Bioorganic & Medicinal Chemistry Letters最新文献

{"title":"Discovery of novel JAK3 inhibitors for the treatment of atopic dermatitis","authors":"Weijie Ren ,&nbsp;Lifang Cen ,&nbsp;Xinyue Li ,&nbsp;Jiajie Yu ,&nbsp;Shiqi Wu ,&nbsp;Jing Liu ,&nbsp;Luhua Wang ,&nbsp;Xiangying Kong ,&nbsp;Yi Zou ,&nbsp;Yungen Xu","doi":"10.1016/j.bmcl.2025.130219","DOIUrl":"10.1016/j.bmcl.2025.130219","url":null,"abstract":"<div><div>Janus kinase 3 (JAK3), a member of the Janus kinase family, plays a pivotal role in the signaling pathways of various pro-inflammatory cytokines such as IL-2 and IFN-<em>γ</em>. Compared to non-selective JAK inhibitors, selective JAK3 inhibitors specifically target distinct signaling pathways, thereby reducing the broad inhibition of other cytokines and minimizing potential side effects. This selectivity renders them potentially advantageous for the treatment of autoimmune and inflammatory disease. In this study, we describe the discovery of compound <strong>X15</strong>, a novel JAK3 inhibitor with potent JAK3 inhibitory activity (IC₅₀ = 14.56 nM) and an acceptable pharmacokinetic profile (F = 27.38 %, T_1/2 = 20.33 h). Furthermore, compound <strong>X15</strong> alleviated the symptoms of dermatitis in a DNCB-induced atopic dermatitis Balb/c mice model, with reduced ear thickness at a high dose (90 mg/kg, 0.038 mm) compared to the model group (0.106 mm). Preliminary mechanistic studies indicated that compound <strong>X15</strong> inhibited the production of inflammatory cytokines IL-2 and IL-6 when compared to the model group. Collectively, our findings suggest that compound <strong>X15</strong> is a novel covalent JAK3 inhibitor with promising <em>in vitro</em> and <em>in vivo</em> efficacy, potentially serving as a valuable molecular tool for exploring the biological functions of JAK3.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130219"},"PeriodicalIF":2.5,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834896","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":"Suppression of stress granule assembly by pyridoxal hydrochloride attenuates oxidative damage in skin fibroblasts","authors":"Seong Hyun Kim ,&nbsp;Yong Hwan Kim ,&nbsp;Joon Bum Kim ,&nbsp;Na Yeon Park ,&nbsp;Jun Hee So ,&nbsp;Daeun Park ,&nbsp;Dong Kyu Choi ,&nbsp;Eunbyul Yeom ,&nbsp;Youngdae Gwon ,&nbsp;Doo Sin Jo ,&nbsp;Jin-A Lee ,&nbsp;Ji-Eun Bae ,&nbsp;Dong-Hyung Cho","doi":"10.1016/j.bmcl.2025.130238","DOIUrl":"10.1016/j.bmcl.2025.130238","url":null,"abstract":"<div><div>Stress granules (SGs) are membrane-less cytoplasmic structures that form in response to various stress stimuli and play a critical role in maintaining cellular homeostasis. Dysregulation of SG dynamics has been implicated in several diseases, including neurodegenerative and inflammatory conditions; however, their role in skin biology remains largely unexplored. In this study, we identified pyridoxal hydrochloride, a form of vitamin B6, as a novel regulator of SG formation through a metabolite library screening. Our results demonstrate that pyridoxal hydrochloride significantly suppresses oxidative stress-induced SG formation in skin fibroblasts, exhibiting effects comparable to G3Ia, a known SG inhibitor. Furthermore, pyridoxal hydrochloride mitigates oxidative stress by reducing reactive oxygen species (ROS) accumulation and preventing cell toxicity. Notably, it also attenuates ROS-induced upregulation of MMP1, thereby preserving collagen1 stability. These findings suggest the crucial role of SGs in skin fibroblast homeostasis and suggest that pyridoxal hydrochloride may serve as a potential therapeutic agent for oxidative stress-related skin disorders.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130238"},"PeriodicalIF":2.5,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828462","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 of New Non-Symmetrical Heterocyclic Pentanoid Derivatives Targeting Metastatic Triple-Negative Breast Cancer","authors":"Poh Yen Khor ,&nbsp;Johnson Stanslas ,&nbsp;Nurulfazlina Edayah Rasol ,&nbsp;Kok Meng Chan ,&nbsp;Phooi Yan Mock ,&nbsp;Kok Wai Lam","doi":"10.1016/j.bmcl.2025.130232","DOIUrl":"10.1016/j.bmcl.2025.130232","url":null,"abstract":"<div><div>This study describes the synthesis and structure-activity relationship (SAR) analysis of non- symmetrical heterocyclic pentanoid derivative as potential anti-cancer agents. The lead compound, <strong>5d</strong>, exhibited potent (IC₅₀ = 0.38 ± 0.05 μM) and selective (Selectivity Index: 2–9) growth inhibitory effects on the metastatic triple-negative breast cancer (TNBC) cells. Mechanistic studies revealed that <strong>5d</strong> attenuates proteasomal degradation activity via the ubiquitin-proteasome pathway, leading to G2/M phase cell cycle arrest and the induction of apoptotic cell death.