Bioorganic Chemistry最新文献

{"title":"A mini review of supramolecular antagonists based on macrocyclic host compounds.","authors":"Shanshan Li, Pengcheng Li, Yuhan Tian, Rui Zeng, Qixiong Zhang, Chuan Pi","doi":"10.1016/j.bioorg.2024.107974","DOIUrl":"10.1016/j.bioorg.2024.107974","url":null,"abstract":"<p><p>In the interdisciplinary domains of medicine and chemistry, addressing the issue of residual drugs (toxicants) that fail to fully exert therapeutic effects while potentially inducing toxic side effects has become increasingly critical. Researchers are actively seeking innovative solutions to this multifaceted challenge. Conventional small-molecule antagonists, commonly used in clinical settings, typically depend on \"drug-receptor interactions\" yet pose substantial developmental challenges. Recent advancements in the investigation of macrocyclic host compounds present a promising alternative. By leveraging the principles of host-guest chemistry, these macrocyclic hosts form stable inclusion complexes with residual drugs (toxicants), thereby decreasing their free concentration in the bloodstream and effectively mitigating associated toxic side effects. Consequently, macrocyclic host compounds represent a novel class of supramolecular antagonists (SAs). This article reviews recent progress in the application of macrocyclic host molecules-such as cyclodextrin, calix[n]arene, pillar[n]arene, and cucurbit[n]uril-as SA and examines current issues and future development prospects within the field.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107974"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685675","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":"Identification of adenosine analogues as nsp14 N7‑methyltransferase inhibitors for treating coronaviruses infection.","authors":"Qishu Chen, Qifan Zhou, Sidi Yang, Fan Pan, Hongqi Tao, Yuanmei Wen, Yang Chao, Cailing Xie, Weixin Ou, Deyin Guo, Yingjun Li, Xumu Zhang","doi":"10.1016/j.bioorg.2024.107894","DOIUrl":"10.1016/j.bioorg.2024.107894","url":null,"abstract":"<p><p>Coronaviruses are RNA viruses that have coevolved with humans and animals over time, exhibiting high mutation rates and mortality rates upon epidemic outbreaks. The nonstructural protein (nsp14) is crucial for various coronaviruses processes, including genome replication, protein translation, virus particle assembly, and evasion of host immunity via RNA methylation modification. In this study, a series of adenosine analogs were designed, synthesized, and evaluated for their inhibitory activities. Among them, MTI013 exhibited the strongest nsp14 MTase inhibition and antiviral activity, with an IC₅₀ of 10.33 μM in HCoV-229E-infected Huh7 cells, along with low cytotoxicity. When combined with the RdRp inhibitor ATV014, MTI013 showed a synergistic antiviral effect, indicating its potential both as a standalone therapy and in combination treatments. Furthermore, MTI013 displayed high selectivity against the SARS-CoV-2 nsp10-nsp16 complex and five human methyltransferases. These results offer valuable structural insights for future exploration of nsp14 as a drug target for SARS-CoV-2 and other coronaviruses.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107894"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566703","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":"Functional interplay between short antimicrobial peptides and model lipid membranes.","authors":"Lorena Gratino, Marta Gogliettino, Marco Balestrieri, Alessandra Porritiello, Principia Dardano, Bruno Miranda, Rosa Luisa Ambrosio, Monica Ambrosio, Luigi Nicolais, Gianna Palmieri","doi":"10.1016/j.bioorg.2024.107939","DOIUrl":"10.1016/j.bioorg.2024.107939","url":null,"abstract":"<p><p>Antimicrobial peptides (AMPs) are considered an attractive generation of novel antibiotics due to their advantageous properties such as a broad spectrum of antimicrobial activity against pathogens, low cytotoxicity, and drug resistance. Although they have common structural features and it has been widely demonstrated that bacterial membranes represent the main target of the peptide activity, the exact mechanism underlying the membrane perturbation by AMPs is not fully understood. Nevertheless, all the proposed modes of action implicate the preliminary interaction of AMPs with the negatively charged lipids in bacterial membranes. Recently, the structural and functional characterization of two AMPs, RiLK1 and RiLK3, was reported. Specifically, both peptides were revealed to be multitalented compounds capable of binding Gram-positive and Gram-negative liposome models with high affinity, but their mechanism of action remains elusive. In this paper, the effects of RiLK1 and RiLK3 on vesicles mimicking prokaryotic and eukaryotic cell membranes were further examined by using different approaches. Fluorescence and quenching assays either by