Bioorganic & Medicinal Chemistry Letters最新文献

{"title":"Isoquinocycline B induces G0/G1 cell cycle arrest and apoptosis in MDA-MB-231 cancer cells","authors":"Gyeong Han Jeong ,&nbsp;Hanui Lee ,&nbsp;Ja Young Cho ,&nbsp;Jung-Rae Rho ,&nbsp;Byung Yeoup Chung ,&nbsp;Sanghwa Park ,&nbsp;Hyoung-Woo Bai","doi":"10.1016/j.bmcl.2025.130244","DOIUrl":"10.1016/j.bmcl.2025.130244","url":null,"abstract":"<div><div>Breast cancer remains one of the leading causes of cancer-related deaths, with therapeutic resistance and limited treatment options posing significant challenges. This study investigated the anticancer properties of isoquinocycline B (IQCB), an anthraquinone derivative obtained from a freshwater sponge microbiome <em>Micromonospora</em> sp. MS-62 (FBCC-B8445), against the MDA-MB-231 human breast cancer cell line. IQCB showed the greatest activity against cytotoxicity with an IC₅₀ values of 9.2 ± 1.0 μM. IQCB treatment led to G0/G1 cell cycle arrest and apoptosis through mitochondrial pathways by suppressing cyclin D1/CDK4 expression, enhancing p27 levels, and reducing phosphorylated Akt levels. Furthermore, IQCB induced oxidative stress by promoting excessive reactive oxygen species (ROS) production, thereby activating JNK and p38-MAPK signaling while simultaneously inhibiting ERK phosphorylation. Apoptotic markers such as PARP cleavage and caspase-3 activation confirmed that mitochondrial-mediated apoptosis was a key mechanism of action. These results highlight the potential of IQCB as a therapeutic candidate for breast cancer and underscore the need for further research to explore its efficacy and mechanisms.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130244"},"PeriodicalIF":2.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143867876","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":"Mini review: SHEN26, a novel oral antiviral drug for COVID-19 treatment","authors":"Peisen Zheng ,&nbsp;Guanguan Li ,&nbsp;Yuanguang Chen ,&nbsp;Shuo Li ,&nbsp;Sidi Yang ,&nbsp;Deyin Guo ,&nbsp;Qifan Zhou ,&nbsp;Xumu Zhang","doi":"10.1016/j.bmcl.2025.130243","DOIUrl":"10.1016/j.bmcl.2025.130243","url":null,"abstract":"<div><div>Over two years into the pandemic, global collaboration led to effective antiviral drugs targeting SARS-CoV-2's RdRp and 3CL protease. However, the virus continues to evolve, and certain low-virulence variants still circulate. Despite reduced virulence, ongoing transmission raises the risk of new mutations, underscoring the need for continued vigilance, research, and expansion of our antiviral and vaccine strategies. Our research team has developed SHEN26, a promising small-molecule antiviral drug for the treatment of COVID-19. This mini-review explores its development, including history, synthesis, preclinical evaluations, and findings from Phase I and II clinical trials. Data from each research phase further underscores SHEN26's potential as a safe and effective oral antiviral treatment for COVID-19, while also emphasizing its broader relevance in combating emerging RNA viral infections.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130243"},"PeriodicalIF":2.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876785","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":"Biological evaluation as antimalarial of two families of biscationic compounds featuring two different sulphur linkers","authors":"Pilar M. Luque Navarro ,&nbsp;M. Paz Carrasco-Jiménez ,&nbsp;Emilio Parisini ,&nbsp;Daniela Lanari ,&nbsp;Laura M. Odina ,&nbsp;Atis Jekabsons ,&nbsp;Sonia Perales ,&nbsp;Diana Zelencova-Gopejenko ,&nbsp;Guiomar Pérez-Moreno ,&nbsp;Cristina Bosch-Navarrete ,&nbsp;Dolores González-Pacanowska ,&nbsp;Luisa Carlota López-Cara","doi":"10.1016/j.bmcl.2025.130241","DOIUrl":"10.1016/j.bmcl.2025.130241","url":null,"abstract":"<div><div><em>Plasmodium