Bioorganic & Medicinal Chemistry Letters最新文献

{"title":"Synthesis and biological evaluation of novel 4-Arylaminoquinolines derivatives as EGFR/HDAC inhibitors","authors":"Keke Yao ,&nbsp;Yaxin Li ,&nbsp;Wei Wei ,&nbsp;Sisi Liu ,&nbsp;Xiaoli Wang ,&nbsp;Jiamin Xu ,&nbsp;Ranran Zhang ,&nbsp;Zhigang Wu ,&nbsp;Chunyan Guo ,&nbsp;Leifu Yang ,&nbsp;Liming Hu","doi":"10.1016/j.bmcl.2025.130214","DOIUrl":"10.1016/j.bmcl.2025.130214","url":null,"abstract":"<div><div>Lung cancer, particularly non-small cell lung cancer (NSCLC), remains a leading cause of cancer-related mortality worldwide. Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and the role of epigenetic modifications, such as histone deacetylation, in cancer progression underscore the need for novel therapeutic strategies. This study reports the design, synthesis, and biological evaluation of novel 4-arylaminoquinoline derivatives as dual inhibitors targeting EGFR and histone deacetylase (HDAC). Leveraging structure-activity relationship insights, a series of compounds were synthesized by integrating pharmacophoric elements of EGFR-TKIs and HDAC inhibitors and their kinase and cellular activities were evaluated. Compound <strong>22c2</strong> exhibited the highest inhibitory activities against EGFR (IC₅₀ = 4.81 nM) and HDAC (IC₅₀ = 119.4 nM and 354.8 nM for HDAC1 and HDAC3, respectively). Moreover, <strong>22c2</strong> demonstrated excellent anti-proliferative effects on four human cancer cell lines. These findings provide a foundation for developing dual EGFR/HDAC inhibitors as potential anticancer therapeutics.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130214"},"PeriodicalIF":2.5,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747689","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":"A small-molecule pretargeting approach for PSMA-targeted conjugates","authors":"Nooshin Mesbahi,&nbsp;Hosog Yoon,&nbsp;Melody D. Fulton,&nbsp;Clifford E. Berkman","doi":"10.1016/j.bmcl.2025.130213","DOIUrl":"10.1016/j.bmcl.2025.130213","url":null,"abstract":"<div><div>We developed pretargeting approach for the targeted delivery of molecular payloads to prostate cancer cells expressing the hallmark enzyme-biomarker, prostate-specific membrane antigen (PSMA). We employed a phosphoramidate-based PSMA ligand (CTT1298) with a click-ready DBCO group for strain-promoted azide-alkyne cycloaddition (SPAAC) and used 6-FAM-Azide as a model payload. PSMA+ cells were treated with a fluorescent PSMA-targeted probe (FAM-C6–1298), confirming delivery and accumulation. Further, live-cell experiments with DBCO-C6–1298 and 5-FAM-azide demonstrated selective pretargeted delivery. These results validate the feasibility of this pretargeting strategy in PSMA+ cells, suggesting its potential for preclinical applications with therapeutic and diagnostic payloads, enhancing the specificity and safety of prostate cancer treatments.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130213"},"PeriodicalIF":2.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750568","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 4-((quinolin-8-ylthio)methyl)benzamide derivatives as a new class of SARS-CoV-2 nsp13 inhibitors","authors":"Danchen Fan ,&nbsp;Yuanting Huang ,&nbsp;Rui Yao ,&nbsp;Guo Zhang ,&nbsp;Shengyong Yang ,&nbsp;Linli Li","doi":"10.1016/j.bmcl.2025.130207","DOIUrl":"10.1016/j.bmcl.2025.130207","url":null,"abstract":"<div><div>Antivirals have provided important protection against COVID-19, however, the emergence of SARS-CoV-2 variants and drug-resistant mutants calls for the development of novel anti-coronavirus drugs with alternative mechanisms of action. The nonstructural protein 13 (nsp13) of SARS-CoV-2 plays a conserved role in the replication of coronaviruses and has been identified as a promising target. In this study, we report a series of 4-((quinolin-8-ylthio)methyl)benzamide derivatives as inhibitors of SARS-CoV-2 nsp13. Through structure-activity relationship (SAR) analyses, we identified compound <strong>6r</strong>, which demonstrated potent inhibition of nsp13 with an IC₅₀ value of 0.28 ± 0.11 μM. Collectively, we discovered a new potent SARS-CoV-2 nsp13 inhibitor, which could be taken as a promising lead compound for further drug development targeting SARS-CoV-2 nsp13.