Pub Date : 2025-02-22DOI: 10.1016/j.ejmech.2025.117420
Ying Lin, Jing Liu, Xinjian Tian, Jin Wang, Huahua Su, Jianpin Xiang, Tao Cao, Yonghui Wang, Qiong Xie, Xufen Yu
Bruton’s tyrosine kinase (BTK) has been an attractive target in the B-cell malignancies. Significant progress has been achieved in developing effective BTK-targeting small-molecule inhibitors and proteolysis targeting chimeras (PROTACs). Based on noncovalent inhibitor ARQ-531, we previously developed two potent BTK PROTACs 6e and SC-3e, which exhibited poor pharmacokinetic property. Herein, we present our extensive structure-activity relationship (SAR) studies focused on BTK binder, linker and cereblon (CRBN) ligand of SC-3e, resulting in two novel BTK PROTACs FDU28 (compound 25) and FDU73 (compound 27). Compounds 25 and 27 selectively induced rapid and robust degradation of wild type (WT) and C481S mutant BTK in a concentration-, time- and ubiquitin-proteasome system (UPS)-dependent manner without affecting CRBN neo-substrates. Furthermore, compound 27 displayed excellent cell antiproliferative activities, metabolic stability in mouse liver microsomes and improved bioavailability in mice. Overall, 27 is a highly effective and selective BTK degrader that is suitable for in vivo efficacy investigations.
{"title":"Design, Synthesis, and Biological Evaluation of Novel BTK-targeting Proteolysis Targeting Chimeras (PROTACs) with Enhanced Pharmacokinetic Properties","authors":"Ying Lin, Jing Liu, Xinjian Tian, Jin Wang, Huahua Su, Jianpin Xiang, Tao Cao, Yonghui Wang, Qiong Xie, Xufen Yu","doi":"10.1016/j.ejmech.2025.117420","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117420","url":null,"abstract":"Bruton’s tyrosine kinase (BTK) has been an attractive target in the B-cell malignancies. Significant progress has been achieved in developing effective BTK-targeting small-molecule inhibitors and proteolysis targeting chimeras (PROTACs). Based on noncovalent inhibitor ARQ-531, we previously developed two potent BTK PROTACs 6e and SC-3e, which exhibited poor pharmacokinetic property. Herein, we present our extensive structure-activity relationship (SAR) studies focused on BTK binder, linker and cereblon (CRBN) ligand of SC-3e, resulting in two novel BTK PROTACs <strong>FDU28</strong> (compound <strong>25</strong>) and <strong>FDU73</strong> (compound <strong>27</strong>). Compounds <strong>25</strong> and <strong>27</strong> selectively induced rapid and robust degradation of wild type (WT) and C481S mutant BTK in a concentration-, time- and ubiquitin-proteasome system (UPS)-dependent manner without affecting CRBN neo-substrates. Furthermore, compound <strong>27</strong> displayed excellent cell antiproliferative activities, metabolic stability in mouse liver microsomes and improved bioavailability in mice. Overall, <strong>27</strong> is a highly effective and selective BTK degrader that is suitable for <em>in vivo</em> efficacy investigations.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"18 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143471025","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}
Diabetes mellitus necessitates strict control of postprandial hyperglycemia via α-glucosidase inhibitors. In this study, novel azole derivatives of Echinocystic acid (EA), a natural pentacyclic triterpenoid, were synthesized through molecular hybridization to enhance hypoglycemic potential. Compound A4 exhibited superior α-glucosidase inhibition (IC50 = 2.72 μM) than that of EA (IC50 = 59.91 μM), and acarbose (IC50 = 342.0 μM). Kinetic analysis revealed mixed-type inhibition (Ki = 15.31 μM, Kis = 10.23 μM), suggesting ternary complex formation. Analysis by spectroscopic studies confirmed A4 altered the enzyme's microenvironment and secondary structure. The combination of molecular docking and molecular dynamics simulations further elucidated the interaction between A4 and α-glucosidase. A4 enhanced binding stability through π-cation and π-π stacking interactions, with low RMSD values indicating structural stability. In vivo studies showed that A4 has an excellent safety profile, with no organ damage observed at a single dose of 0.5 g/kg. In a sucrose loading test in normal mice, A4 demonstrated glucose control comparable to that of acarbose at the same dose. Diabetic mice treated with A4 exhibited reduced fasting blood glucose, improved glucose tolerance, lipid normalization, and antioxidant effects, underscoring its therapeutic promise.
