2 was then investigated by JNK1 enzyme assay and protein degradation assay, which suggested that PA2 had an anti-JNK1 ability and provided insights for the future use of JNK1-targeted PROTAC as treatment drugs for pulmonary fibrosis.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108044"},"PeriodicalIF":4.5,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862549","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":"Multifunctional porphyrin-substituted phenylalanine-phenylalanine nanoparticles for diagnostic and therapeutic applications in Alzheimer's disease.","authors":"Ning Xia, Yaliang Huang, Cancan He, Yadi Li, Suling Yang, Lin Liu","doi":"10.1016/j.bioorg.2024.108065","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108065","url":null,"abstract":"<p><p>β-Amyloid (Aβ) peptides are believed as the diagnostic biomarkers and therapeutic targets of Alzheimer's disease (AD). Their complexes with copper ions can catalyze the generation of reactive oxygen species (ROS) to further promote neuronal death. Herein, we suggested that porphyrin-substituted phenylalanine-phenylalanine nanoparticles (TPP-FF NPs) could inhibit the aggregation of Aβ monomers, disassemble the fibrillar Aβ aggregates under light illumination, and depressing the Cu²⁺-induced generation of ROS. Meanwhile, the TPP-FF NPs could be used as the nanocarriers and quenchers of fluorescently-labeled probes for the detection of Aβ oligomer (AβO). Inhibition of Aβ assembly and dissolution of Aβ aggregates were monitored by Thioflavin T (ThT)-based fluorescent assay and characterized by atomic force microscopy. The Aβ/Cu²⁺-induced generation of ROS was limited by TPP-FF NPs. The fluorescein-labeled probe aptamers attached on the surface of TPP-FF NPs emitted low fluorescence. The interaction between AβO and aptamers induced the release of the probes from the surface of TPP-FF NPs, driving the fluorophore far away from the quenchers and turning on the fluorescence. The signal-on strategy can be used for the detection of AβO with a low detection limit. This work should be evaluable for the development of multifunctional candidates for the diagnosis and treatment of AD.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108065"},"PeriodicalIF":4.5,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851699","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":"Topical application of magnolol ameliorates psoriasis-like dermatitis by inhibiting NLRP3/Caspase-1 pathway and regulating tryptophan metabolism.","authors":"Yi Chen, Shasha Song, Yongfang Wang, Lili Wu, Jianbing Wu, Zhengmeng Jiang, Xinyu Li","doi":"10.1016/j.bioorg.2024.108059","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108059","url":null,"abstract":"<p><p>Psoriasis (PSO) is a common inflammatory skin disease caused by multiple factors. Magnolia officinalis is an important medicinal plant in China, with various values such as ecology, medicine, food, and daily chemicals. However, its diverse application potential has not been fully explored. Magnolol (MGO) is the main active compound of Magnolia officinalis with significant anti-inflammatory effect. To investigate the application potential of MGO in inflammatory skin disease, the effects and underlying mechanisms of topical MGO treating psoriasis were explored in this study. Network pharmacology and molecular docking firstly predicted that topical MGO may treat psoriasis by regulating pyroptosis pathway and acting on caspase-1 (CASP1). In vitro experiments then demonstrated that MGO could inhibit the level of inflammatory cytokines and the key protein expression of NOD-like receptor protein 3 (NLRP3)/Caspase-1 pathway in lipopolysaccharide (LPS)-stimulated phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells. Meanwhile, MGO could inhibit CuSO₄-induced neutrophils migration in Tg (mpx:EGFP) zebrafish by suppressing inflammation and pyroptosis. This study further indicated that topical application of MGO ameliorated imiquimod (IMQ)-induced psoriasis-like dermatitis by reducing the release of inflammatory factors and decreasing the key protein expression of pyroptosis-related NLRP3/Caspase-1 pathway. Metabolomics analysis revealed that topical application of MGO could significantly regulate tryptophan metabolism and affect the level of tryptophan in skin lesions. Tryptophan could also regulate inflammation-related genes and inhibit pyroptosis-related NLRP3/Caspase-1 pathway in LPS-stimulated PMA-differentiated THP-1 cells. In conclusion, this study suggested that topical MGO may ameliorate psoriasis-like dermatitis by inhibiting NLRP3/Caspase-1 pathway and regulating tryptophan metabolism.