Pub Date : 2025-01-06DOI: 10.1016/j.ejmech.2025.117242
Bin Huang, Zhongren Xu, Dezhong Liao, Yuxia Zhang, Mengze Ruan, Zhiyue Fan, Wukun Liu, Ya-Qiu Long
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.
{"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 (<strong>1</strong>) is a benzoquinone meroterpenoid known for its wide-spectrum antitumor and antibiotic activities, notably acting as natural inhibitors of the thioredoxin reductase (TrxR). Pleurotin (<strong>1</strong>) 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 <strong>14f</strong> with benzonitrile substituent exhibited more potent TrxR inhibitory activity with an IC<sub>50</sub> of 3.5 μM than the positive control micheliolide (IC<sub>50</sub> = 6.23 μM). Furthermore, the mechanism study revealed that compound <strong>14f</strong> 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 (<strong>1</strong>) 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}
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.
{"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}
Pub Date : 2025-01-04DOI: 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
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.
{"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: (<em>R</em>)-<strong>6</strong>, IC<sub>50</sub> = 18.6 nM and (<em>S</em>)-<strong>6</strong>, IC<sub>50</sub> = 1.6 nM). <em>In vitro</em> autoradiography studies of [<sup>18</sup>F](<em>R</em>)-<strong>6</strong> (codenamed [<sup>18</sup>F]<strong>MAGL-2304</strong>) and [<sup>18</sup>F](<em>S</em>)-<strong>6</strong> (codenamed [<sup>18</sup>F]<strong>MAGL-2305</strong>) demonstrated heterogeneous distribution and specific binding affinity to MAGL-rich brain regions. Autoradiography with MAGL knockout mouse brain tissues confirmed the binding specificity of [<sup>18</sup>F](<em>S</em>)-<strong>6</strong>. Dynamic PET imaging studies revealed that [<sup>18</sup>F](<em>S</em>)-<strong>6</strong> exhibited limited brain uptake and homogenous distribution in rat brains. <em>In vivo</em> P-gp inhibition enhanced [<sup>18</sup>F](<em>S</em>)-<strong>6</strong> uptake in the brain, suggesting that [<sup>18</sup>F](<em>S</em>)-<strong>6</strong> 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}
Pub Date : 2025-01-04DOI: 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
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.
{"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}
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.
天然生物活性产物粘菌素和碘素均为非那嗪5,10-二氧化物，在体外具有较强的抗菌和抗癌活性。本文描述了以1,3-二羟基吩那嗪5,10-二氧化为原料，合成并衍生出新的粘菌素和碘素区域异构体。化合物对结核分枝杆菌（Mtb）菌株、人AML细胞系（MOLM-13）和两种非癌性哺乳动物细胞系（NRK和H9c2）的活性进行了评估。高效的类似物对MTB的IC50值低至20 nM，对人AML细胞的IC50值低至1.4 μM。1- oh -3- o -烷基取代衍生物在正常细胞中显示出对Mtb的高疗效和低毒性。粘菌素和碘素的2,3取代区域异构体被证明是无活性的，突出了支架位置1的氧取代基的重要性。发现抗mtb和抗aml活性之间存在很强的正相关，提示其在细菌和癌细胞中具有共同的作用机制。这些发现证明了1,3- o功能化的吩那嗪5,10-二氧化物在Mtb和AML化疗中的治疗潜力，并有助于了解吩那嗪5,10-二氧化物的结构-活性及其生物活性。
{"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 <em>M. tuberculosis</em> (<em>Mtb</em>) strains, a human AML cell line (MOLM-13), and two non-cancerous mammalian cell lines (NRK and H9c2). Highly potent analogs were developed having IC<sub>50</sub> values against MTB down to 20 nM and 1.4 μM for human AML cells. 1-OH-3-<em>O</em>-alkyl substituted derivatives demonstrated high efficacy against <em>Mtb</em> 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-<em>O</em>-functionalized phenazine 5,10-dioxides in chemotherapy for <em>Mtb</em> 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}
Pub Date : 2025-01-03DOI: 10.1016/j.ejmech.2024.117235
Hailiu Liang, Shuqing Li, Xiaopeng Peng, Hao Xiao
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.
{"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}
Pub Date : 2025-01-03DOI: 10.1016/j.ejmech.2025.117237
Yajing Ji, Yuan Gao, Xiang Li, Honggang Hu, Yuefan Zhang, Yejiao Shi
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.