{"title":"Design and synthesis of azole derivatives of echinocystic acid as α-glucosidase inhibitors with hypoglycemic activity","authors":"Hao Deng , Qian Xu , Guo-Qing Chen, Xing Huang, Jin-Ying Liu, Ya-Lan Wang, Yin-Sheng Quan, Rui Yan, Zhe-Shan Quan, Qing-Kun Shen","doi":"10.1016/j.ejmech.2025.117437","DOIUrl":"10.1016/j.ejmech.2025.117437","url":null,"abstract":"<div><div>Diabetes mellitus necessitates strict control of postprandial hyperglycemia via α-glucosidase inhibitors. In this study, novel azole derivatives of Echinocystic acid (EA), a natural pentacyclic triterpenoid, were synthesized through molecular hybridization to enhance hypoglycemic potential. Compound <strong>A4</strong> exhibited superior α-glucosidase inhibition (IC<sub>50</sub> = 2.72 μM) than that of EA (IC<sub>50</sub> = 59.91 μM), and acarbose (IC<sub>50</sub> = 342.0 μM). Kinetic analysis revealed mixed-type inhibition (<em>K</em>i = 15.31 μM, <em>K</em>is = 10.23 μM), suggesting ternary complex formation. Analysis by spectroscopic studies confirmed <strong>A4</strong> altered the enzyme's microenvironment and secondary structure. The combination of molecular docking and molecular dynamics simulations further elucidated the interaction between <strong>A4</strong> and α-glucosidase. <strong>A4</strong> enhanced binding stability through π-cation and π-π stacking interactions, with low RMSD values indicating structural stability. <em>In vivo</em> studies showed that <strong>A4</strong> has an excellent safety profile, with no organ damage observed at a single dose of 0.5 g/kg. In a sucrose loading test in normal mice, <strong>A4</strong> demonstrated glucose control comparable to that of acarbose at the same dose. Diabetic mice treated with <strong>A4</strong> exhibited reduced fasting blood glucose, improved glucose tolerance, lipid normalization, and antioxidant effects, underscoring its therapeutic promise.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117437"},"PeriodicalIF":6.0,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473418","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 : 2025-02-21DOI: 10.1016/j.ejmech.2025.117425
Wenbo Zhang , Linjie Zhang , Dongshuo Meng , Kunfan Zhang , Zixue Zhang , Guan Wang , Feng Ni
Chronic idiopathic constipation (CIC) is a prevalent gastrointestinal disorder with limited therapeutic options that balance efficacy and safety. Current therapies, such as the 5-HT4 receptor (5-HT4R) agonist prucalopride, demonstrate efficacy but are often associated with systemic side effects, highlighting the need for gut-restricted alternatives. Herein, we report for the first time the rational design and synthesis of gut-restricted bivalent agonists targeting mucosal 5-HT4R by integrating pharmacophores of prucalopride and tenapanor. Structural optimization, particularly of linker length and properties, led to the discovery of compound 4, which exhibited potent 5-HT4R agonistic activity, high selectivity, and favorable physicochemical properties. Preclinical studies demonstrated that compound 4 significantly enhanced whole-gut and colonic transit, increased fecal output and water content, while maintaining minimal systemic absorption, confirming its gut-restricted nature. These findings underscore the feasibility of gut-restricted 5-HT4R agonists as a novel therapeutic strategy for CIC and provide valuable insights into the development of safer, more effective treatments for gastrointestinal disorders.