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108059"},"PeriodicalIF":4.5,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851814","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":"Pharmacological investigation of selected 1,2,4 triazole derivative against ethanol induced gastric ulcer.","authors":"Jawad Azam, Muhammad Noman, Humaira Nadeem, Nadeem Ahmad, Zaheer Ul-Haq, Fahim Hilal, Nadeem Irshad","doi":"10.1016/j.bioorg.2024.108040","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108040","url":null,"abstract":"<p><p>The present study aims to assess the therapeutic potential of (2S,3S,4S,5S,6S-2-(acetoxymethyl)-6-(4-chlorophenyl)-3-(pyridine-4-yl)5-thioxo-4,5-dihydro-1,2,4-triazol-1-yl tetrahydro-2H-pyran 3,4,5tryltriacetate (JAK05) on gastric ulcer. The current study was designed to evaluate the anti-ulcer potential of JAK05 against ethanol-induced gastric ulcer by employing in silico, in vitro and in vivo techniques. In silico studies, JAK05 has a binding score ranging from -8.51 to -21.38 (kcal/mol). Molecular dynamics simulation at 100 ns shows better structural stability, stable binding affinity and stable conformation when bonded to H⁺/K⁺-ATPase. In vitro study demonstrates that JAK05 inhibits Helicobactor pylori. In vivo study confirmed that JAK05 promotes ulcer healing in rats at a dose of 40 mg/kg and demonstrated a protective effect on the gastric mucosa, comparable to omeprazole by modulating acid secretion and fluid volume. Glutathione, glutathione-s-transferase and catalase levels increased in rat stomach tissue while nitric oxide decreased with the administration of JAK05. Additionally, lipid peroxide levels were found to have significantly decreased. Pathological histopathology analysis shows improved tissue structure and reduced inflammatory markers. These findings were confirmed using immunohistochemistry and enzyme-linked immunosorbent assay. JAK05 exhibits a high affinity for selected targets. JAK05 shows anti-ulcer properties by targeting through multiple mechanisms inhibiting H. pylori, reducing oxidative stress, suppressing inflammation and blocking acid production.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108040"},"PeriodicalIF":4.5,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851703","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":"Synthesis and bioevaluation of a new ⁶⁸Ga-labelled niraparib derivative that targets PARP-1 for tumour imaging.","authors":"Qianna Wang, Zuojie Li, Yuhao Jiang, Junhong Feng, Qing Ruan, Guangxing Yin, Peiwen Han, Junbo Zhang","doi":"10.1016/j.bioorg.2024.108063","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108063","url":null,"abstract":"<p><p>Poly ADP-ribose polymerase (PARP) inhibitors prevent the repair of DNA single-strand breaks in cancer cells with abnormal homologous recombination, producing a synthetic lethal effect. Thus, PARP inhibitors have become clinically effective anticancer drugs. Labelling with radionuclides may extend the use of PARP inhibitors as tracers in nuclear medicine diagnostics, helping to stratify patients. In the present study, niraparib was selected as a skeleton molecule modified with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and labelled with gallium-68 to obtain [⁶⁸Ga]Ga-DOTANPB with high radiochemical purity (>95 %). To verify the accuracy of the [⁶⁸Ga]Ga-DOTANPB structure, [^natGa]Ga-DOTANPB was also synthesized, and in vitro affinity experiments were performed, which revealed a high affinity for PARP-1 (IC₅₀ = 82.21 nM). [⁶⁸Ga]Ga-DOTANPB is hydrophilic and has good in vitro stability within 3 h. In in vitro experiments, [⁶⁸Ga]Ga-DOTANPB has a high uptake in HeLa cells and can enter the cell to target PARP-1. In coronal PET imaging of HeLa tumour-bearing mice, [⁶⁸Ga]Ga-DOTANPB showed significant radioconcentration at the tumour site at 0.5 h, 1 h, and 2 h. Biodistribution and autoradiography experiments revealed that [⁶⁸Ga]Ga-DOTANPB has obvious tumour uptake and can be significantly inhibited (3.37 ± 0.33 % ID/g vs. 2.50 ± 0.27 % ID/g, **P < 0.01), suggesting that it has PARP-1 specificity. Thus, these findings suggested that [⁶⁸Ga]Ga-DOTANPB may be a potential niraparib-based PET tracer for targeting PARP-1.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108063"},"PeriodicalIF":4.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862492","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":"2-Trifluoromethyl-2H-chromene ethers: The dual triumph of anti-inflammation and analgesia with minimal ulcer threat.","authors":"Nan Cai, Xiang Gao, Ling Jia, Yunzhe Liu, Jinfeng Zhao, Jingping Qu, Yuhan Zhou","doi":"10.1016/j.bioorg.2024.108050","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108050","url":null,"abstract":"<p><p>In this report, we disclose the design and synthesis of a series of 2-trifluoromethyl-2H- chromene ethers as novel COX-2 inhibitors with low ulcerogenicity. Among them, 6-fluoro-3-(4-methoxyphenyl)-2-(2-(thiophen-3-yl)ethoxy)-2-(trifluoromethyl)-2H-chromene (E25) significantly suppressed LPS-induced release of NO and PGE₂, expression of COX-2 and iNOS, and activation of NF-κB pathway. The inhibitory effect of E25 on human recombinant COX-2 (IC₅₀ = 70.7 ± 4.7 nM) and molecular docking studies suggest that E25 functions as a COX-2 inhibitor. Moreover, the results