European Journal of Medicinal Chemistry最新文献_第6页

Development of molecular Trojan horses targeting New Delhi metallo-β-lactamase-1 for the restoration of meropenem susceptibility in drug-resistant bacteria 靶向新德里金属-β-内酰胺酶-1的分子特洛伊木马的开发，用于恢复耐药菌对美罗培南的敏感性

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-01-06 DOI: 10.1016/j.ejmech.2025.117243

Wandong Liu, Yan Guo, Chen Zhang, Chenyu Liu, Sheng Chen, Xiaoyang Li, Jiazhang Qiu, Shengbiao Wan

{"title":"Development of molecular Trojan horses targeting New Delhi metallo-β-lactamase-1 for the restoration of meropenem susceptibility in drug-resistant bacteria","authors":"Wandong Liu, Yan Guo, Chen Zhang, Chenyu Liu, Sheng Chen, Xiaoyang Li, Jiazhang Qiu, Shengbiao Wan","doi":"10.1016/j.ejmech.2025.117243","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117243","url":null,"abstract":"The emergence of New Delhi metallo-β-lactamase-1 (NDM-1) poses a significant threat to the clinical application of antibiotics, as it possesses the ability to hydrolyze nearly all β-lactam antibiotics. Regrettably, there are currently no clinical drugs targeting NDM-1, making it imperative to develop highly potent and minimally toxic NDM-1 inhibitors. Herein, a series of molecular Trojan horses targeting NDM-1 were synthesized by introducing ebselen into 7-aminocephalosporanic acid derivatives via a C-Se bond. Representative compound 18b exhibited potent inhibitory activity against NDM-1, with an IC50 value of 7.03 μM, and combining with meropenem (Mem) decreased the minimum inhibitory concentration (MIC) of Mem by 4-32-fold in NDM-1 expressing bacteria. Mechanistically, 18b released the ebselen moiety at the active site of NDM-1, forming a Se-S bond with Cys208 to achieve targeted drug delivery of ebselen. Importantly, 18b demonstrated potent inhibition of resistant bacterial growth and replication in mice when administered in combination with Mem. These results suggest that 18b is a promising candidate for treating infections caused by resistant bacteria expressing NDM-1.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"28 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142934823","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}

引用次数: 0

Design, synthesis and biological evaluation of bisnoralcohol derivatives as novel IRF4 inhibitors for the treatment of multiple myeloma 双诺醇衍生物作为新型IRF4抑制剂治疗多发性骨髓瘤的设计、合成和生物学评价

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-01-06 DOI: 10.1016/j.ejmech.2025.117240

Jing-Zan Zhang, Lin Zhang, Xin Ding, Min Wu, De-Jie Zhang, Yujie Wu, Mingyao Liu, Chen-Chen Li, Zhengfang Yi, Wen-Wei Qiu

{"title":"Design, synthesis and biological evaluation of bisnoralcohol derivatives as novel IRF4 inhibitors for the treatment of multiple myeloma","authors":"Jing-Zan Zhang, Lin Zhang, Xin Ding, Min Wu, De-Jie Zhang, Yujie Wu, Mingyao Liu, Chen-Chen Li, Zhengfang Yi, Wen-Wei Qiu","doi":"10.1016/j.ejmech.2025.117240","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117240","url":null,"abstract":"Interferon regulatory factor 4 (IRF4) is specifically overexpressed in multiple myeloma (MM) and mediates MM progression and survival, making it an emerging target for MM treatment. However, no chemical entity with a defined structure capable of directly binding to and inhibiting IRF4 has been reported. We screened our small library of steroid analogs and identified bisnoralcohol (BA) derivative 18 as a novel hit compound capable of inhibiting IRF4, with an IC50 of 13.46 μM. Based on 18, a series of BA derivatives was synthesized and evaluated for their inhibitory effects on IRF4 and antiproliferative activities against MM cell lines. Among these compounds, 41 (SH514) exhibited the highest potency, with an IC50 value of 2.63 μM for inhibiting IRF4, and IC50 values of 0.08 μM and 0.11 μM for inhibiting the proliferation of IRF4-high-expressing NCI-H929 and MM.1R MM cells, respectively. SH514 can bind to the IRF4-DBD domain with a KD of 1.28 μM. SH514 selectively and potently inhibits IRF4-high-expressing MM cells over IRF4-low-expressing MM cells. Mechanistic studies demonstrated that SH514 suppresses the downstream genes of IRF4, including CCNC, CANX, E2F5, CMYC, HK2, and Blimp1, and inhibited the expression of cell cycle-related proteins CDC2, Cyclin B1, Cyclin D1, Cyclin E1, and CMYC in MM cells. In vivo, SH514 effectively inhibited the proliferation of MM tumors, showing much better antitumor efficacy than the clinical drug lenalidomide, and exhibited no significant toxicity. Thus, these IRF4 inhibitors could serve as promising leads for the development of novel anti-multiple myeloma agents.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142934827","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}