{"title":"Novel gut-restricted bivalent agonists targeting mucosal 5-HT4R: Design, synthesis, and biological evaluation","authors":"Wenbo Zhang , Linjie Zhang , Dongshuo Meng , Kunfan Zhang , Zixue Zhang , Guan Wang , Feng Ni","doi":"10.1016/j.ejmech.2025.117425","DOIUrl":"10.1016/j.ejmech.2025.117425","url":null,"abstract":"<div><div>Chronic idiopathic constipation (CIC) is a prevalent gastrointestinal disorder with limited therapeutic options that balance efficacy and safety. Current therapies, such as the 5-HT<sub>4</sub> receptor (5-HT<sub>4</sub>R) agonist prucalopride, demonstrate efficacy but are often associated with systemic side effects, highlighting the need for gut-restricted alternatives. Herein, we report for the first time the rational design and synthesis of gut-restricted bivalent agonists targeting mucosal 5-HT<sub>4</sub>R by integrating pharmacophores of prucalopride and tenapanor. Structural optimization, particularly of linker length and properties, led to the discovery of compound <strong>4</strong>, which exhibited potent 5-HT<sub>4</sub>R agonistic activity, high selectivity, and favorable physicochemical properties. Preclinical studies demonstrated that compound <strong>4</strong> significantly enhanced whole-gut and colonic transit, increased fecal output and water content, while maintaining minimal systemic absorption, confirming its gut-restricted nature. These findings underscore the feasibility of gut-restricted 5-HT<sub>4</sub>R agonists as a novel therapeutic strategy for CIC and provide valuable insights into the development of safer, more effective treatments for gastrointestinal disorders.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117425"},"PeriodicalIF":6.0,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143471030","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 : 2025-02-21DOI: 10.1016/j.ejmech.2025.117433
Zhongyang Ren, Xu Zhang, Xin Li, Xiaotong Wang, Jie Yang, Guoyun Liu
Two series of diarylmethylamine derivatives were synthesized by 1,6-addition reaction between para-quinone methides and 1-methylpiperazine or 2-oxazolidinone, and their structures were identified by 1H NMR,13C NMR and HRMS. In the lipopolysaccharide-induced inflammatory Raw264.7 cells model, 3-CF3 modified active derivative 1l was screened out by inhibiting the excessive production of NO (IC50 = 5.82 μM), and can inhibit the excessive production of ROS. Western blot analyses indicated that 1l can also inhibit the excessive production of pro-inflammatory cytokines (IL-6 and TNF-α) and the nuclear transfer of NF-κB in inflammatory cells. In the dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice model, 1l can effectively inhibit the colonic shortening and suppress inflammatory symptoms of the colonic tissue (HE). Western blot analyses and biochemical indicators demonstrated that 1l can protect the colon of UC mice by regulating the inflammation-related TLR4/NF-κB signaling pathway and the oxidative stress-related Nrf2/HO-1 signaling pathway. Besides, the safety evaluation results of the UC mouse model (serum biochemical indicators, pathological tissue analysis and organ indexes) and the oral acute toxicity test revealed that 1l had certain safety in mice and can resist other tissues damage caused by DSS. In summary, 1l is an effective anti-inflammatory agent that can be developed as a potential drug for treating UC.
{"title":"Design, synthesis and biological evaluation of diarylmethyl amine derivatives with anti-ulcerative colitis activity via inhibiting inflammation and oxidative stress","authors":"Zhongyang Ren, Xu Zhang, Xin Li, Xiaotong Wang, Jie Yang, Guoyun Liu","doi":"10.1016/j.ejmech.2025.117433","DOIUrl":"10.1016/j.ejmech.2025.117433","url":null,"abstract":"<div><div>Two series of diarylmethylamine derivatives were synthesized by 1,6-addition reaction between para-quinone methides and 1-methylpiperazine or 2-oxazolidinone, and their structures were identified by <sup>1</sup>H NMR<em>,</em> <sup>13</sup>C NMR and HRMS<em>.</em> In the lipopolysaccharide<em>-</em>induced inflammatory Raw264.7 cells model, 3-CF<sub>3</sub> modified active derivative <strong>1l</strong> was screened out by inhibiting the excessive production of NO (IC<sub>50</sub> = 5<em>.</em>82 μM), and can inhibit the excessive production of ROS. Western blot analyses indicated that <strong>1l</strong> can also inhibit the excessive production of pro-inflammatory cytokines (IL-6 and TNF-α) and the nuclear transfer of NF-κB in inflammatory cells. In the dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice model, <strong>1l</strong> can effectively inhibit the colonic shortening and suppress inflammatory symptoms of the colonic tissue (HE). Western blot analyses and biochemical indicators demonstrated that <strong>1l</strong> can protect the colon of UC mice by regulating the inflammation-related TLR4/NF-κB signaling pathway and the oxidative stress-related Nrf2/HO-1 signaling pathway. Besides, the safety evaluation results of the UC mouse model (serum biochemical indicators, pathological tissue analysis and organ indexes) and the oral acute toxicity test revealed that <strong>1l</strong> had certain safety in mice and can resist other tissues damage caused by DSS. In summary, <strong>1l</strong> is an effective anti-inflammatory agent that can be developed as a potential drug for treating UC.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117433"},"PeriodicalIF":6.0,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143471028","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 : 2025-02-21DOI: 10.1016/j.ejmech.2025.117415