acrylamide or lipophilic probes suggested that the peptides were mainly located at the interface of the negatively charged membranes that mimicked those of Salmonella Typhimurium and Staphylococcus aureus, possibly oriented in a parallel manner. Furthermore, RiLK1 and RiLK3 caused a significant leakage of carboxyfluorescein from bacterial liposomes, demonstrating that they can permeabilize the target membranes at high doses. Conversely, both peptides appear to behave like cell penetrating peptides (CPPs) at concentrations near their MIC values evaluated against the bacterial targets. Moreover, Dynamic Light Scattering provided further insights on the mechanisms of antimicrobial peptide against the bacterial liposomes. Conclusively, in vitro experiments indicated that RiLK1 and RiLK3 displayed potent bacteriostatic efficacy at low micromolar concentrations against an antibiotic-resistant ESKAPE pathogen, making them a valuable tool in preventing and treating infections caused by such bacteria.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107939"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612327","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":"Computational Design, Synthesis, and Bioevaluation of 2-(Pyrimidin-4-yl) oxazole-4-carboxamide Derivatives: Dual Inhibition of EGFR^WT and EGFR^T790M with ADMET Profiling.","authors":"Nilesh Raghunath Khedkar, Milind Sindkhedkar, Alex Joseph","doi":"10.1016/j.bioorg.2024.107910","DOIUrl":"10.1016/j.bioorg.2024.107910","url":null,"abstract":"","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":" ","pages":"107910"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556564","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":"Construction of nucleus-targeted photosensitizer and highly effective photodynamic immunotherapy for cancer.","authors":"Yacong Liao, Xiaoping Lin, Zhenhu He, Juan Chen, Siping Tang, Wei Wang, Wen Chen","doi":"10.1016/j.bioorg.2024.108022","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.108022","url":null,"abstract":"<p><p>Nucleus is the largest and most important organelle within eukaryotic cells, containing most of the cell's genetic material, DNA. It serves as the central hub for genetic regulation and metabolism, making it an ideal target for subcellular drug delivery. The development of nucleus-targeted photosensitizers allows for the rapid and effective destruction of critical components such as DNA within the nucleus. This achieves the goal of efficiently eliminating cancer cells. However, most organic molecules, including photosensitizers, cannot penetrate the nuclear membrane, making the design and synthesis of nucleus-targeted photosensitizers both significant and challenging. The authors have designed and synthesized a nucleus-targeted activatable photosensitive probe (CMT-I). In vitro spectral analyses demonstrate that CMT-I is specifically activated by ct-DNA, significantly enhancing fluorescence-a 49-fold increase is observed upon binding. Furthermore, under 590 nm light irradiation, CMT-I effectively generates ¹O₂. Molecular docking show that CMT-I selectively binds to DNA through hydrogen bonds and ᴨ-ᴨ conjugation. RNA sequencing experiments reveal that photodynamic therapy activates immunity within tumor cells, triggering an adaptive immune response. In vivo therapeutic experiments further verify the enhanced anti-tumor immunity of CMT-I, which is crucial for effectively eliminating immunologically cold tumors and highlights the potential of DNA-targeted photodynamic therapy in precise cancer treatment.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108022"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790526","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":"Tryptophanol-derived oxazoloisoindolinone fluorescent probes for cellular localization studies of p53 activators.","authors":"Hélio L Barros, Margarida Espadinha, Sandra N Pinto, Ricardo J F Ferreira, Joana B Loureiro, Rita Silva, Lucília Saraiva, Ermelinda Maçôas, Maria M M Santos","doi":"10.1016/j.bioorg.2024.107898","DOIUrl":"10.1016/j.bioorg.2024.107898","url":null,"abstract":"<p><p>The protein p53 is a transcription factor with several key roles in cells, including acting as a tumour suppressor. In most human cancers its tumour suppressor function is inactivated, either through inhibition by negative regulators or by mutation in the TP53 gene. Thus, there is a high interest in developing molecules able to activate p53 tumour suppressor activity. Tryptophanol-derived isoindolinones are known to act as wild-type and mutant p53 activators. Specifically, SLMP53-1 is a non-fluorescent wild-type and mutant p53 R280K reactivator, with potent in vivo anti-tumour activity in HCT116 and MDA-MB-231 mice xenograft models. With the aim of studying tryptophanol-derived isoindolinones intracellular localization by fluorescence