Bioorganic & Medicinal Chemistry Letters最新文献

{"title":"Synthesis, antiproliferative activity, and biological profiling of C-19 trityl and silyl ether andrographolide analogs in colon cancer and breast cancer cells","authors":"Tiffany Gu ,&nbsp;Rushika Raval ,&nbsp;Zachary Bashkin ,&nbsp;Carina Zhou ,&nbsp;Sanghyuk Ko ,&nbsp;Natalie Kong ,&nbsp;Seoyeon Hong ,&nbsp;Aditya Bhaskara ,&nbsp;Samarth Shah ,&nbsp;Aditi Joshi ,&nbsp;Samahith Thellakal ,&nbsp;Kaitlyn Rim ,&nbsp;Anushree Marimuthu ,&nbsp;Srishti Venkatesan ,&nbsp;Emma Wang ,&nbsp;Sophia Li ,&nbsp;Aditi Jayabalan ,&nbsp;Alice Tao ,&nbsp;Yilin Fang ,&nbsp;Lorelei Xia ,&nbsp;Edward Njoo","doi":"10.1016/j.bmcl.2025.130163","DOIUrl":"10.1016/j.bmcl.2025.130163","url":null,"abstract":"<div><div>Andrographolide, a labdane diterpenoid isolated from <em>Andrographis paniculata</em>, putatively functions through covalent inhibition of NF-κB, a transcription factor that modulates tumor survival and metastasis. Previous studies have found that functionalization of the C-19 hydroxyl alters the primary mode of action from inhibition of NF-κB to the modulation of the Wnt1/β-catenin signaling pathway. Here, we synthesized a series of twelve C-19 trityl and silyl ether analogs, including three novel substituted trityl analogs and four novel substituted silyl analogs of andrographolide. MTT assays revealed cell line selectivity between colorectal and breast cancer cells, which is consistent with known mechanisms of β-catenin-driven cell proliferation in colorectal cancer cell lines. Most compounds exhibited cell line specific antiproliferative activity in HCT-116 and HT-29 colorectal cancer cell lines. Specifically, within 24 h, C-19 analogs of andrographolide exhibit far more limited antiproliferative activity in MCF-7 breast cancer cells compared to HCT-116, HT-29, and MDA-MB-231 cells. Through <em>in vitro</em> TNF-α-dependent NF-κB reporter and Wnt1-dependent luciferase reporter assays, we observed that several analogs generally exhibit greater inhibitory activity compared to andrographolide. Fluorescence imaging demonstrated that cells treated with andrographolide and its C-19 analogs retained similar distributions of active β-catenin, but notable differences in antiproliferative potency upon co-delivery with GSK-3β inhibitor CHIR99021 indicate that several lead compounds exhibit attenuated biological activity selectively in HT-29 cells. Collectively, this work indicates that modest structural modifications at C-19 of andrographolide can have profound implications for its biological activity in mechanisms connected to its anticancer activity.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130163"},"PeriodicalIF":2.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-activity of Bastadins from the marine sponge Ianthella basta. Modulators of the RYR1 Ca2+ channel","authors":"Melanie A. Franklin ,&nbsp;Mariam N. Salib ,&nbsp;Juliette Gafni ,&nbsp;Isaac N. Pessah ,&nbsp;Tadeusz F. Molinski","doi":"10.1016/j.bmcl.2025.130165","DOIUrl":"10.1016/j.bmcl.2025.130165","url":null,"abstract":"<div><div>The RYR1 Ca²⁺ channel mediates essential steps of excitation-contraction in skeletal muscle. Bastadins-5 and -6, highly brominated macrodilactams assembled from tyrosine and tyramine by the marine sponge <em>Ianthella basta</em>, were identified as potent sensitizers of RYR1 channel activation. Here, we present a structure-activity relationships study of a wide panel of bastadins, and related analogs, and define the minimum requirements for stabilizing the RYR1 complex open or closed conformations.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130165"},"PeriodicalIF":2.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenyl urea based adjuvants for β-lactam antibiotics against methicillin resistant Staphylococcus aureus","authors":"Hailey S. Butman ,&nbsp;Monica A. Stefaniak ,&nbsp;Danica J. Walsh ,&nbsp;Vijay S. Gondil ,&nbsp;Mikaeel Young ,&nbsp;Andrew H. Crow ,&nbsp;Ansley M. Nemeth ,&nbsp;Roberta J. Melander ,&nbsp;Paul M. Dunman ,&nbsp;Christian Melander","doi":"10.1016/j.bmcl.2025.130164","DOIUrl":"10.1016/j.bmcl.2025.130164","url":null,"abstract":"<div><div>Penicillin binding protein 4 (PBP4) is essential for <em>Staphylococcus aureus</em> cortical bone osteocyte lacuno-canalicular network (OLCN) invasion, which causes osteomyelitis and serves