Bioorganic Chemistry最新文献

{"title":"S-Alkylated sulfonium betulin derivatives: Synthesis, antibacterial activities, and wound healing applications.","authors":"Yiding Deng, Ruili Wang, Zhiyuan Ma, Weiwei Zuo, Meifang Zhu","doi":"10.1016/j.bioorg.2024.108056","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108056","url":null,"abstract":"<p><p>Betulin, a bioactive triterpenoid derived from Betulaceae bark with antimicrobial and anti-inflammatory properties, holds great potential as a therapeutic agent. In this work, cationic sulfonium-modified betulin derivatives were synthesized to enhance their antibacterial efficacy for wound healing application. Mono- and dual S-alkylated sulfonium derivatives significantly outperformed betulin in antibacterial activity against pathogens such as S. aureus, Methicillin-resistant S. aureus (MRSA), and E. coli. S-nonylated sulfonium betulin reduced the minimum inhibitory concentration of betulin against MRSA from 24 to 0.015 mM. The sulfonium modification enhanced cationic interactions, leading to bacterial membrane disruption. The derivatives expedited the process of wound healing by mitigating inflammation and exhibited satisfactory biosafety, proposing a viable approach to the development of antibacterial agents.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108056"},"PeriodicalIF":4.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823574","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 pyrazolinone derivatives as multifunctional ligands for the treatment of Alzheimer's disease.","authors":"Huabo Wang, Yulu Wu, Anran Liu, Siyi Li, Peng Zhu, Jianguo Zuo, Ying Kuang, Jiaming Li, Xueyang Jiang","doi":"10.1016/j.bioorg.2024.108052","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108052","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the depletion of cholinergic neurons and the accumulation of amyloid β (Aβ) plaques. The complexity and multifaceted nature of AD necessitate further exploration of multi-target drugs for its treatment. In this study, a series of novel pyrazolinone-based compounds were designed, synthesized, and evaluated as acetylcholinesterase (AChE) inhibitors and antioxidants. The lead compounds ET11 and ET21 showed strong inhibitory activity against human AChE, with IC₅₀ values of 6.34 and 1.81 nM, respectively. In vitro DPPH and ORAC_FL assays confirmed the compounds' strong antioxidant capabilities. ET11 exhibited excellent neuroprotective activity in the tBHP-induced SH-SY5Y cell damage model. Benefiting from the pyridopyrazolone moiety, ET11 showed significant Cu²⁺ chelating ability and effectively inhibited Cu²⁺-induced Aβ aggregation. In vivo behavioral studies and histopathology analysis preliminarily confirmed the compound's cognitive improvement and neuroprotective effects. Overall, these findings suggested that compound ET11 is expected to play a synergistic role in the treatment of AD, potentially slowing disease progression.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108052"},"PeriodicalIF":4.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826844","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":"Metabolomic fingerprinting, molecular modelling and experimental bioprospection of Helianthus annuus seed cultivars as Pseudomonas aeruginosa LasR modulators.","authors":"Akshay Raghoonanadan, Yamkela Dweba, Christiana E Aruwa, Saheed Sabiu","doi":"10.1016/j.bioorg.2024.108046","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108046","url":null,"abstract":"<p><p>The Pseudomonas aeruginosa LasR quorum sensing system (QSS) is central to regulating the expression of several pathogenicity factors. Also, while seed- and/or plant-derived products have been investigated as QSS regulators, the impact of Helianthus annuus (Pannar sunflower seed cultivars) extracts and metabolites as LasR modulators remain underexplored. Thus, this study focused on the untargeted metabolomic profiling (Liquid Chromatography-Mass Spectrometry), in vitro and in silico (docking, pharmacokinetics, dynamic simulation) bioprospection of Pannar seed cultivars' extracts and metabolites as LasR modulators. The extracts showed significant QS modulating properties (motility, violacein, biofilm, cell attachment, pyocyanin inhibition) with the PAN 7102 CLP seed cultivar (74.3 %) being the most potent, compared to azithromycin (65 %) and cinnamaldehyde (62 %). Chemometric principal component analysis (PCA) analysis showed distinct metabolite signatures with 52.5 % variance across the six cultivars that was driven by aqueous and