引用次数: 0

Synthesis and discovery of simplified pleurotin analogs bearing tricyclic core as novel thioredoxin reductase inhibitors 新型硫氧还蛋白还原酶抑制剂三环核心简化胸膜蛋白类似物的合成与发现

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-01-06 DOI: 10.1016/j.ejmech.2025.117242

Bin Huang, Zhongren Xu, Dezhong Liao, Yuxia Zhang, Mengze Ruan, Zhiyue Fan, Wukun Liu, Ya-Qiu Long

{"title":"Synthesis and discovery of simplified pleurotin analogs bearing tricyclic core as novel thioredoxin reductase inhibitors","authors":"Bin Huang, Zhongren Xu, Dezhong Liao, Yuxia Zhang, Mengze Ruan, Zhiyue Fan, Wukun Liu, Ya-Qiu Long","doi":"10.1016/j.ejmech.2025.117242","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117242","url":null,"abstract":"Pleurotin (1) is a benzoquinone meroterpenoid known for its wide-spectrum antitumor and antibiotic activities, notably acting as natural inhibitors of the thioredoxin reductase (TrxR). Pleurotin (1) has been chemically synthesized, but only in milligram quantities through at least 13 longest linear steps with 0.8% overall yield due to its complex structure such as fused hexacyclic core with 8 contiguous stereocenters. Therefore, structural simplification strategy is applied to pleurotin natural products for their structure-activity relationship (SAR) study and further therapeutics development. Herein, we judiciously designed pleurotin analogs of tricyclic A/D/E ring core, retaining the putative pharmacophore of para-quinone moiety D and its supportive A and E rings. Thus 16 simplified analogs of pleurotin bearing tricyclic A/D/E core were readily synthesized in only 2 to 6 steps with up to 50% overall yield from commercially available materials. Significantly, the best analog 14f with benzonitrile substituent exhibited more potent TrxR inhibitory activity with an IC50 of 3.5 μM than the positive control micheliolide (IC50 = 6.23 μM). Furthermore, the mechanism study revealed that compound 14f could induce apoptosis of tumor cells by inducing ROS generation and inhibiting TrxR activities. Our study for the first time showed that the tricyclic A/D/E ring scaffold from the natural product pleurotin (1) with proper substitution can maintain or even improve the TrxR inhibitory and antiproliferative activities, with high synthetic accessibility, affording natural product-derived lead compounds for the further development of TrxR inhibitors as anti-tumor therapeutics.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"41 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142934828","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}

引用次数: 0

New FDA Drug Approvals for 2024: Synthesis and Clinical Application 2024年FDA批准新药：合成和临床应用

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-01-04 DOI: 10.1016/j.ejmech.2025.117241