Mai S. El-Shoukrofy , Azza Ismail , Reem H. Elhamammy , Sherien A. Abdelhady , Rasha Nassra , Monica S. Makkar , Mahmoud A. Agami , Ahmed Wahid , Hisham A. Nematalla , Minh Sai , Daniel Merk , Ahmed F. El-Yazbi , Ahmed S.F. Belal , Ali H. Eid , Perihan A. Elzahhar
A hybrid pharmacophore model, based on structural motifs previously identified by our team, was employed to generate ligands that simultaneously target COX-2, 15-LOX, and PPARγ in the context of metabolic dysfunction-associated fatty liver disease (MAFLD). Notable COX-2 inhibitory activities (IC50 = 0.065–0.24 μM) were observed relative to celecoxib (IC50 = 0.049 μM). The two most effective 15-LOX inhibitors, 2a and 2b, exhibited 69 % and 57 % of quercetin's action, respectively. Utilizing the rat hemi-diaphragm model to assess in vitro glucose uptake capacity, compounds 2a and 2b demonstrated significant glucose uptake potential in the absence of insulin, surpassing that of pioglitazone. Compound 2a activated PPARγ with an EC50 value of 3.4 μM in a Gal4-hybrid reporter gene assay, indicating partial agonistic action. Interesting binding interactions with targets of interest were identified by molecular docking studies. As well, the expression levels of 20-HETE, Il-1β and TNF-α were decreased in LPS-challenged RAW264.7 macrophages upon treatment with compound 2a. The pharmacokinetic analysis of 2a and assessment of its in vivo efficacy in addressing hepatic impairment in rat models of diabetes and pre-diabetes were carried out. Together, these findings may offer preliminary insights into the potential of these compounds for further refinement in the existing therapeutic arsenals for metabolic diseases.
{"title":"Novel thiazolones for the simultaneous modulation of PPARγ, COX-2 and 15-LOX to address metabolic disease-associated portal inflammation","authors":"Mai S. El-Shoukrofy , Azza Ismail , Reem H. Elhamammy , Sherien A. Abdelhady , Rasha Nassra , Monica S. Makkar , Mahmoud A. Agami , Ahmed Wahid , Hisham A. Nematalla , Minh Sai , Daniel Merk , Ahmed F. El-Yazbi , Ahmed S.F. Belal , Ali H. Eid , Perihan A. Elzahhar","doi":"10.1016/j.ejmech.2025.117415","DOIUrl":"10.1016/j.ejmech.2025.117415","url":null,"abstract":"<div><div>A hybrid pharmacophore model, based on structural motifs previously identified by our team, was employed to generate ligands that simultaneously target COX-2, 15-LOX, and PPARγ in the context of metabolic dysfunction-associated fatty liver disease (MAFLD). Notable COX-2 inhibitory activities (IC<sub>50</sub> = 0.065–0.24 μM) were observed relative to celecoxib (IC<sub>50</sub> = 0.049 μM). The two most effective 15-LOX inhibitors, <strong>2a</strong> and <strong>2b</strong>, exhibited 69 % and 57 % of quercetin's action, respectively. Utilizing the rat hemi-diaphragm model to assess <em>in vitro</em> glucose uptake capacity, compounds <strong>2a</strong> and <strong>2b</strong> demonstrated significant glucose uptake potential in the absence of insulin, surpassing that of pioglitazone. Compound <strong>2a</strong> activated PPARγ with an EC<sub>50</sub> value of 3.4 μM in a Gal4-hybrid reporter gene assay, indicating partial agonistic action. Interesting binding interactions with targets of interest were identified by molecular docking studies. As well, the expression levels of 20-HETE, Il-1β and TNF-α were decreased in LPS-challenged RAW264.7 macrophages upon treatment with compound <strong>2a</strong>. The pharmacokinetic analysis of <strong>2a</strong> and assessment of its <em>in vivo</em> efficacy in addressing hepatic impairment in rat models of diabetes and pre-diabetes were carried out. Together, these findings may offer preliminary insights into the potential of these compounds for further refinement in the existing therapeutic arsenals for metabolic diseases.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117415"},"PeriodicalIF":6.0,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143471026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-20DOI: 10.1016/j.ejmech.2025.117432
Wenxing Lv , Xiaojuan Jia , Bowen Tang , Chao Ma , Xiaopeng Fang , Xurui Jin , Zhangming Niu , Xin Han