ethanolic extracts of PAN 7102, 7160, and 7156 cultivars. The presence of methoxymellein, hydroxytetradecanedioic acid, koninginin G, geoside, pinellic acid and methylpicraquassioside A were reported for the first time. The profiled metabolites were subjected to a 100-ns molecular dynamics simulation following molecular docking. Binding free energy (ΔG_bind) calculations revealed obolactone (-48.26 kcal/mol), 1,4-bis(phenylglyoxaloyl)benzene (-45.06 kcal/mol), cyclocanaliculatin (-43.41 kcal/mol), 5-hydroxy-7-methoxy-2-phenylchroman-4-one (-39.18 kcal/mol) and lonchocarpin (-33.78 kcal/mol) as first-time putative leads relative to azithromycin (-32.09 kcal/mol). All lead metabolites also conformed to Lipinski's rule of 5 (Ro5), and their LasR bound complexes were thermodynamically stable and compact given their strong bond interactions. Findings indicate that metabolomic profiling remain key to identifying new compounds from underexplored species. H. annuus lead metabolites and extracts may also play key roles as LasR modulators. Further structural modification of the 5 leads could aid their development into novel, oral therapeutics targeting LasR to mitigate resistant P. aeruginosa infections.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108046"},"PeriodicalIF":4.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851784","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":"KAHA ligation as a platform for the rapid discovery of Protein Tyrosine phosphatase 1B (PTP1B) inhibitors.","authors":"Jing Tian, Sijia Tan, Liqian Gao, Lakshminarayanan Rajamani, Rajavel Srinivasan","doi":"10.1016/j.bioorg.2024.108028","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108028","url":null,"abstract":"<p><p>We have successfully designed and assembled a 66-member library of protein tyrosine phosphatases (PTP) inhibitor candidates using α-ketoacid-hydroxylamine (KAHA) ligation. Subsequent in situ enzymatic screening revealed a potent hit (IC₅₀ = 1.67 μM) against PTP1B, which displayed 6.8- to 50-fold selectivity over other phosphatases.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108028"},"PeriodicalIF":4.5,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823569","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":"Diversity-oriented synthesis of second generation guanidinium-rich transporters toward cell-selective penetration.","authors":"Duc Tai Nguyen, Michael Desgagné, Andréanne Laniel, Christine Lavoie, Pierre-Luc Boudreault","doi":"10.1016/j.bioorg.2024.108041","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108041","url":null,"abstract":"<p><p>Cell-penetrating peptides (CPPs) hold significant promise for intracellular delivery of various cargo molecules such as therapeutics. However, the lack of selectivity remains a critical challenge and limits the clinical application of CPPs. Using an automated peptide synthesizer, we generated a diversity-oriented library of 256 peptidomimetics containing four modified peptoid guanidine-bearing monomers incorporated alternatively with four α-amino acids. These α-amino acids were chosen to enhance lipophilic interactions with the cell membrane (Phe, 2Nal) or to bear pH-sensitive properties (His), which could enhance cancer cell selectivity. The synthesized library exhibits selective internalization, with an average selectivity index (SI) of 1.49 for HeLa cells in comparison to non-cancerous HEK293 cells. Compounds 155 and 187, containing three His residues and either Phe or 2Nal, show high cellular uptake in HeLa cells (64.6% and 75.7%, respectively) and possess an SI of 2.7 and 2.9, respectively, at the tested dose of 5 μM. Altogether, these findings highlight the use of diversity-oriented library synthesis to identify cell-permeable candidates as well as their potential for targeted cellular delivery and enhanced specificity.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108041"},"PeriodicalIF":4.5,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821541","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 GH1 β-glucosidase from the Fervidobacterium pennivorans DSM9078 showed extraordinary thermostability and distinctive ability in the efficient transformation of ginsenosides.","authors":"Kailu Zhou, Yangyang Zhang, Minghao Xu, Yikai Zhou, Ao Sun, Hao Zhou, Ye Han, Daqing Zhao, Shanshan Yu","doi":"10.1016/j.bioorg.2024.108049","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108049","url":null,"abstract":"<p><p>A novel GH1 β-glucosidase Fpglu1 from Fervidobacterium pennivorans DSM9078 was successfully cloned and expressed