{"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 <em>Entamoeba histolytica</em>. It has been found possesses selective anti-inflammatory effects both <em>in vitro</em> and <em>in vivo</em>. Nonetheless, like many peptide therapeutics, MLIF has relatively poor proteolytic stability and short half-life <em>in vivo</em>, 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 <em>N</em>-terminal modifications, <sub>D</sub>-amino acid replacement, <em>N</em>-methylation, sulfhydryl modification, cyclization, and splicing strategy. Among all the MLIF derivatives, MLIF 30 with replacing <sub>L</sub>-methionine (Met) with <sub>D</sub>-Met and linking the polyethylene glycol (PEG) to cysteine (Cys) of MLIF displayed enhanced <em>in vitro</em> anti-inflammatory activities. Further <em>in vivo</em> 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}
Pub Date : 2025-01-03DOI: 10.1016/j.ejmech.2024.117209
Hyejin Kim, Haebeen Park, Joonhong Jun, Jihyun Moon, Jooyoung Oh, Swapnil P. Bhujbal, Jung-Mi Hah
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.
{"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 (<em>E</em>)-1-(2-aminopyrimidin-4-yl)-4-styryl-1<em>H</em>-pyrazole-3-carboxamide derivatives. Through systematic structural modifications and extensive SAR analysis, we identified compounds <strong>24a</strong> and <strong>26a</strong> as highly potent JNK3 inhibitors, with IC<sub>50</sub> values of 12 and 19 nM, respectively. Especially, <strong>24a</strong> revealed its potent and selective inhibition of JNK3, coupled with inhibition of the GSK3α/β kinases involved in Tau phosphorylation. <em>In vitro</em> studies revealed significant neuroprotective effects against Aβ<sub>1-42</sub>-induced toxicity in primary neuronal cells and western blot analyses confirmed the compounds' ability to mitigate Aβ<sub>1-42</sub>-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}
Pub Date : 2025-01-03DOI: 10.1016/j.ejmech.2024.117231
Shaoshan Xu, Xiaosheng Jiang, Mengdi Xu, Chengjian Ai, Guanyi Zhao, Tao Jiang, Yang Liu, Zhen Tian, Meihui Zhang, Jinhua Dong
Tropomyosin receptor kinase (TRK) has emerged as a promising therapeutic target in cancers driven by NTRK gene fusions. Herein, we report a highly potent TRK inhibitor, C11, developed using bioisosteric replacement and computer-aided drug design (CADD) strategies. Compound C11 demonstrated significant antiproliferative effects against TRK-dependent cell lines (Km-12), and exhibited a dose-dependent inhibition of both colony formation and cell migration. Mechanistic study revealed that C11 induced cancer cell death by arresting the cell cycle, triggering apoptosis, and reducing phosphorylated TRK levels. In vitro stability assays showed that compound C11 possessed excellent plasma stability (t1/2 > 480 min) and moderate liver microsomal stability (t1/2 = 38.9 min). Pharmacokinetic evaluation further indicated an oral bioavailability of 15.2% for compound C11. These results highlight compound C11 as a promising lead compound for the further development of TRK inhibitors.