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130232"},"PeriodicalIF":2.5,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847963","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":"Identification of small molecule activators targeting TYK2 pseudokinase domain","authors":"Hirokazu Matsumoto ,&nbsp;Tien-Cheng Wang ,&nbsp;Haruka Taniguchi ,&nbsp;Yu Nishioka ,&nbsp;Mariko Hatakeyama ,&nbsp;Takayoshi Kinoshita ,&nbsp;Masaaki Sawa","doi":"10.1016/j.bmcl.2025.130233","DOIUrl":"10.1016/j.bmcl.2025.130233","url":null,"abstract":"<div><div>Tyrosine kinase 2 (TYK2) plays a crucial role in both adaptive and innate immune responses. The catalytic activity of the TYK2 JH1 kinase domain is controlled by the TYK2 JH2 pseudokinase domain and stabilized to maintain its inactive state until the upstream receptor activations. Here, we report the discovery of aminopyridine analogs as novel TYK2 activators through structural modification of a known JH2 binder. Compound <strong>16b</strong> demonstrated a dose-dependent increase in TYK2 enzymatic activity.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130233"},"PeriodicalIF":2.5,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143843375","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 antiproliferative activity of thiazole bioisosteres of goniofufurone and 7-epi-goniofufurone","authors":"Miloš Svirčev ,&nbsp;Mirjana Popsavin ,&nbsp;Bojan Levovnik ,&nbsp;Sanja Djokić ,&nbsp;Jelena Kesić ,&nbsp;Ivana Kovačević ,&nbsp;Goran Benedeković ,&nbsp;Bojana Srećo Zelenović ,&nbsp;Velimir Popsavin ,&nbsp;Vesna Kojić","doi":"10.1016/j.bmcl.2025.130218","DOIUrl":"10.1016/j.bmcl.2025.130218","url":null,"abstract":"<div><div>Several new goniofufurone (<strong>1</strong>) and 7-<em>epi</em>-goniofufurone (<strong>2</strong>) mimics in which the benzene ring has been replaced with a thiazole residue have been designed, synthesized and evaluated for their antiproliferative activity against a panel of human tumour cell lines. The key steps of the synthesis represent the initial condensation of suitably protected furanose urononitriles with cysteine ethyl ester hydrochloride, followed by the subsequent oxidation of resulting C-4′ epimeric thiazolines with BrCCl₃ and DBU, to build up the thiazole ring. Biological studies have shown that the HeLa cell line is most sensitive to the action of synthesized analogues with IC₅₀ values in the range of 0.01–7.67 μM. The most active compound in this cell culture was 7-<em>epi</em>-goniofufurone mimic <strong>28</strong>, with a thiazole-carboxamide function at C-7 and a benzyloxy group at the C-5 position. Compound <strong>28</strong> exhibited 89-fold higher antiproliferative potency in this cell line than lead <strong>2</strong> and was 7-fold more active than the commercial antitumour agent doxorubicin. A SAR study identified structural features responsible for the antiproliferative activity of synthesized analogues. The analogues <strong>3</strong>–<strong>28</strong> are completely inactive toward the normal MRC-5 cell line. Their selectivity indexes (SI) range from 4.1 to 17,470.7.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130218"},"PeriodicalIF":2.