in Escherichia coli. This hyperthermophilic enzyme possesses unique features that make it valuable in biochemistry and pharmacology. It exhibited optimal activity at temperatures exceeding 100 °C, a trait rarely observed in other enzymes, and demonstrated extraordinary thermostability. It displayed multifunctional activity, with the highest activity observed for p-nitrophenyl-β-d-glucopyranoside (pNPGlu) at 92.47 U/mg. Furthermore, the distinctive capacity of Fpglu1 to transform ginsenosides (Rb1, Rb2, and Rc) into Compound-K (C-K) sets it apart from the other enzymes. It effectively cleaved the external β-(1-6) glycosidic linkage at the C-20 position of ginsenosides Rb1, Rb2, and Rc, followed by hydrolysis ofthe internal glycosidic bond connected to the C-3 position. The k_cat/K_m value of Fpglu1 for Rb1 was 453 ± 1.27 mM^-1/s, significantly higher than those of Fpglu1 for other ginsenosides. The crystal structure of Fpglu1, determined at 1.85 Å resolution, provided a deeper understanding of its catalysis and substrate specificity. The evaluation of the binding conformation, hydrogen bond, and key amino acids of β-glucosidase Fpglu1 with different ginsenosides (Rb1, Rb2, and Rc) further elucidated the structural basis of its substrate-binding preference. In summary, Fpglu1, which had excellent thermostability and unique ginsenoside-transforming ability, was a highly promising catalyst for the industrial production of ginsenoside C-K. Additionally, structural studies have laid a theoretical foundation for further improving the catalytic properties of the enzyme through directed evolution in the future.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108049"},"PeriodicalIF":4.5,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816636","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 meroterpenoids from Arnebia euchroma and their anti-inflammatory effects through NF-κB pathway.","authors":"Xiaojing Shi, Shengyun Dai, Jianguo Song, Shuyuan Zhang, Wenhao Zhang, Yao Guo, Shujing Zhang, Ying Wang, Wencai Ye, Jian Zheng, Xiaochi Ma, Wenyu Zhao","doi":"10.1016/j.bioorg.2024.108048","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108048","url":null,"abstract":"<p><p>Meroterpenoids in the traditional Chinese medicine Arnebia euchroma are thought to be key components in its anti-inflammatory activity. In the present study, 17 meroterpenoids including four types of structural skeletons (1-17), together with a monoterpenoid (18), were isolated from the roots of A. euchroma. HRESIMS, 1D and 2D NMR, electronic circular dichroism, and quantum computing-assisted methods were employed to determine the structures of four previously undescribed compounds (1-3, and 14). Zicaomeroterin B (2) feature with a novel benzo[b]oxepin moiety was confirmed by X-ray analysis based on the crystalline mate method. Meroterpenoids 2, 5, 6, 13, and 17 exhibited significant inhibition against the production of NO, IL-6, and TNF-α in LPS-stimulated macrophages without obvious cytotoxic effects. Furthermore, compounds 2, 5, and 6 significantly inhibited the phosphorylation activation of NF-κB p65 and its nuclear translocation in luciferase reporter test, immunoblotting, and immunofluorescence imaging, which in turn inhibited the NF-κB pathway and exerted anti-inflammatory effects. These findings suggested that meroterpenoids 2, 5, and 6 in A. euchroma are the potential lead compounds for anti-inflammatory agents based on NF-κB signaling pathway.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108048"},"PeriodicalIF":4.5,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811616","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":"Trolox derivatives: Synthesis, structure-activity relationship and promote wound healing by regulating oxidative stress and inflammation.","authors":"Jie Zhao, Shan Gao, Long Zhou, Kuanrong Rong, Fangfang Zuo, Wenjian Tang, Lili Zhu","doi":"10.1016/j.bioorg.2024.108045","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108045","url":null,"abstract":"<p><p>To find new antioxidants, 13 Trolox amides (2a-2m) and 7 Trolox esters (3a-3g) were synthesized and evaluated for their anti-inflammatory and antioxidant activity. Compounds 2e, 2i, 3b and 3d showed potent anti-inflammatory and antioxidant activity, amongst them, 3d demonstrated the most photoprotective effects on UVB-irradiated human skin keratinocyte (HaCaT) cells (IC₅₀ = 5.13 µM) through efficiently scavenging free radicals and dose-dependently reducing reactive oxygen species (ROS) and apoptosis generation, as well as effectively promoting wound healing. 