microscopy, three SLMP53-1 based fluorescent probes were prepared. Here we report the design, synthesis, photophysical characterization, antiproliferative activity and cell localization studies of these fluorescent probes. The previously described structure-activity relationships of the SLMP53-1 scaffold set the basis for the design the fluorescent probes. The probes were prepared by connecting a small fluorophore (dansyl or 7-nitrobenzofurazan) to the indole nitrogen of the tryptophanol-derived oxazoloisoindolinone SLMP53-1 through two different linkers. The antiproliferative activity and cell localization studies of the three fluorescent probes were performed in HCT116 cells. The three probes showed enhanced internalization when compared with their fluorophore-linker intermediates, good photo-stability and high affinity for the endoplasmic reticulum, indicating the potential involvement of endoplasmic reticulum in the mechanism of action of tryptophanol-derived oxazoloisoindolinones.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107898"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491818","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 FXR partial agonistic activity of anthranilic acid derivatives bearing aryloxy moiety as therapeutic agents for metabolic dysfunction-associated steatohepatitis.","authors":"Cong Chen, Xianghui Zhou, Wa Cheng, Xin Li, Bing Zhang, Jiaojiao Tu, Jieyun Meng, Yanfen Peng, Xiaoqun Duan, Qiming Yu, Xiangduan Tan","doi":"10.1016/j.bioorg.2024.107940","DOIUrl":"10.1016/j.bioorg.2024.107940","url":null,"abstract":"<p><p>Farnesoid X receptor (FXR) is considered a promising therapeutic target for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Increasing evidence suggests that targeting FXR with full agonists may lead to side effects. FXR partial agonists, which moderately activate FXR signaling, are emerging as a feasible approach to mitigate side effects and address MASH. Herein, a series of novel anthranilic acid derivatives bearing aryloxy moiety were designed and synthesized using a hybrid strategy from the previously identified FXR partial agonists DM175 and AIV-25. Particularly, compound 26 exhibited potent FXR partial agonistic activity in a dual-luciferase reporter gene assay with an EC₅₀ value of 0.09 ± 0.02 µM (75.13 % maximum efficacy relative to OCA). In the MASH mice model, compound 26 significantly ameliorated the pathological features of the liver, including steatosis, inflammation, and fibrosis. In addition, compound 26 displayed high selectivity, good oral bioavailability, high liver distribution, as well as an acceptable safety profile. Molecular simulation studies showed that compound 26 fitted well with the binding site of FXR. Collectively, these findings demonstrated that compound 26 might serve as a promising candidate targeting FXR for MASH treatment.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107940"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602189","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":"Expression of PPAR-γ TF by newly synthesized thiazolidine-2,4-diones to manage glycemic control: Insights from in silico, in vitro and experimental pharmacology in wistar rats.","authors":"Shankar Gharge, Shankar G Alegaon, Shriram D Ranade, Rohini S Kavalapure, B R Prashantha Kumar, Pravin C Mhaske","doi":"10.1016/j.bioorg.2024.107966","DOIUrl":"10.1016/j.bioorg.2024.107966","url":null,"abstract":"<p><p>In pursuit of novel antidiabetic agents to combat type II diabetes mellitus, our study focused on identifying pharmacophoric features responsible for PPAR-γ expression, a key regulator of glucose homeostasis and lipid metabolism. This goal was achieved through pharmacophore model generation and screening of rationally designed library of thiazolidine-2,4-dione hybrids (7a-7f). The top hits were synthesized, characterized, and evaluated for their in vitro and in vivo antidiabetic activities. Among these, compounds 7b and 7c emerged as promising candidates, exhibiting significant in vitro inhibitory activity against human pancreatic α-amylase (HPA) and human liver α-glucosidase (HLAG) enzymes, along with enhanced glucose uptake in L6 myotube cell lines. Specifically, compound 7b showed 29.04 ± 1.13 µM HPA inhibition, 34.21 ± 1.16 µg/mL HLAG inhibition, and 77.12 ± 1.02 % glucose uptake, while compound 7c displayed 28.35 ± 1.01 µM HPA inhibition, 26.21 ± 1.17 µM HLAG inhibition, and 78.54 ± 0.54 % glucose uptake. Mechanistic studies revealed a dose-dependent increase in PPAR-γ transcription factor expression, supported by molecular docking that showed favorable interactions with key residues TYR473, SER289, and HIE323. Molecular dynamics simulations confirmed the stability of these interactions, and MM/GBSA binding free energy calculations indicated potential for further optimization. In vivo studies in STZ-induced diabetic Wistar rats demonstrated significant improvements in glucose homeostasis, insulin sensitivity, and lipid metabolism, with a notable decrease in triglycerides and VLDL levels. Compound 7c also showed an improved pharmacokinetic profile with a half-life of 4.01 h and an elimination rate constant of 0.325, compared to compound 7b. Both compounds enhanced glycogen content and antioxidant biomarkers, with a high safety profile (LD₅₀ of 500 mg/kg). Overall, compound 7c stands out as a promising lead for further development, with compound 7b also showing strong potential, providing valuable insights for future antidiabetic drug development efforts.