Yingying Wang, Fuwei Yang, Baizhi Wang, Lijuan Xie, Wanying Chen

{"title":"New FDA Drug Approvals for 2024: Synthesis and Clinical Application","authors":"Yingying Wang, Fuwei Yang, Baizhi Wang, Lijuan Xie, Wanying Chen","doi":"10.1016/j.ejmech.2025.117241","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117241","url":null,"abstract":"In 2024, the U.S. Food and Drug Administration (FDA) has approved a range of new drugs, including both 32 new chemical entities (NCEs) and 18 biological entities (NBEs). Among the approved new drugs, small-molecule chemical drugs remained the main force for innovation, taking a commanding lead with a proportion of 64%, covering targets like LACTB, PBP, THR-β, Raf, PDE3/4, and HIF. Monoclonal antibodies followed with 13 drugs (26%), along with 2 protein-based drugs (4%), 2 small nucleic acid drugs (4%), and 1 parathyroid hormone analogue (2%). The diseases treated by these approved new drugs were diverse, with the total number of new drugs for treating rare diseases and cancers ranking high. Additionally, multiple new drugs were also approved in the fields of anti-infective and central nervous system diseases. Similar to previous years, many of these drugs are likely to undergo accelerated approval processes to address urgent medical needs, particularly for rare diseases. This review provides an overview of the synthesis and clinical applications of NCEs approved by the FDA in 2024. The increasing importance of clinical applications has also been discussed. This review aims to provide valuable insights for the design of future drugs, particularly in the context of rare and complex diseases.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"160 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925183","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}

引用次数: 0

Radiosynthesis and Evaluation of Novel 18F Labeled PET Ligands for Imaging Monoacylglycerol Lipase 用于成像单酰基甘油脂肪酶的新型18F标记PET配体的放射合成和评价

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-01-04 DOI: 10.1016/j.ejmech.2025.117246

Yinlong Li, Wakana Mori, Ahmad Chaudhary, Chunyu Zhao, Tomoteru Yamasaki, Zachary Zhang, Siyan Feng, Tim Ware, Jian Rong, Masayuki Fujinaga, Jiahui Chen, Katsushi Kumata, Yiding Zhang, Kuan Hu, Lin Xie, Xin Zhou, Zhendong Song, Yabiao Gao, Zhenkun Sun, Jimmy S. Patel, Steven H. Liang

{"title":"Radiosynthesis and Evaluation of Novel 18F Labeled PET Ligands for Imaging Monoacylglycerol Lipase","authors":"Yinlong Li, Wakana Mori, Ahmad Chaudhary, Chunyu Zhao, Tomoteru Yamasaki, Zachary Zhang, Siyan Feng, Tim Ware, Jian Rong, Masayuki Fujinaga, Jiahui Chen, Katsushi Kumata, Yiding Zhang, Kuan Hu, Lin Xie, Xin Zhou, Zhendong Song, Yabiao Gao, Zhenkun Sun, Jimmy S. Patel, Steven H. Liang","doi":"10.1016/j.ejmech.2025.117246","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117246","url":null,"abstract":"Monoacylglycerol lipase (MAGL) is a 33 kDa cytosolic serine hydrolase that is widely distributed in the central nervous system and peripheral tissues. MAGL hydrolyzes monoacylglycerols into fatty acids and glycerol, playing a crucial role in endocannabinoid degradation. Inhibition of MAGL in the brain elevates levels of 2-arachidonoylglycerol and leads to decreased pro-inflammatory prostaglandin and thromboxane production. As such, MAGL is considered a potential target for treating neuropsychiatric disorders, metabolic syndromes, and cancer. Based on a novel spirocyclic system, we synthesized two fluorinated carbamate scaffolds as reversible MAGL inhibitors (epimers: (R)-6, IC50 = 18.6 nM and (S)-6, IC50 = 1.6 nM). In vitro autoradiography studies of [18F](R)-6 (codenamed [18F]MAGL-2304) and [18F](S)-6 (codenamed [18F]MAGL-2305) demonstrated heterogeneous distribution and specific binding affinity to MAGL-rich brain regions. Autoradiography with MAGL knockout mouse brain tissues confirmed the binding specificity of [18F](S)-6. Dynamic PET imaging studies revealed that [18F](S)-6 exhibited limited brain uptake and homogenous distribution in rat brains. In vivo P-gp inhibition enhanced [18F](S)-6 uptake in the brain, suggesting that [18F](S)-6 constitutes a P-gp efflux substrate. This research could provide new directions in the design of MAGL PET ligands that are based on spirocyclic scaffolds.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"34 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925241","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}