Targeted protein degradation (TPD) techniques, particularly proteolysis-targeting chimeras (PROTAC) and molecular glue degraders (MGD), have offered novel strategies in drug discovery. With rapid advancement of computer-aided drug design (CADD) and artificial intelligence-driven drug discovery (AIDD) in the biomedical field, a major focus has become how to effectively integrate these technologies into the TPD drug discovery pipeline to accelerate development, shorten timelines, and reduce costs. Currently, the main research directions for applying CADD and AIDD in TPD include: 1) ternary complex modeling; 2) linker generation; 3) strategies to predict degrader targets, activities and ADME/T properties; 4) In silico degrader design and discovery. Models developed in these areas play a crucial role in target identification, drug design, and optimization at various stages of the discovery process. However, the limited size and quality of datasets related to TPD present challenges, leaving room for further improvement in these models. TPD involves the complex ubiquitin-proteasome system, with numerous factors influencing outcomes. Most current models adopt a static perspective to interpret and predict relevant tasks. In the future, it may be necessary to shift toward dynamic approaches that better capture the intricate relationships among these components. Furthermore, incorporating new and diverse chemical spaces will enhance the precision design and application of TPD agents.
{"title":"In silico modeling of targeted protein degradation","authors":"Wenxing Lv , Xiaojuan Jia , Bowen Tang , Chao Ma , Xiaopeng Fang , Xurui Jin , Zhangming Niu , Xin Han","doi":"10.1016/j.ejmech.2025.117432","DOIUrl":"10.1016/j.ejmech.2025.117432","url":null,"abstract":"<div><div>Targeted protein degradation (TPD) techniques, particularly proteolysis-targeting chimeras (PROTAC) and molecular glue degraders (MGD), have offered novel strategies in drug discovery. With rapid advancement of computer-aided drug design (CADD) and artificial intelligence-driven drug discovery (AIDD) in the biomedical field, a major focus has become how to effectively integrate these technologies into the TPD drug discovery pipeline to accelerate development, shorten timelines, and reduce costs. Currently, the main research directions for applying CADD and AIDD in TPD include: 1) ternary complex modeling; 2) linker generation; 3) strategies to predict degrader targets, activities and ADME/T properties; 4) <em>In silico</em> degrader design and discovery. Models developed in these areas play a crucial role in target identification, drug design, and optimization at various stages of the discovery process. However, the limited size and quality of datasets related to TPD present challenges, leaving room for further improvement in these models. TPD involves the complex ubiquitin-proteasome system, with numerous factors influencing outcomes. Most current models adopt a static perspective to interpret and predict relevant tasks. In the future, it may be necessary to shift toward dynamic approaches that better capture the intricate relationships among these components. Furthermore, incorporating new and diverse chemical spaces will enhance the precision design and application of TPD agents.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117432"},"PeriodicalIF":6.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-20DOI: 10.1016/j.ejmech.2025.117427
Weicong Liu , Manli Guo , Yuanyuan Hu , Yuhang Chen , Yan Wang , Alireza Nezamzadeh-Ejhieh , Honghui Li , Chengyu Lu , Jianqiang Liu
Malignant bone tumors seriously affect the quality of life of terminal patients and impose severe economic burdens on social health management owing to the complex pathogenesis, multiresistance, tumor recurrence, and metastasis, for which traditional clinical treatments are difficult to achieve the ideal therapeutic effects. Metal-based nanomaterials have shown great application potential in the treatment of malignant bone tumors because of their unique physicochemical properties, biological activities, and structural features, which have greatly improved their ability to kill malignant bone tumor cells and inhibit bone tumor growth by being designed as carriers, therapeutic agents, and coatings/scaffolds, combined with multimodal treatment methods, which have effectively overcome the problems of low efficacy, easy resistance, metastasis, and recurrence faced by traditional treatment methods. This paper summarizes the latest progress in malignant bone tumor treatment using metal-based nanomaterials through three modes of carriers, therapeutic agents, and coatings/scaffolds in recent years. In addition, the challenges and future development directions of metal-based nanomaterials in treating malignant bone tumors, such as improving biocompatibility, targeting ability, and therapeutic efficacy, were also investigated. Finally, the advantages and prospects of metal-based nanomaterials for the treatment of malignant bone tumors are summarized, providing a helpful reference for future research.