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143800084","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":"The novel Piperine derivative YL-1-9 exhibits anti-breast Cancer effects by inducing apoptosis via the p53/p21 pathway","authors":"Chongyun Zhou ,&nbsp;Jiayun Wang ,&nbsp;Lili Zhou ,&nbsp;Hanxue Li ,&nbsp;Xing Liu ,&nbsp;Sen Wang ,&nbsp;Xingyu Zhang ,&nbsp;Xiaoqing Ye ,&nbsp;Hongyu Ren ,&nbsp;Kaile Zeng ,&nbsp;Xiuming Li ,&nbsp;Dan Wang ,&nbsp;Jing Ji","doi":"10.1016/j.bmcl.2025.130231","DOIUrl":"10.1016/j.bmcl.2025.130231","url":null,"abstract":"<div><div>The tumor suppressor protein p53 plays a crucial role in the pathogenesis of breast cancer; however, its function is often compromised due to MDM2 overexpression or mutations in the p53 gene, which occurs in approximately 30–35 % of breast cancer cases. Piperine, a natural bioactive compound, has shown potential in inhibiting breast cancer cell growth by upregulating p53 expression. However, its clinical application is hindered by poor bioavailability, potential toxicity, and the risk of undesirable drug interactions. In the present study, a novel derivative of Piperine, <strong>YL-1-9</strong>, was synthesized and evaluated for its anticancer activity against breast cancer. <strong>YL-1-9</strong>, a bicyclic amide derivative of Piperine, was evaluated for antitumor effects both in vitro and in vivo using MTT assays and the chick embryo chorioallantoic membrane (CAM) model. Further investigations into its effects on breast cancer cell clonogenicity, adhesion, invasion, and migration were conducted through colony formation assays, EdU assays, cell adhesion and invasion studies, and wound healing experiments. Western blot analysis was performed to elucidate the effects of <strong>YL-1-9</strong> on the cell cycle and apoptosis, which were further validated using YO-PRO-1 and propidium iodide dual staining. <strong>YL-1-9</strong> significantly inhibited breast cancer cell proliferation, adhesion, invasion, and migration, while inducing cell cycle arrest and promoting apoptosis. Mechanistically, <strong>YL-1-9</strong> downregulated critical proteins in the CDK4/6-cyclin D-Rb-E2F pathway and the Caspase 3/Bax/Bcl-2 apoptosis signaling pathway. These findings position <strong>YL-1-9</strong> as a promising candidate for breast cancer therapy; however, further clinical studies are necessary to fully assess its therapeutic potential.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130231"},"PeriodicalIF":2.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824109","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 of farnesoid X receptor antagonists from Salvia miltiorrhiza based on virtual screening and activity verification","authors":"Jiaojiao Tu ,&nbsp;Wa Cheng ,&nbsp;Zhenghu Ban,&nbsp;Jiayi Ning,&nbsp;Xiangduan Tan","doi":"10.1016/j.bmcl.2025.130222","DOIUrl":"10.1016/j.bmcl.2025.130222","url":null,"abstract":"<div><div>The farnesoid X receptor (FXR) is a promising therapeutic target for the treatment of non-alcoholic fatty liver disease (NAFLD). <em>Salvia miltiorrhiza</em>, a traditional Chinese medicine, has demonstrated significant efficacy in the prevention and treatment of liver diseases. Consequently, investigating the potential effects of <em>Salvia miltiorrhiza</em> on FXR could provide new insights for NAFLD treatment. This study explores whether active ingredients from <em>Salvia miltiorrhiza</em> can target FXR and serve as therapeutic agents for treating NAFLD. The findings revealed that cynaroside and lithospermic acid displayed strong FXR antagonistic activity, with IC₅₀ values of 5.41 ± 1.08 μM and 16.92 ± 2.68 μM, respectively. Salvianolic acid A also showed moderate activity (IC₅₀ = 56.35 ± 4.54 μM). MTT assays demonstrated that these three compounds were non-toxic to HepG2 and LO2 cells at a concentration of 200 μM. Molecular dynamics simulations were conducted to elucidate the interaction mechanisms of cynaroside and lithospermic acid with FXR. These results suggest that cynaroside and lithospermic acid from <em>Salvia miltiorrhiza</em> may be potential candidates for targeting FXR in treating NAFLD.