引用次数: 0

Repurposing FDA-approved drugs to target G-quadruplexes in breast cancer 重新利用fda批准的药物靶向乳腺癌中的g -四联体

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-01-04 DOI: 10.1016/j.ejmech.2025.117245

Federica Moraca, Valentina Arciuolo, Simona Marzano, Fabiana Napolitano, Giuliano Castellano, Federica D’Aria, Anna Di Porzio, Laura Landolfi, Bruno Catalanotti, Antonio Randazzo, Bruno Pagano, Anna Maria Malfitano, Jussara Amato

{"title":"Repurposing FDA-approved drugs to target G-quadruplexes in breast cancer","authors":"Federica Moraca, Valentina Arciuolo, Simona Marzano, Fabiana Napolitano, Giuliano Castellano, Federica D’Aria, Anna Di Porzio, Laura Landolfi, Bruno Catalanotti, Antonio Randazzo, Bruno Pagano, Anna Maria Malfitano, Jussara Amato","doi":"10.1016/j.ejmech.2025.117245","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117245","url":null,"abstract":"Breast cancer, a leading cause of cancer-related mortality in women, is characterized by genomic instability and aberrant gene expression, often influenced by noncanonical nucleic acid structures such as G-quadruplexes (G4s). These structures, commonly found in the promoter regions and 5’-untranslated RNA sequences of several oncogenes, play crucial roles in regulating transcription and translation. Stabilizing these G4 structures offers a promising therapeutic strategy for targeting key oncogenic pathways. In this study, we employed a drug repurposing approach to identify FDA-approved drugs capable of binding and stabilizing G4s in breast cancer-related genes. Using ligand-based virtual screening and biophysical methods, we identified several promising compounds, such as azelastine, belotecan, and irinotecan, as effective G4 binders, with significant antiproliferative effects in breast cancer cell lines. Notably, belotecan and irinotecan exhibited a synergistic mechanism, combining G4 stabilization with their established topoisomerase I inhibition activity to enhance cytotoxicity in cancer cells. Our findings support the therapeutic potential of G4 stabilization in breast cancer, validate drug repurposing as an efficient strategy to identify G4-targeting drugs, and highlight how combining G4 stabilization with other established drug activities may improve anticancer efficacy.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"21 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925209","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}

引用次数: 0

Functionalized regioisomers of the natural product phenazines myxin and iodinin as potent inhibitors of Mycobacterium tuberculosis and human acute myeloid leukemia cells 天然产物非那嗪、粘菌素和碘的功能化区域异构体作为结核分枝杆菌和人急性髓性白血病细胞的有效抑制剂

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-01-04 DOI: 10.1016/j.ejmech.2025.117244

Goraksha Machhindra Khose, Siva Krishna Vagolu, Reidun Aesoy, Ísak Máni Stefánsson, Snorri Geir Ríkharðsson, Dagmar Ísleifsdóttir, Maonian Xu, Håvard Homberset, Tone Tønjum, Pål Rongved, Lars Herfindal, Elvar Örn Viktorsson