as a bacterial niche for recurring bone infection. Moreover, PBP4 is also a key determinant of <em>S. aureus</em> resistance to fifth-generation cephalosporins (ceftobiprole and ceftaroline). From these perspectives, the development of <em>S. aureus</em> PBP4 inhibitors may represent dual functional therapeutics that prevent osteomyelitis, and reverse PBP4-mediated β-lactam resistance. A high-throughput screen for small molecules that inhibit <em>S. aureus</em> PBP4 function identified compound <strong>1</strong>. We recently described a preliminary structure activity relationship (SAR) study on <strong>1</strong>, identifying several compounds with increased PBP4 inhibitory activity, some of which also inhibit PBP2a. Herein, we expand our exploration of phenyl ureas as antibiotic adjuvants, investigating their activity with penicillins and additional cephalosporins against PBP2a-mediated methicillin-resistant <em>S. aureus</em> (MRSA). We screened the previously reported pilot library, and prepared an additional series of phenyl ureas based on compound <strong>1</strong>. Lead compounds potentiate multiple β-lactam antibiotics, lowering minimum inhibitory concentrations (MICs) below susceptibility breakpoints, with up to 64-fold reductions in MIC.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130164"},"PeriodicalIF":2.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bulky substrates of isoleucine 2-epimerase: α-Neopentylglycine and NV-5138","authors":"Noa T. Sorbara ,&nbsp;Amanda K.A. Black ,&nbsp;Stephen L. Bearne","doi":"10.1016/j.bmcl.2025.130160","DOIUrl":"10.1016/j.bmcl.2025.130160","url":null,"abstract":"<div><div>Isoleucine 2-epimerase from <em>Lactobacillus buchneri</em> (<em>Lb</em>IleE) catalyzes the pyridoxal 5′-phosphate-dependent, reversible, racemization or epimerization of nonpolar amino acids at the C-2 position. The integral role of the enzyme in the biosynthesis of branched-chain <span>d</span>-amino acids makes it a potential target for the development of antimicrobial agents. Probing the hydrophobic active-site pocket with a series of alkyl boronic acids, we show that the hydrophobic pocket accommodates the neopentyl group with enhanced binding affinity relative to the sec-butyl group. Subsequently, we show that <em>Lb</em>IleE catalyzes the racemization of <span>l</span>- and <span>d</span>-α-neopentylglycine, exhibiting binding affinities for these substrates 6- and 24-fold greater than those for <span>l</span>-Ile and <span>d</span>-<em>allo</em>-Ile, but with catalytic efficiencies (<em>k</em>_cat/<em>K</em>_m) reduced 46- and 27-fold, respectively. NV-5138 is a ligand of the leucine-binding site of Sestrin2, which activates the mechanistic target of rapamycin complex1 (mTORC1) and is structurally similar to α-neopentylglycine. Our demonstration that <em>Lb</em>IleE catalyzes the racemization of <span>l</span>-NV-5138 (<em>k</em>_cat/<em>K</em>_m = 2.2 ± 0.2 s⁻¹ mM⁻¹), along with the fact that <em>L</em>. <em>buchneri</em> can be present in the human gut microbiome, suggests that formation of <span>d</span>-NV-5138 could occur in humans when <span>l</span>-NV-5138 is used as a pharmacological intervention for depression.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130160"},"PeriodicalIF":2.5,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of 1,3-Disubstituted Pyrazole derivatives as Mycobacterium tuberculosis inhibitors","authors":"Guoquan Wan ,&nbsp;Chao Gao ,&nbsp;Xiaorui Zhang ,&nbsp;Huapei Qiu ,&nbsp;Qifan Tang ,&nbsp;Jumei Zeng ,&nbsp;Luoting Yu","doi":"10.1016/j.bmcl.2025.130156","DOIUrl":"10.1016/j.bmcl.2025.130156","url":null,"abstract":"<div><div>Tuberculosis is a global epidemic caused by <em>Mycobacterium tuberculosis</em>, predominantly impacting underprivileged regions worldwide. Here, we identified a novel 1,3-disubstituted pyrazole derivative, compound <strong>A</strong>, that exhibits antitubercular activity through <em>in vitro</em> screening. Further SAR studies resulted in the identification of compounds <strong>4c</strong> and <strong>6b</strong>, which exhibited improved antitubercular activity, with MIC values of 5.34 and 5.04 μg/mL against H37Ra, respectively. Additionally, compounds <strong>4c</strong> and <strong>6b</strong> exhibited favorable safety profiles, showing no obvious toxicity to Vero, A549, and HepG2 cell lines. Our docking studies suggest that PptT may serve as one of the potential targets for these compounds. These encouraging results provide valuable insights for the development of novel structured antitubercular agents.