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130207"},"PeriodicalIF":2.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727114","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":"Redox-responsive ferulic acid-biotin conjugate: Design, synthesis, and enhanced anticancer efficacy","authors":"Xiaoshuang Dai ,&nbsp;Ke Mei ,&nbsp;Jianpeng Liu ,&nbsp;Bin Sun ,&nbsp;Neng Qiu","doi":"10.1016/j.bmcl.2025.130209","DOIUrl":"10.1016/j.bmcl.2025.130209","url":null,"abstract":"<div><div>In this study, ferulic acid (FA) was conjugated with biotin via a disulfide bond to improve its anticancer activity. The resulting conjugate (FA-SS-Bio) was characterized by proton nuclear magnetic resonance (¹H NMR) and exhibited an amorphous structure, in contrast to the crystalline nature of FA. FA-SS-Bio demonstrated accelerated drug release under reductive and oxidative conditions. Biotinylation significantly increased cell uptake of the drug in biotin receptor (BR)-positive HeLa and MCF-7 cells, as confirmed by cellular uptake studies and molecular docking, which revealed strong biotin-BR interactions. Additionally, the cytotoxicity of FA-SS-Bio was significantly improved, with IC₅₀ values that were 2.94-fold and 2.95-fold lower than those of free FA against HeLa and MCF-7 cells, respectively. BR blockade with biotin reduced FA-SS-Bio cytotoxicity in a concentration-dependent manner, confirming biotin-mediated targeting. Apoptosis assays showed enhanced FA-induced apoptosis due to biotin and disulfide bonds. FA-SS-Bio demonstrated excellent blood compatibility, with a hemolysis rate below 0.5 %, compared to ∼1.5 % for FA. Additionally, FA-SS-Bio exhibited higher cell viability in MCF-10 A cells than in cancer cells, highlighting its favorable safety profile. These findings provide a novel perspective on the design of prodrug conjugates for improved cancer therapy.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130209"},"PeriodicalIF":2.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715530","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":"PEG-ASO conjugates for efficient targeted delivery and migration inhibition in Cancer cell","authors":"Chunhui Zhao ,&nbsp;Xiangjun Li ,&nbsp;Zixin He ,&nbsp;Chun Ye ,&nbsp;Feng Chen ,&nbsp;Jia Cheng","doi":"10.1016/j.bmcl.2025.130208","DOIUrl":"10.1016/j.bmcl.2025.130208","url":null,"abstract":"<div><div>Antisense oligonucleotides (ASO) specifically bind target RNAs resulted in gene silencing, thereby inhibiting cancer cell growth. Chemical modification based on polyethylene glycol (PEG) usually improve resistance to nuclease degradation. However, the specificity and cellular uptake of PEG-conjugated ASOs for tumor cells is still a challenge. In this work, the folate (FA) and maleimide co-modified PEG was prepared and bound with thiol-modified anti-miRNA-21 ASO to form the FA-PEG-ASO conjugates by thiol-maleimide Michael addition. During the FA-PEG-ASO preparation process, removing tris-(2-carboxyethyl) phosphine hydrochloride (TCEP) is the key for the high yields. Cell imaging results showed FA-PEG-ASO internalized by the cells taken up ∼5 times higher than the control HO-PEG-ASO prepared by maleimide modified PEG and anti-miRNA-21 ASO. In addition, FA-PEG-ASO exhibited higher target cleavage and a greater reduction in tumor cell migration ability. Together, FA-PEG-ASO is a promising therapeutic platform.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130208"},"PeriodicalIF":2.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143704054","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, molecular docking and ADME of novel phenylalanine derivatives as mushroom tyrosinase inhibitors","authors":"Longhao Wang,&nbsp;Shunshun Lei,&nbsp;Liyun Du,&nbsp;Chengyao Lai,&nbsp;Weijie Yang,&nbsp;Liqin Qiu,&nbsp;Rihui Cao","doi":"10.1016/j.bmcl.2025.130211","DOIUrl":"10.1016/j.bmcl.2025.130211","url":null,"abstract":"<div><div>Tyrosinase is the key rate-limiting enzyme for melanin synthesis. The accumulation and excessive production of melanin lead to skin pigmentation. Therefore, tyrosinase is the target of tyrosinase inhibitors to control melanin synthesis. Only a few