falciparum</em> kinases have been widely studied due to their potential as targets for the discovery of alternatives to artemisinin-combined therapies. Their role in parasite blood-stage replication and their homology with human kinases has led to the exploitation of already tested antitumoral kinase inhibitors as antiplasmodial drugs. <em>Plasmodium falciparum</em> choline kinase (<em>Pf</em>CK), a cytosolic enzyme involved in phospholipid synthesis, is a promising target for parasite resistant strains. <em>Pf</em>CK uses the host choline and catalyzes its transformation in phosphocholine, a key step for the formation of the lipid membranes required by the new parasite progeny inside the erythrocyte. Previously, we described the synthesis of two libraries (<strong>PL</strong> and <strong>FP</strong>) of human choline kinase (hCK) inhibitors, which we generated following a <em>green by design</em> approach. Some of these compounds were found to exhibit antitumoral properties. Here, we evaluated the same compounds as potential inhibitors of <em>Pf</em>CK and antimalarial agents. Interestingly, while the compounds of the <strong>FP</strong> library, which feature a disulphide linker, show <em>Pf</em>CK inhibition in the nM range independently of the cationic head (<strong>FP3</strong> being the most active compound, <em>Pf</em>CK IC₅₀ = 0.16 μM), they show no effect on infected erythrocytes. On the other hand, the compounds of the <strong>PL</strong> library, which feature a dithioethane linker, show in vitro activity against the parasite but no inhibitory activity against the isolated enzyme (<strong>PL40</strong> exhibits the highest antimalarial activity, with IC₅₀ = 10 nM). This lack of correlation could be due to either cellular disulphide degradation in vitro or to the existence of alternative targets for the dithioethane library. Considering the previously reported anticancer potential of the <strong>PL</strong> family and the antiparasitic activity reported herein, these compounds may be considered as good starting points for the development of multifunctional drugs.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130241"},"PeriodicalIF":2.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143843261","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 2,4-diaminopyrimidine inhibitors of hematopoietic progenitor kinase 1","authors":"Chunting Li ,&nbsp;Jiuyu Liu ,&nbsp;Le Ren ,&nbsp;Long Zhang ,&nbsp;Na Zhang ,&nbsp;Shaoxuan Yan ,&nbsp;Yu Wang ,&nbsp;Siyu Fu ,&nbsp;Jiakuan Wei ,&nbsp;Hao Yue ,&nbsp;Yongshuo Wu ,&nbsp;Minghui Tong ,&nbsp;Xuan Shi ,&nbsp;Han Wang ,&nbsp;Dong Zhao ,&nbsp;Qingfeng Shao ,&nbsp;Yuanle Zhang ,&nbsp;Yanfang Zhao ,&nbsp;Yunlei Hou","doi":"10.1016/j.bmcl.2025.130242","DOIUrl":"10.1016/j.bmcl.2025.130242","url":null,"abstract":"<div><div>Cancer immunotherapy is an emerging anti-cancer strategy that enhances immune circulation by targeting the immune system. Among the various targets, HPK1, a member of the mammalian Ste20-like protein serine/threonine kinase family, serves as a crucial negative regulator of immune-mediated mechanisms, positioning it as a promising target for immunotherapy. Herein, based on the reported HPK1 inhibitors characterized by 2,4-diaminopyrimidine components, four series of derivatives were obtained through structural optimization methods. Compound <strong>10c</strong> demonstrates significant inhibitory effects on HPK1 kinase, with an IC₅₀ of 0.09 nM. Additionally, it markedly inhibits the phosphorylation of the downstream adaptor protein SLP76, with an IC₅₀ of 33.74 nM, and effectively stimulates the secretion of the T cell activation marker IL-2, exhibiting an EC₅₀ of 84.24 nM. These findings suggest that compound <strong>10c</strong> holds considerable promise for applications in immunotherapy.