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130156"},"PeriodicalIF":2.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and evaluation of a targeted PET radioligand [18F]FCOB02 for monoamine oxidase B","authors":"Zhixiong Zhang ,&nbsp;Ge Zhang ,&nbsp;Jingquan Xue ,&nbsp;Yuxuan Zhang ,&nbsp;Yu Liu ,&nbsp;Wenjiang Yang ,&nbsp;Jianjun Wang","doi":"10.1016/j.bmcl.2025.130157","DOIUrl":"10.1016/j.bmcl.2025.130157","url":null,"abstract":"<div><div>Monoamine oxidase B (MAO-B) is a membrane-bound flavinase that plays an important role in the regulation of monoamine neurotransmission. Positron emission tomography (PET) provides a way to study the molecular mechanisms of MAO-B-related diseases and to evaluate the effects of drugs. In this study, we designed and synthesized [¹⁸F]FCOB02, a 4-methylcoumarin-like targeting probe.[¹⁸F]FCOB02 is straightforward to synthesize and has a high affinity for MAO-B with an IC₅₀ = 10.68 ± 3.25 nM. Successful radiolabeling with fluorine-18 was achieved, resulting in a labeling rate of 35 % along with favorable lipid solubility (log <em>D</em>_7.4 = 2.4). Automated radiolabelling was achieved after optimization of the conditions. The radiochemical yield was 9.6 % ± 1.2 %(<em>n</em> = 3) with good radiochemical purity (&gt;98 %), good stability in saline for 4 h and high specific activity (105.08 ± 19GBq/μmol，n = 3). Biodistribution studies conducted in mice revealed significant initial brain uptake of 8.22 ± 0.86 % ID/g at 2 min post-injection, followed by rapid metabolism primarily via the liver and kidneys. Brain uptake was comparable to the same type of probe [¹⁸F]SMBT-1 (brain _2min = 7.85 % ID/g). PET-CT images of [¹⁸F]FCOB02 in SD rats showed significant differences in brain uptake before and after inhibition by the inhibitor L-deprenyl. Whole brain uptake was reduced by 20 % after inhibition, indicating specific uptake of the probe in the brain, with a 40-min brain clearance rate of 81 %. The potential utility of [¹⁸F]FCOB02 for achieving specific MAO-B imaging as well as quantitative analysis in vivo warrants further investigation regarding its clinical translational value.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130157"},"PeriodicalIF":2.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143512106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 sulfur-containing tetrahydroxanthones as potential anti-tumor agents","authors":"Huimin Zheng ,&nbsp;Youyi Wang ,&nbsp;Yitao Ren ,&nbsp;Xueying Wang ,&nbsp;Lu Sui ,&nbsp;Hongxi Xu ,&nbsp;Changwu Zheng","doi":"10.1016/j.bmcl.2025.130154","DOIUrl":"10.1016/j.bmcl.2025.130154","url":null,"abstract":"<div><div>Given the rising incidence and mortality rates of cancer, the development of highly effective, low-toxicity therapeutics is critical. Xanthones, a class of natural secondary metabolites, are notable for their distinct structure and exhibit promising antitumor activity, underscoring their potential as scaffolds for drug design. Sulfur heterocycles are also valuable in the development of bioactive small molecules. Therefore, we explored the introduction of sulfur in the core structure of xanthones, leading to the synthesis of a series of sulfur-containing tetrahydroxanthones. The in vitro cytotoxicity of these compounds was evaluated using the CCK8 assay, revealing that several derivatives exhibit anti-proliferative effects against HepG2 cells. Among them, compound <strong>4</strong><strong>k</strong> displayed potent inhibitory activity with an IC₅₀ value of 6.08 μM and showed favorable selectivity, exhibiting low toxicity toward normal cells. Further studies demonstrated that <strong>4</strong><strong>k</strong> inhibited colony formation and migration of HepG2 cells, and induced apoptosis.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130154"},"PeriodicalIF":2.