{"title":"Functionalized regioisomers of the natural product phenazines myxin and iodinin as potent inhibitors of Mycobacterium tuberculosis and human acute myeloid leukemia cells","authors":"Goraksha Machhindra Khose, Siva Krishna Vagolu, Reidun Aesoy, Ísak Máni Stefánsson, Snorri Geir Ríkharðsson, Dagmar Ísleifsdóttir, Maonian Xu, Håvard Homberset, Tone Tønjum, Pål Rongved, Lars Herfindal, Elvar Örn Viktorsson","doi":"10.1016/j.ejmech.2025.117244","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117244","url":null,"abstract":"The natural bioactive products myxin and iodinin are phenazine 5,10-dioxides possessing potent anti-bacterial and anti-cancer activity in vitro. This work describes the synthesis and derivatization of new myxin and iodinin regioisomers, developed from 1,3-dihydroxyphenazine 5,10-dioxide. Compounds were evaluated for activity towards M. tuberculosis (Mtb) strains, a human AML cell line (MOLM-13), and two non-cancerous mammalian cell lines (NRK and H9c2). Highly potent analogs were developed having IC50 values against MTB down to 20 nM and 1.4 μM for human AML cells. 1-OH-3-O-alkyl substituted derivatives demonstrated high efficacy against Mtb and low toxicity in normal cells. 2,3-substituted regioisomers of myxin and iodinin were shown to be inactive, highlighting the importance of oxygen substituent in position 1 of the scaffold. A strong positive correlation between anti-MTB and anti-AML activity was revealed, suggesting a common mechanism of action in bacteria and cancer cells. These findings demonstrate the therapeutic potential of 1,3-O-functionalized phenazine 5,10-dioxides in chemotherapy for Mtb and AML and contribute to the structure-activity understanding of phenazine 5,10-dioxides with respect to their biological activity.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"14 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925210","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}

引用次数: 0

Overview of the Epigenetic/Cytotoxic Dual-Target Inhibitors for Cancer Therapy 用于癌症治疗的表观遗传/细胞毒性双靶点抑制剂综述

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-01-03 DOI: 10.1016/j.ejmech.2024.117235

Hailiu Liang, Shuqing Li, Xiaopeng Peng, Hao Xiao

{"title":"Overview of the Epigenetic/Cytotoxic Dual-Target Inhibitors for Cancer Therapy","authors":"Hailiu Liang, Shuqing Li, Xiaopeng Peng, Hao Xiao","doi":"10.1016/j.ejmech.2024.117235","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117235","url":null,"abstract":"Epigenetic dysregulation plays a pivotal role in the initiation and progression of various cancers, influencing critical processes such as tumor growth, invasion, migration, survival, apoptosis, and angiogenesis. Consequently, targeting epigenetic pathways has emerged as a promising strategy for anticancer drug discovery in recent years. However, the clinical efficacy of epigenetic inhibitors, such as HDAC inhibitors, has been limited, often accompanied by resistance. To overcome these challenges, innovative therapeutic approaches are required, including the combination of epigenetic inhibitors with cytotoxic agents or the design of dual-acting inhibitors that target both epigenetic and cytotoxic pathways. In this review, we provide a comprehensive overview of the structures, biological functions and inhibitors of epigenetic regulators (such as HDAC, LSD1, PARP, and BET) and cytotoxic targets (including tubulin and topoisomerase). Furthermore, we discuss recent advancement of combination therapies and dual-target inhibitors that target both epigenetic and cytotoxic pathways, with a particular focus on recent advances, including rational drug design, pharmacodynamics, pharmacokinetics, and clinical applications.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"159 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924473","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}

引用次数: 0

Discovery of proteolytically stable monocyte locomotion inhibitory factor peptide through systematic structural optimization 通过系统结构优化发现蛋白水解稳定的单核细胞运动抑制因子肽

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-01-03 DOI: 10.1016/j.ejmech.2025.117237