TYR inhibitors have been proven to be effective and safe to treat skin pigmentation. This highlights the importance of developing new tyrosinase inhibitors. Based on the reported tyrosinase inhibitors with phenylalanine structure, a series of novel phenylalanine derivatives were synthesized and investigated as mTYR inhibitors. The results demonstrated that most of these derivatives had more potent mTYR inhibitory activities than positive controls. Compound <strong>3e</strong> was found to be the strongest inhibitor with an IC₅₀ value of 4.86 ± 0.026 μM. The Lineweaver-Burk plots of mTYR inhibition kinetics revealed that the selected compounds <strong>2d</strong> and <strong>3e</strong> were reversible and competitive inhibitors. In addition, molecular docking results of compounds <strong>2d</strong> and <strong>3e</strong> show they could compete with the substrate for the active center, including mTYR and hTYR. And the ADME prediction of selected derivatives assess the potential druglikeness. These results indicated that this class of compounds could be used as leads for developing new TYR inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130211"},"PeriodicalIF":2.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143725539","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 amino-conjugated bile acid derivatives against non-alcoholic steatohepatitis","authors":"Zhitao Wu ,&nbsp;Mingge Zhang ,&nbsp;Meng Kun Yan ,&nbsp;Chenyue Li ,&nbsp;Guoyu Pan ,&nbsp;Lijiang Xuan","doi":"10.1016/j.bmcl.2025.130210","DOIUrl":"10.1016/j.bmcl.2025.130210","url":null,"abstract":"<div><div>Non-alcoholic steatohepatitis (NASH) is emerging as a rapidly growing health concern. Bile acids (BAs) function as endocrine signaling molecules and exhibit therapeutic potential for NASH. To develop safer and more effective BA derivatives for NASH treatment, 25 amino acid-conjugated bile acid derivatives were designed and synthesized based on the pharmacological properties of the leading compound <strong>A17.</strong> The anti-lipid accumulation, anti-inflammatory and anti-fibrosis activities of these compounds were evaluated, and their structure-activity relationships were elucidated. Notably, compound <strong>C04</strong> exhibited superior in vitro activity compared to obeticholic acid and demonstrated enhanced efficacy in improving both NASH and fibrosis in preclinical murine models via oral administration. These findings suggest that <strong>C04</strong> is a promising candidate for NASH treatment and warrants further investigation.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130210"},"PeriodicalIF":2.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727152","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":"Imide-based enones: A new scaffold that inhibits biofilm formation in Gram-negative pathogens","authors":"J. Israel Barrera-Hernández ,&nbsp;Jesús R. Pérez-Velázquez ,&nbsp;Ángel Ramírez-Trinidad ,&nbsp;Jesús Oria-Hernández ,&nbsp;Eduardo Hernández-Vázquez","doi":"10.1016/j.bmcl.2025.130206","DOIUrl":"10.1016/j.bmcl.2025.130206","url":null,"abstract":"<div><div>We prepared a series of enones containing different substituents as potential antibiofilm molecules. The design considered the structural features previously found in <em>N-</em>acylhomoserine lactones, but it replaced the labile furanone with different imides portions. After evaluation, some of the analogs inhibited 50 % or more the formation of the biofilm from <em>P. aeruginosa</em> or <em>A. baumannii</em>; moreover, substituents attached at the phenyl ring, the size of the enone as well as the type of imide seemed relevant for the selectivity against the tested pathogens<em>.</em> In the end, we performed a molecular docking study using the crystallized LasR to describe the main interactions of the ligand-receptor complex and propose a plausible mechanism of action.