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery and biological evaluation of carborane-containing derivatives as TEAD auto palmitoylation inhibitors","authors":"Chaofan Li ,&nbsp;Yingshuang Zhang ,&nbsp;Ziyin Zhang ,&nbsp;Yirong Zhang ,&nbsp;Yuxuan Song ,&nbsp;Linyuan Wang ,&nbsp;Changxian Yuan ,&nbsp;Guanxiang Hao ,&nbsp;Nan Sun ,&nbsp;Hongjing Li ,&nbsp;Zhiguang Zhang ,&nbsp;Yundong He ,&nbsp;Sinan Wang","doi":"10.1016/j.bmcl.2025.130155","DOIUrl":"10.1016/j.bmcl.2025.130155","url":null,"abstract":"<div><div>Transcriptional enhanced associate domain (TEAD) proteins are key downstream effectors of the Hippo signaling pathway that play a crucial role in various cell processes including tissue development, regeneration, cell proliferation and cancer. TEADs contain a hydrophobic auto-palmitoylation pocket that can bind palmitic acid and stabilize TEADs from being degraded. Inhibitors targeting this palmitoylation pocket typically consist of hydrophobic pharmacophores. Carboranes is a cage-shaped molecule exhibiting superior hydrophobicity compared to adamantane or phenyl groups. Herein, we incorporated carborane into known TEAD inhibitors for better interaction with the hydrophobic palmitate pocket. Compounds <strong>1f</strong> and <strong>1l</strong> are identified as TEAD transcription inhibitors with strong anti-proliferation and anti-migration activities toward prostate cancer cell lines. They also significantly reduced TEAD-regulated downstream gene expressions.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130155"},"PeriodicalIF":2.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N-alkyl substituted armeniaspirol analogs show potent antibiotic activity and have low susceptibility to resistance","authors":"Michael G. Darnowski,&nbsp;Taylor D. Lanosky,&nbsp;Antonio D. Spada,&nbsp;Jason Ma,&nbsp;André R. Paquette,&nbsp;Christopher N. Boddy","doi":"10.1016/j.bmcl.2025.130137","DOIUrl":"10.1016/j.bmcl.2025.130137","url":null,"abstract":"<div><div>The armeniaspirol family of antibiotics have been shown to inhibit the ATP-dependent proteases ClpXP and ClpYQ and to disrupt the electrical membrane potential (ΔΨ) bacterial proton motive force. The synthesis and characterization of first generation armeniaspirol analogs shows the <em>N</em>-alkyl group is amenable to modification. Herein we synthesize eleven second generation <em>N</em>-alkyl analogs and show they display excellent antibiotic potency against multiple MRSA strains and retain the ability to disrupt membrane electrical potential. We also show that it is difficult to generate resistant MRSA mutants to these new compounds, making them appealing leads for new antibiotic development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130137"},"PeriodicalIF":2.5,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sensitive and reliable gastric ulcer related MicroRNA detection by bridge catalytic hairpin assembly (bCHA) mediated primer exchange reaction","authors":"Ligong Wang ,&nbsp;Shan Zhao ,&nbsp;Pang Hui ,&nbsp;Kaige Zhang","doi":"10.1016/j.bmcl.2025.130153","DOIUrl":"10.1016/j.bmcl.2025.130153","url":null,"abstract":"<div><div>MicroRNAs (miRNA) have a significant role in the progression of gastric ulcer, and the sensitive and reliable detection of miRNAs is pivotal for the early diagnosis and treatment of gastrointestinal diseases. In this study, we developed a novel and efficient method for detecting miRNA-122, a crucial biomarker used to assess the prognosis of gastric ulcers. This method combines the bridge catalytic hairpin assembly (bCHA)-based target sequence recycling with the primer exchange reaction (PER), resulting in a highly sensitive and label-free approach. Specifically, the bridge CHA technique, which offers superior target recognition accuracy and increased signal amplification efficiency compared to the classic CHA procedure, can selectively identify the target miRNA and release the complementary sequence to serve as a primer to facilitate the PER. This PER process produces a large number of G-quadruplex sequences, which then bind with thioflavin T to significantly increase its fluorescence. This enhanced fluorescence is used to detect miRNA-122, with a detection limit as low as 3.12 fM. The proposed approach can achieve exact discrimination of the target miRNA-122. Due to its label-free character, high selectivity, and sensitivity, this technology can serve as a practical and universal approach for detecting different biomarkers in the early stages of gastrointestinal diseases.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130153"},"PeriodicalIF":2.5,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}