of the cellular thermal shift assay also substantiate the interaction between E25 and COX-2. E25 manifests potent anti-inflammatory and analgesic efficacy on a par with or even superior to indomethacin in rodent models including carrageenan-induced paw edema, cotton pellet-induced granuloma, acetic acid-induced writhes, and adjuvant-induced arthritis. The possible mechanism of action of E25 might be to bind to COX-2 and suppress the NF-κB pathway as well as the expression of related proteins, thereby exerting anti-inflammatory and analgesic effects. Encouragingly, compared with indomethacin, E25 induces smaller areas and fewer ulcers, a lower level of inflammatory infiltration, a lower expression of MMP-9 and apoptosis of mucosal epithelial cells in rat gastric tissues. Overall, E25 and other analogues are promising candidates worthy of further investigation for the treatment of inflammation and pain, as well as other symptoms in which COX-2 and PGE₂ play a role in their etiology.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108050"},"PeriodicalIF":4.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826839","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 marine ent-eudesmane sesquiterpenoids as angiogenic inhibitors via suppressing VEGF-A/VEGFR2 signaling pathway.","authors":"Wan-Shan Li, Xue-Ping Lei, Zhan Li, Yong He, Mu Chen, Zhong-Ping Jiang, Guang-Ying Chen","doi":"10.1016/j.bioorg.2024.108055","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108055","url":null,"abstract":"<p><p>Increasing evidence underscores the pivotal role of tumor angiogenesis for tumorigenesis and tumor metastasis. Inhibiting the tumor angiogenesis process is a promising therapeutic approach for cancer. In order to search for natural angiogenic inhibitors, the chemical constitutes of a marine-derived fungus Eutypella sp. F0219 were investigated, leading to the isolation and identification of twelve new ent-eudesmane sesquiterpenoids named eutypenes A-L (1-12). Their structures including absolute configurations were determined by extensive spectroscopic investigations, single crystal X-ray diffraction analyses, modified Mosher's method, and ECD calculations. Notably, eutypene A (1) represents a rare rearranged ent-eudesmane sesquiterpenoid with 5/7 fused ring system. Tube formation assay was performed to evaluate the antiangiogenic effect of all compounds. The results showed that compounds 4, 6, 7, 9, and 10 obviously suppressed the tube formation of human microvascular endothelial cell line (HMEC-1) cells in a dose-dependent manner. Moreover, the most bioactive and less toxic compound 9 displayed significant antiangiogenic effect in vitro and ex vivo. Further mechanistic investigation revealed that compound 9 restrained tumor angiogenesis by reducing the VEGF-A level and suppressing the VEGF-A/VEGFR2 signaling pathway. Our findings give insight into the application of marine ent-eudesmane sesquiterpenoids as potential angiogenesis inhibitor.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108055"},"PeriodicalIF":4.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862557","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":"Coumarin-based fluorescent probes for the detection of copper (II) and imaging in mice of Wilson's disease.","authors":"Chunpo Ge, Feng Pei, Xiaoyu Wang, Pengcheng Zhang, Huilin Li, Zhipeng Sai, Yan Yang, Kaiwen Chang, Tianjun Ni, Zhijun Yang","doi":"10.1016/j.bioorg.2024.108051","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108051","url":null,"abstract":"<p><p>Copper is an essential redox-active metal nutrient, with tightly regulated homeostasis. Copper homeostasis is closely linked to various diseases, making it a critical area of study. Fluorescent probes serve as powerful tools for investigating these conditions. In this study, a fluorescent probe, Con-Cu400 for detecting Cu²⁺ was developed. Con-Cu400 exhibited a strong \"turn-on\" fluorescence signal in response to Cu²⁺, demonstrating high selectivity and sensitivity. Con-Cu400 also exhibited good biocompatibility and was successfully employed for fluorescence sensing of Cu²⁺ in both cellular and mouse models under conditions of normal, copper-depleted, and copper-overloaded. This probe effectively detected elevated Cu²⁺ levels in the livers of mice with Wilson's disease. This work may contribute to the broader application of fluorescent probes in studying Cu²⁺ dysregulation-related diseases in cellular and animal models.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108051"},"PeriodicalIF":4.