3d protected HaCaT cells against oxidative stress, inflammation and cellular damage by the activation of Nrf2/HO-1 signaling and inhibition of NF-κB pathway, further significantly improving wound healing. In acute UVB-induced skin injury mouse model, 3d significantly reduced the level of pro-inflammatory factors, improved the effect of UVB radiation on the activity of antioxidant enzymes, and maintained normal metabolic capacity. In conclusion, 3d may be a potential candidate for developing cosmetics with UVB protective effect.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108045"},"PeriodicalIF":4.5,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821544","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":"Thiazole - A promising scaffold for antituberculosis agents and structure-activity relationships studies.","authors":"Xuanming Zhao, Jing Di, Dingjie Luo, Rameshwari Verma, Santosh Kumar Verma, Shekhar Verma, Lekkala Ravindar, Anubhuti Koshle, Hitesh Kumar Dewangan, Raksha Gupta, Sunita Chandra, Samta Deshpande, Kamal, Yogesh Vaishnav, Kadalipura P Rakesh","doi":"10.1016/j.bioorg.2024.108035","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108035","url":null,"abstract":"<p><p>Research on thiazole derivatives has been a popular topic in medicine and one of the most active fields in heterocyclic chemistry. Pharmacological and industrial researchers have been studying thiazole-containing derivatives in great detail because they have a lot of biological uses. These compounds are one of the best examples of a five-membered heterocyclic compound that has a lot of potential and has had a lot of success in recent decades. Investigating viable hybrid designs utilizing thiazole is critical for the development of new anti-tuberculosis medications. This article offers a thorough overview of the latest advancements in thiazole-containing hybrids, offering potential therapeutic applications as anti-TB drugs. We also discussed the structure-activity correlations (SAR) of the powerful thiazole moiety and its several functional groups, along with a few potential molecular targets.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108035"},"PeriodicalIF":4.5,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851813","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":"Chemotherapeutic potential of radotinib against blood and solid tumors: A beacon of hope in drug repurposing.","authors":"Suryaa Manoharan, Ekambaram Perumal","doi":"10.1016/j.bioorg.2024.108017","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108017","url":null,"abstract":"<p><p>Tyrosine kinase inhibitors (TKIs) represent a pivotal class of targeted therapies in oncology, with multiple generations developed to address diverse molecular targets. Imatinib is the first TKI developed to target the BCR-ABL1 chimeric protein, which is the key driver oncogene implicated in Philadelphia chromosome-positive chronic myeloid leukemia (CML). Several second-generation tyrosine kinase inhibitors (2GTKIs), such as nilotinib, dasatinib, bosutinib, and radotinib (RTB), followed the groundbreaking introduction of imatinib. RTB occupies the unique position of being the least explored member of this class. While nilotinib, dasatinib, and bosutinib have garnered significant attention and extensive research focus, RTB remains relatively uncharted in comparison to its counterparts. Fundamental drug characteristics, such as the pharmacokinetic and pharmacodynamic properties of RTB, remain unavailable in existing sources. Compared to other 2GTKIs, RTB has been less utilized in combinatorial drug studies, and no investigations have been reported on its effects on solid tumors to date. However, the effects of RTB have been studied in acute myeloid leukemia (AML), multiple myeloma (MM), Parkinson's disease, and idiopathic pulmonary fibrosis (IPF). Although RTB has been investigated in some conditions, these studies are still in their preliminary stages and are comparatively lesser than studies on other 2GTKIs. This review is the first attempt that extensively presents a compilation of data on RTB and describes its therapeutic potential against blood and solid tumors. Further investigations on RTB could expand its chemotherapeutic usage in various solid tumors and enhance the possibility of drug repurposing in cancer therapy.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108017"},"PeriodicalIF":4.5,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794040","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}