Yajing Ji, Yuan Gao, Xiang Li, Honggang Hu, Yuefan Zhang, Yejiao Shi

{"title":"Discovery of proteolytically stable monocyte locomotion inhibitory factor peptide through systematic structural optimization","authors":"Yajing Ji, Yuan Gao, Xiang Li, Honggang Hu, Yuefan Zhang, Yejiao Shi","doi":"10.1016/j.ejmech.2025.117237","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117237","url":null,"abstract":"The identification of novel molecular candidates capable of treating osteoarthritis (OA) has significant clinical implications. Monocyte locomotion inhibitory factor peptide (MLIF) is a pentapeptide derived from Entamoeba histolytica. It has been found possesses selective anti-inflammatory effects both in vitro and in vivo. Nonetheless, like many peptide therapeutics, MLIF has relatively poor proteolytic stability and short half-life in vivo, hindering its effective clinical applicability. To overcome these limitations, structural optimizations are needed to enhance the stability of MLIF while preserving or even enhancing its anti-inflammatory activities. Herein, a series of MLIF derivatives were designed and synthesized based on diverse structural modifications including N-terminal modifications, D-amino acid replacement, N-methylation, sulfhydryl modification, cyclization, and splicing strategy. Among all the MLIF derivatives, MLIF 30 with replacing L-methionine (Met) with D-Met and linking the polyethylene glycol (PEG) to cysteine (Cys) of MLIF displayed enhanced in vitro anti-inflammatory activities. Further in vivo experiment demonstrated MLIF 30 could reduce cartilage inflammation and attenuate cartilage damage more effectively in the collagenase induced osteoarthritis (CIOA) mice due to its improved serum stability compared to the linear MLIF. These findings laid foundation for the development of potent and stable anti-inflammatory peptide therapeutics and pushed the frontier of MLIF for clinical OA treatment.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"122 9 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917487","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}

引用次数: 0

Targeting JNK3 for Alzheimer's Disease: Design and Synthesis of Novel Inhibitors with Aryl Group Diversity utilizing Wide Pocket 靶向JNK3治疗阿尔茨海默病：设计和合成具有广泛芳基多样性的新型抑制剂

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-01-03 DOI: 10.1016/j.ejmech.2024.117209

Hyejin Kim, Haebeen Park, Joonhong Jun, Jihyun Moon, Jooyoung Oh, Swapnil P. Bhujbal, Jung-Mi Hah

{"title":"Targeting JNK3 for Alzheimer's Disease: Design and Synthesis of Novel Inhibitors with Aryl Group Diversity utilizing Wide Pocket","authors":"Hyejin Kim, Haebeen Park, Joonhong Jun, Jihyun Moon, Jooyoung Oh, Swapnil P. Bhujbal, Jung-Mi Hah","doi":"10.1016/j.ejmech.2024.117209","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117209","url":null,"abstract":"JNK3, a brain-specific stress-activated protein kinase, plays a critical role in Alzheimer's disease pathogenesis through phosphorylation of Tau and APP. This study aimed to develop selective JNK3 inhibitors based on a pyrazole scaffold, focusing on (E)-1-(2-aminopyrimidin-4-yl)-4-styryl-1H-pyrazole-3-carboxamide derivatives. Through systematic structural modifications and extensive SAR analysis, we identified compounds 24a and 26a as highly potent JNK3 inhibitors, with IC50 values of 12 and 19 nM, respectively. Especially, 24a revealed its potent and selective inhibition of JNK3, coupled with inhibition of the GSK3α/β kinases involved in Tau phosphorylation. In vitro studies revealed significant neuroprotective effects against Aβ1-42-induced toxicity in primary neuronal cells and western blot analyses confirmed the compounds' ability to mitigate Aβ1-42-induced c-Jun and APP phosphorylation, suggesting a multi-faceted approach to neuroprotection. Docking studies validated the retention of optimal interactions within the JNK3 binding pocket. Importantly, BBB PAMPA assays and ADME predictions indicated favorable blood-brain barrier permeability and pharmacokinetic profiles for the lead compounds. These findings represent a significant advancement in the development of selective JNK3 inhibitors, providing a strong foundation for further preclinical development of potential Alzheimer's disease therapeutics.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"6 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924571","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}

引用次数: 0