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130242"},"PeriodicalIF":2.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847964","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 coumarin-containing 2,4-diphenylpyrimidine derivatives as novel focal adhesion kinase inhibitors for treatment of non-small cell lung cancer","authors":"Mengrong Lei ,&nbsp;Hanxue Huang ,&nbsp;Jiayi Li ,&nbsp;Jinlin Zhang ,&nbsp;Geng Yu ,&nbsp;Xin Jin ,&nbsp;Junyan Liu ,&nbsp;Fenghua Kang ,&nbsp;Zhaoqian Liu","doi":"10.1016/j.bmcl.2025.130240","DOIUrl":"10.1016/j.bmcl.2025.130240","url":null,"abstract":"<div><div>A series of hybrids (<strong>8a-h</strong> and <strong>11a-h</strong>) containing 2,4-diphenylpyrimidine scaffold and coumarin moiety were designed and synthesized as novel focal adhesion kinase (FAK) inhibitors for the intervention of non-small-cell lung cancer (NSCLC). Most compounds effectively suppressed the proliferative of NSCLC cells, and compound <strong>8a</strong> was identified as the most active compound with IC₅₀ value of 0.28 μM in H1299 cells, superior to TAE226 (IC₅₀ = 2.28 μM). In addition, <strong>8a</strong> was also found to inhibit the invasion and migration of NSCLC cells. Furthermore, <strong>8a</strong> exhibited potent kinase inhibitory activity of FAK (IC₅₀ = 4.968 nM) with a considerable selectivity profile against various kinase families, subsequently resulting in cell cycle arrest, apoptosis- inducing as well as the decrease of MMP-2 and MMP-9 expression in H1299 cells dose-dependently. Moreover, <strong>8a</strong> was relatively safe to mice and inhibited the growth of implanted NSCLC tumors more potently than TAE226 in mice. Therefore, <strong>8a</strong> may be a promising candidate for the treatment of NSCLC.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130240"},"PeriodicalIF":2.5,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847965","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 biological evaluation of diastereomeric natural products: Discovery of a novel synergistic combination for α-glucosidase inhibition","authors":"Thang M. Le ,&nbsp;Huyen N. Nguyen ,&nbsp;Ngoc T. Vu ,&nbsp;Phong Q. Le","doi":"10.1016/j.bmcl.2025.130239","DOIUrl":"10.1016/j.bmcl.2025.130239","url":null,"abstract":"<div><div>Cabraleahydroxylactone (<strong>1a</strong>) and 3-epi-cabraleahydroxylactone (<strong>1b</strong>) are naturally diastereomers found in <em>Aglaia abbreviata</em>, known for their biological potential. While <strong>1b</strong> has been synthesized and studied as an anti-diabetic agent, the activity of <strong>1a</strong> remained unexplored. This study successfully enhanced <strong>1a</strong> in the reaction mixture through the reduction of cabralealactone (<strong>2</strong>), increasing its ratio from trace levels to 9.5:1 (<strong>1b</strong>:<strong>1a</strong>). Molecular docking revealed distinct binding interactions of these diastereomers with α-glucosidase allosteric sites, suggesting a drug synergy mechanism. Kinetic studies confirmed non-competitive inhibition by both compounds, with <strong>1a</strong> exhibiting superior binding affinity (lower Ki). Synergistic α-glucosidase inhibition was observed in specific <strong>1b</strong>:<strong>1a</strong> ratios (9:1, 8:2, 2:8, and 1:9). Furthermore, these combinations displayed reduced hemolytic toxicity compared to individual compounds. The findings highlight the <strong>1b</strong>:<strong>1a</strong> diastereomeric combination as a promising lead for anti-diabetic drug development, offering enhanced efficacy and safety through synergistic interactions.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130239"},"PeriodicalIF":2.5,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824110","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 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}