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130206"},"PeriodicalIF":2.5,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703925","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":"Design, synthesis, and evaluation of a novel protein degrader FPFT-2216","authors":"Yasuyuki Ueda,&nbsp;Takashi Ando,&nbsp;Yoshiteru Eikyu,&nbsp;Takumi Okamoto,&nbsp;Hironori Yokoyama,&nbsp;Naoshi Kunimura,&nbsp;Daiki Kanaoka,&nbsp;Shotaro Izuno,&nbsp;Mayumi Watanabe","doi":"10.1016/j.bmcl.2025.130193","DOIUrl":"10.1016/j.bmcl.2025.130193","url":null,"abstract":"<div><div>For multiple myeloma (MM), various modalities of therapeutic drugs have been approved in recent years, and treatment outcomes for MM have greatly improved, but unmet medical needs still exist and new therapeutic drugs are needed. With the aim of developing a therapeutic drug for MM that has a scaffold different from the protein degrader immunomodulatory drugs (IMiDs), exploratory research was performed using the highly useful Huisgen cycloaddition reaction, and a novel lead compound 3-(4-(thiophen-3-yl)-<em>1H</em>-1,2,3-triazol-1-yl)piperidine-2,6-dione (FPFT-2127) was discovered. Optimization studies identified FPFT-2216, which exhibited stronger antitumor activity against MM than existing thalidomide derivatives. Furthermore, FPFT-2216 showed a synergistic combination effect with Daratumumab (Dara), a standard treatment for MM.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130193"},"PeriodicalIF":2.5,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699279","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 liver-selective glucokinase activators comprising N-(4-alkylthiazol-2-yl)benzamides and N-(3-alkyl-1,2,4-thiadiazol-5-yl)benzamides for the treatment of metabolic disorders","authors":"David S. Yoon,&nbsp;Shung Wu,&nbsp;Sean S. Chen,&nbsp;Rebecca A. Smirk,&nbsp;Robert P. Brigance,&nbsp;Wei Meng,&nbsp;Yan Shi,&nbsp;Shiwei Tao,&nbsp;Ying Wang,&nbsp;Hao Zhang,&nbsp;Arvind Mathur,&nbsp;Helen Grace Catanio,&nbsp;Stephen Kalinowski,&nbsp;Rachel Zebo,&nbsp;Jacob Zalaznick,&nbsp;Joseph Taylor,&nbsp;Bradley Zinker,&nbsp;Lisa M. Kopcho,&nbsp;Kamelia Behnia,&nbsp;Carrie Xu,&nbsp;Peter T.W. Cheng","doi":"10.1016/j.bmcl.2025.130192","DOIUrl":"10.1016/j.bmcl.2025.130192","url":null,"abstract":"<div><div>Glucokinase (“GK”) plays a critical role in regulating glucose homeostasis within the body. Proof-of-concept animal models demonstrated that small molecule GK activation enhances glucose uptake and utilization by various tissues, including liver and pancreas. Accordingly, glucokinase activators (“GKAs”) were extensively explored as a potential therapy for carbohydrate metabolism disorders. Yet in clinical trials, mechanism-based hypoglycemia was often observed when GK was activated in both liver and pancreas. One ameliorative approach was to pursue hepatocentric GKAs. Described herein is a series of liver selective GKAs based on <em>N</em>-(4-alkylthiazol-2-yl)benzamide and <em>N</em>-(3-alkyl-1,2,4-thiadiazol-5-yl)benzamide pharmacophores. Optimization efforts revealed that enhanced liver selectivity could be achieved by replacing diethylphosphonate group (compound <strong>1</strong>) with a dimethylphosphinate (compound <strong>3</strong>). Due to mutagenicity of a putative aminoheterocycle metabolite of <strong>3</strong>, subsequent amines were triaged using SOS chromotest. Efforts ultimately led to identification of thiazole-based compounds <strong>11</strong>–<strong>13</strong>, which exhibited significant glucose lowering in acute DIO (“diet-induced obese”) mouse OGTT (“oral glucose tolerance test”) studies. However, insulin secretion was observed at higher doses, and thus the desired therapeutic window between efficacy and insulin secretion was not achieved. Thiadiazole-based compounds were then explored to assess whether this modification could obviate the insulin secretion observed with the thiazole series. Several thiadiazoles were discovered with exceptionally high liver selectivity and drug liver concentrations when evaluated in mouse pharmacokinetic studies. Compounds <strong>17</strong>–<strong>19</strong> and <strong>20</strong>–<strong>22</strong> were advanced into acute DIO OGTT studies, but were inactive. Notably, a relatively higher degree of plasma protein binding was observed for the non-efficacious vs. efficacious compounds.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130192"},"PeriodicalIF":2.5,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699280","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}