{"title":"Design, synthesis and biological evaluation of novel 1H-indole-3-carbonitrile derivatives as potent TRK Inhibitors","authors":"Shaoshan Xu, Xiaosheng Jiang, Mengdi Xu, Chengjian Ai, Guanyi Zhao, Tao Jiang, Yang Liu, Zhen Tian, Meihui Zhang, Jinhua Dong","doi":"10.1016/j.ejmech.2024.117231","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117231","url":null,"abstract":"Tropomyosin receptor kinase (TRK) has emerged as a promising therapeutic target in cancers driven by <em>NTRK</em> gene fusions. Herein, we report a highly potent TRK inhibitor, <strong>C11</strong>, developed using bioisosteric replacement and computer-aided drug design (CADD) strategies. Compound <strong>C11</strong> demonstrated significant antiproliferative effects against TRK-dependent cell lines (Km-12), and exhibited a dose-dependent inhibition of both colony formation and cell migration. Mechanistic study revealed that <strong>C11</strong> induced cancer cell death by arresting the cell cycle, triggering apoptosis, and reducing phosphorylated TRK levels. <em>In vitro</em> stability assays showed that compound <strong>C11</strong> possessed excellent plasma stability (t<sub>1/2</sub> > 480 min) and moderate liver microsomal stability (t<sub>1/2</sub> = 38.9 min). Pharmacokinetic evaluation further indicated an oral bioavailability of 15.2% for compound <strong>C11.</strong> These results highlight compound <strong>C11</strong> as a promising lead compound for the further development of TRK inhibitors.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"34 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917488","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}
Pub Date : 2025-01-02DOI: 10.1016/j.ejmech.2024.117232
Lin Yue, Zui Tan, Wei Wei, Hongyao Liu, Taixiong Xue, Xingping Su, Xiuli Wu, Yuting Xie, Peilin Li, Doudou Wang, Zhihao Liu, Cailing Gan, Tinghong Ye
Organ fibrosis, such as lung fibrosis and liver fibrosis, is a progressive and fatal disease. Fibroblast growth factor receptors (FGFRs) play an important role in the development and progression of fibrosis. Through scaffold hopping, bioisosteric replacement design, and structure-activity relationship optimization, we developed a series of highly potent FGFRs inhibitors, and the indazole-containing candidate compound A16 showed potent kinase activity comparable to that of AZD4547. In addition, A16 effectively suppressed the activation of lung fibroblasts and hepatic stellate cells (HSCs) induced by TGF-β1, leading to a reduction in collagen deposition. Notably, A16 exhibited potent anti-fibrotic effects through the inhibition of the FGFR pathway in vitro. Compound A16 also showed reasonable pharmacokinetic properties (F = 21.84%) and favorable cardiac safety (hERG IC50 > 20 μM). Moreover, in models of pulmonary fibrosis, A16 ameliorated (in the prevention model) and reversed (in the treatment model) bleomycin-induced lung fibrosis, as well as mitigated inflammatory immune response in the lung. Furthermore, in the CCl4-induced liver fibrosis model, when A16 was administrated orally at a dose of 30 mg/kg/day for 3 weeks, it effectively improved liver function, restored damaged liver structures, and reduced collagen deposition. Taken together, these results suggest that A16 could be a potential drug candidate for the treatment of organ fibrosis.
{"title":"Design, Synthesis, and Biological Evaluation of a Potent and Orally Bioavailable FGFRs Inhibitor for Fibrotic Treatment","authors":"Lin Yue, Zui Tan, Wei Wei, Hongyao Liu, Taixiong Xue, Xingping Su, Xiuli Wu, Yuting Xie, Peilin Li, Doudou Wang, Zhihao Liu, Cailing Gan, Tinghong Ye","doi":"10.1016/j.ejmech.2024.117232","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117232","url":null,"abstract":"Organ fibrosis, such as lung fibrosis and liver fibrosis, is a progressive and fatal disease. Fibroblast growth factor receptors (FGFRs) play an important role in the development and progression of fibrosis. Through scaffold hopping, bioisosteric replacement design, and structure-activity relationship optimization, we developed a series of highly potent FGFRs inhibitors, and the indazole-containing candidate compound <strong>A16</strong> showed potent kinase activity comparable to that of <strong>AZD4547</strong>. In addition, <strong>A16</strong> effectively suppressed the activation of lung fibroblasts and hepatic stellate cells (HSCs) induced by TGF-β1, leading to a reduction in collagen deposition. Notably, <strong>A16</strong> exhibited potent anti-fibrotic effects through the inhibition of the FGFR pathway <em>in vitro</em>. Compound <strong>A16</strong> also showed reasonable pharmacokinetic properties (<em>F</em> = 21.84%) and favorable cardiac safety (hERG IC<sub>50</sub> > 20 μM). Moreover, in models of pulmonary fibrosis, <strong>A16</strong> ameliorated (in the prevention model) and reversed (in the treatment model) bleomycin-induced lung fibrosis, as well as mitigated inflammatory immune response in the lung. Furthermore, in the CCl<sub>4</sub>-induced liver fibrosis model, when <strong>A16</strong> was administrated orally at a dose of 30 mg/kg/day for 3 weeks, it effectively improved liver function, restored damaged liver structures, and reduced collagen deposition. Taken together, these results suggest that <strong>A16</strong> could be a potential drug candidate for the treatment of organ fibrosis.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"26 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911571","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}
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