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823567","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 pentacyclic triterpene conjugates as HBV polymerase/NTCP dual-targeting inhibitors with potent anti-HBV activities.","authors":"Yixin Chen, Meitao Duan, Jianling Xu, Ao Duan, Haocheng Yang, Hongquan Tao, Shuo Tian, Zishan Zhou, Wenzhang Li, Huaming Tao, Yongyan Zhu, Quanhong Zhu","doi":"10.1016/j.bioorg.2024.108054","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108054","url":null,"abstract":"<p><p>The inhibition of HBV DNA and elimination of HBsAg has already been established as an indicator for HBV clinic cure, and a novel dual-targeting inhibitors of HBV polymerase/entry are designed and synthesized in this study. Pentacyclic triterpenes (PTs) scaffold of exhibiting a high affinity to NTCP, including glycyrrhitinic acid (GA), oleanolic acid (OA), ursolic acid (UA), and betulinic acid (BA) were linked neatly with the nucleoside drug zidovudine (AZT) through a molecular hybrid strategy to synthesize twenty of PTs-AZT conjugates for targeting HBV polymerase as well as sodium taurocholate cotransporting polypeptide (NTCP). The conjugates showed significant inhibitory effects on the secretion of HBsAg and HBeAg in HepG2.2.15 cells, and the activity on HBsAg were better. Moreover, HBV DNA replication was also notably suppressed after incubated with the conjugates. The IC₅₀ value of BA-AZT1 on HBsAg inhibition was 0.65 ± 0.07 μM, and it was 284.2 times and 442.2 times higher comparing to corresponding parent compound BA and AZT. Additionally, the therapeutic index (TI) was also improved by 87.8 times than AZT. And the IC₅₀ value of BA-AZT1 on inhibition of HBV DNA replication was 0.70 ± 0.02 μM, 10.4 times higher than that of AZT besides conspicuous TI. Molecular docking suggested that AZT skeleton of conjugate BA-AZT1 interacted with B region of HBV Polymerase reverse transcription region, and BA structure simultaneously targeted to C region of polymerase via hydrophobic chain, establishing strong binding interactions with the HBV Pol protein. In addition, docked with NTCP, BA-AZT1 with flat pentacyclic structure inserted into the interface and also formed hydrogen bonds, hydrophobic and van der Waals forces with the amino residue 157-165 of NTCP. Further SPR analysis demonstrated the binding affinity of BA-AZT1 to C region of polymerase was 19.55 μM, stronger than 53.21 μM of BA and 31.82 μM of AZT. BA-AZT1 selectively bound to the 157-165 epitopes of NTCP receptors in host cell but not PreS1 of virus. As a result, we deduced that the designed conjugates targeted NTCP and HBV polymerase, not only prevented HBV from entering host cells via selective binding NTCP, but also inhibited HBV DNA replication through obstructing the function of HBV polymerase, and it could potentially serve as a promising dual-functional and dual-target inhibitor with both replication and entry inhibition to exert anti-HBV activity.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108054"},"PeriodicalIF":4.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862584","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":"Hypoglycemic activity and metabolite diversity of Archangium sp. UTMC 4535 with the first report on magnodelavin biosynthesis by bacteria.","authors":"Fatemeh Saadatpour, Yan-Duo Wang, Saman A Mohammed, Gang Ding, Fatemeh Mohammadipanah","doi":"10.1016/j.bioorg.2024.108053","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108053","url":null,"abstract":"<p><p>Diabetes has been declared an epidemy by the World Health Organization and represents a significant metabolic comorbidity. Given the promising pharmaceutical activities of myxobacterial secondary metabolites, we investigated the inhibitory potential of compounds from the soil myxobacterium Archangium sp. UTMC4535, leading to the identification of magnodelavin C, a guaiane sesquiterpene lactone.This study details the isolation, structural elucidation, and biological evaluation of magnodelavin C against enzymes associated with type 2 diabetes (T2D), specifically alpha (α)-glucosidase and glucose transferase, utilizing molecular docking and in vitro assessments. Docking studies identified five binding pockets in α-glucosidase, with magnodelavin C displaying favorable binding scores between -5.4 to -6.7 kcal/mol. Experimental results indicated that magnodelavin C inhibited α-glucosidase approximately three times more effectively than the crude extract, exhibiting potency comparable to the standard drug acarbose. Furthermore, magnodelavin C demonstrated an inducing effect on glucose transport with an average uptake percentage of 80 % compared to the drug control. MTT assay results confirmed that magnodelavin C exhibited no cytotoxic effects on the L929 fibroblast cell line at any tested concentration, contrasting with acarbose's approximately 25 % mortality rate. This compound also demonstrated advantageous drug-likeness properties and human intestinal absorption while exhibiting lower toxicity compared to acarbose. The discovery of magnodelavin C highlights the rich diversity of secondary metabolites produced by myxobacteria and their potential applications in drug discovery.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108053"},"PeriodicalIF":4.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845417","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}