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107966"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694891","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":"Copper(II) aromatic heterocyclic complexes of Gatifloxacin with multi-targeting capabilities for antibacterial therapy and combating antibiotic resistance.","authors":"Xiao-Yin Wu, Qi-Yan Liu, Shan Jiang, Zheng-Yin Pan, Jia-Hao Dong, Bai-Hua Chen, Jin-Hao Li, Ya-Shu Liu, Yingju Liu, Liang He","doi":"10.1016/j.bioorg.2024.107938","DOIUrl":"10.1016/j.bioorg.2024.107938","url":null,"abstract":"<p><p>In recent years, the pace of novel antibiotic development has been relatively slow, intensifying the urgency of the antibiotic resistance issue. Consequently, scientists have turned their attention to enhancing antibiotic activity by coordinating antibiotics with metal elements. This study designs and synthesizes three novel antibacterial copper complexes based on Gatifloxacin. These complexes exhibit potent antibacterial activity, notably Cu-1, with a minimum inhibitory concentration (MIC) of only 0.063 μg/mL against Staphylococcus aureus (S.aureus), demonstrating potent bacteriostatic capabilities. Further investigations unveil the antibacterial mechanisms of complex Cu-1, revealing its ability not only to suppress the activities of DNA gyrase and topoisomerases IV, but also to effectively inhibit biofilm formation and disrupt the integrity of cell membrane. This multi-targeting action contributes to mitigating the risk of bacterial resistance emergence. Additionally, synergy between Cu-1 and conventional antibiotics is confirmed through checkerboard assays, offering novel strategies for antibacterial therapy. In vivo experiments using a murine model of S.aureus infection demonstrate the significant antibacterial efficacy of Cu-1, providing robust support for its potential in treating S.aureus infections. This study demonstrates that the coordination complexes formed by copper, Gatifloxacin and suitable aromatic heterocyclic ligands exhibit multi-targeting characteristics against bacteria, offering a new direction for combating antibiotic resistance in antibacterial therapy.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107938"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613406","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 AAK1/HDACs dual inhibitors against SARS-CoV-2 entry.","authors":"Nian-Dong Mao, Yueying Xu, Xia Yao, Yuan Gao, Zi Hui, Hao Che, Chenchen Wang, Jinshan Lu, Jie Yu, Suwen Hu, Hang Zhang, Xiang-Yang Ye","doi":"10.1016/j.bioorg.2024.107973","DOIUrl":"10.1016/j.bioorg.2024.107973","url":null,"abstract":"<p><p>AP2-associated protein kinase 1 (AAK1) is a crucial regulator of clathrin-mediated endocytosis, involved in various cellular processes, including viral infection. Histone deacetylases (HDACs) are essential in regulating gene transcription through the process of histone deacetylation and have become promising therapeutic targets for the treatment of cancer and viral infections. In this study, several AAK1/HDACs dual inhibitors based on our previous reported compounds were designed and synthesized, and the antiviral activity of these dual inhibitors were evaluated. Among them, compound 12 showed remarkable dual inhibitory activity against both AAK1 and HDACs, with IC₅₀ values of 15.9 nM for AAK1, 148.7 nM for HDAC1, and 5.2 nM for HDAC6. Notably, this compound exhibited superior efficacy in suppressing SARS-CoV-2 entry into host cells compared to its close analogs 4, 13a, and 13b. Mechanistically, compound 12 attenuated AAK1-induced phosphorylation of adaptor protein-2 μ subunit (AP2M1) threonine 156, disrupting the direct interaction between AP2M1 and ACE2, thus inhibiting the CME-mediated SARS-CoV-2 endocytosis. Additionally, compound 12 increased the acetylation levels of H3K27 and α-tubulin, suggesting its potential as an epigenetic modulator. Overall, our findings propose compound 12 as a promising dual inhibitor against AAK1 and HDACs, highlighting its therapeutic potential in antiviral infections.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107973"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708820","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}