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130222"},"PeriodicalIF":2.5,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810235","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 of novel Ebola entry inhibitors with 1,2,3,4-tetrahydroisoquinoline-3-carboxamide based on (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl) decahydroisoquinoline-3-carboxamide scaffold","authors":"Junzhen Lin ,&nbsp;Fuling Xiao ,&nbsp;Sheng Han ,&nbsp;Youhong Hu ,&nbsp;Jianping Zuo ,&nbsp;Xiankun Tong ,&nbsp;Wuhong Chen","doi":"10.1016/j.bmcl.2025.130230","DOIUrl":"10.1016/j.bmcl.2025.130230","url":null,"abstract":"<div><div>Novel Ebola entry inhibitors were designed and synthesized based on decahydroisoquinolines by streamlining non-essential functional groups that do not compromise activity. All novel derivatives were evaluated for their anti-Ebola activities and cytotoxicitiies in a defective Ebola virus model. A novel tetrahydroisoquinoline Ebola virus entry inhibitor, <strong>Hu7</strong>, was readily available with antiviral activity comparable to previous findings, while demonstrating a marked reduction in toxicity. Such new compounds with simple and easy-to-synthesize structures could be potential leads for further optimizing the development of anti-Ebola drugs.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130230"},"PeriodicalIF":2.5,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143808194","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":"Optimization of a DNA encoded library derived autotaxin inhibitor hit to a potent in vivo LPA lowering quinazolinone compound with a non‑zinc binding mode","authors":"Rainer E. Martin ,&nbsp;Alexander L. Satz ,&nbsp;Christoph Kuratli,&nbsp;Daniel Hunziker ,&nbsp;Patrizio Mattei ,&nbsp;Jérôme Hert ,&nbsp;Christoph Ullmer ,&nbsp;Markus G. Rudolph ,&nbsp;André M. Alker,&nbsp;Remo Hochstrasser,&nbsp;Andreas Marx,&nbsp;Martin Binder,&nbsp;Stephan Müller","doi":"10.1016/j.bmcl.2025.130221","DOIUrl":"10.1016/j.bmcl.2025.130221","url":null,"abstract":"<div><div>In recent years, lysophospholipase autotaxin (ATX) has emerged as an attractive target for treating a variety of human diseases, including inflammation, neurodegeneration, angiogenesis, cancer, ocular and fibrotic diseases, among others. Starting with the quinazolinone hit structure <strong>1,</strong> which emerged from a DNA-encoded library screen, the potent, non-Zn²⁺ binding ATX inhibitor <strong>31</strong> with good overall physicochemical properties has been developed. This compound demonstrated a sustained reduction of lysophosphatidic acid (LPA) in an <em>in vivo</em> rat experiment, qualifying it as a proof-of-concept compound for further mechanistic studies.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130221"},"PeriodicalIF":2.5,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802182","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 and synthesis of β-carboline-benzofuran based hybrids as antibacterial agents against Staphylococcus aureus","authors":"Mursalim Ali Khan ,&nbsp;Kishan Kumar Parida ,&nbsp;Dastari Sowmya ,&nbsp;Naveen Chand Rallabandi ,&nbsp;Nitin Pal Kalia ,&nbsp;Nagula Shankaraiah","doi":"10.1016/j.bmcl.2025.130220","DOIUrl":"10.1016/j.bmcl.2025.130220","url":null,"abstract":"<div><div>The significant threat posed by <em>Staphylococcus aureus</em> (MRSA) is attributed to various antibiotic resistance and its role in severe infections. As an approach to combat this, a series of novel β-carboline-benzofuran based molecular hybrids were designed, synthesized, and evaluated for their antibacterial activity against <em>Staphylococcus aureus</em> ATCC 29213. Among the series, the minimum inhibitory concentration (MIC) of key compounds <strong>13e</strong>, <strong>13</strong> <strong>h</strong>, and <strong>13q</strong> was determined to be 4 μg/mL, compared to ciprofloxacin 0.125 μg/mL. The docking results also supported the potent compounds' ability to inhibit DNA gyrase. These compounds demonstrated bacteriostatic effects at higher concentrations, with significant inhibition of biofilm formation (MBIC₅₀ ranging from 12.78 to 30.68 μg/mL). Additionally, the compounds displayed minimal cytotoxicity against HepG2 cells and inhibited DNA gyrase, which is proven by DNA supercoiling assays and molecular docking studies. In addition, ADMET predictions indicated favorable drug-like properties, adhering to Lipinski's rule of five. These findings suggest that the synthesized β-carboline-benzofuran hybrids possess significant potential as leads for developing new antibacterial agents against MRSA.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130220"},"PeriodicalIF":2.5,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794401","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}