{"title":"Recent advances in metal-based nanomaterials for malignant bone tumor therapy","authors":"Weicong Liu , Manli Guo , Yuanyuan Hu , Yuhang Chen , Yan Wang , Alireza Nezamzadeh-Ejhieh , Honghui Li , Chengyu Lu , Jianqiang Liu","doi":"10.1016/j.ejmech.2025.117427","DOIUrl":"10.1016/j.ejmech.2025.117427","url":null,"abstract":"<div><div>Malignant bone tumors seriously affect the quality of life of terminal patients and impose severe economic burdens on social health management owing to the complex pathogenesis, multiresistance, tumor recurrence, and metastasis, for which traditional clinical treatments are difficult to achieve the ideal therapeutic effects. Metal-based nanomaterials have shown great application potential in the treatment of malignant bone tumors because of their unique physicochemical properties, biological activities, and structural features, which have greatly improved their ability to kill malignant bone tumor cells and inhibit bone tumor growth by being designed as carriers, therapeutic agents, and coatings/scaffolds, combined with multimodal treatment methods, which have effectively overcome the problems of low efficacy, easy resistance, metastasis, and recurrence faced by traditional treatment methods. This paper summarizes the latest progress in malignant bone tumor treatment using metal-based nanomaterials through three modes of carriers, therapeutic agents, and coatings/scaffolds in recent years. In addition, the challenges and future development directions of metal-based nanomaterials in treating malignant bone tumors, such as improving biocompatibility, targeting ability, and therapeutic efficacy, were also investigated. Finally, the advantages and prospects of metal-based nanomaterials for the treatment of malignant bone tumors are summarized, providing a helpful reference for future research.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117427"},"PeriodicalIF":6.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452070","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 : 2025-02-20DOI: 10.1016/j.ejmech.2025.117413
Shuaishuai Xing , Yijun Liu , Huanfang Xie , Can Guo , Xiaolong Wang , Bingbing Lv , Xinyu Li , Jikuan Shao , Qinglong Guo , Feng Feng , Haopeng Sun
The acquired resistance of doxorubicin (DOX) significantly limits their application in breast cancer treatment. In earlier investigations, a pan-inhibitor, S07–2010, exhibiting inhibitory activity against Aldo-Keto Reductase 1C1–1C4 (AKR1C1–1C4) was discovered through virtual screening. In this study, four rounds of structural modifications were conducted, and the optimized compound 29 exhibited potent inhibitory activity against AKR1C1–1C4 (AKR1C1 IC50 = 0.09 μM, AKR1C2 IC50 = 0.28 μM, AKR1C3 IC50 = 0.05 μM, AKR1C4 IC50 = 0.51 μM). Molecular dynamics (MD) simulations revealed that 29 consistently occupied both SP2 and SP3 pockets, which may explain its pan-inhibitory activity. Utilizing highly DOX resistant MCF-7/ADR cells, 29 demonstrated superior potential as a therapeutic agent for re-sensitizing drug-resistant cell lines to chemotherapy both in vitro and in vivo, suggesting that pan-inhibition of AKR1C1–1C4 may serve as a more promising therapeutic strategy for drug-resistant breast cancer. In summary, Compound 29 may be a promising therapeutic adjuvant in the development of novel strategies to overcome drug resistance.
{"title":"Discovery of highly potent AKR1Cs pan-inhibitors as chemotherapeutic potentiators to restore breast cancer drug resistance","authors":"Shuaishuai Xing , Yijun Liu , Huanfang Xie , Can Guo , Xiaolong Wang , Bingbing Lv , Xinyu Li , Jikuan Shao , Qinglong Guo , Feng Feng , Haopeng Sun","doi":"10.1016/j.ejmech.2025.117413","DOIUrl":"10.1016/j.ejmech.2025.117413","url":null,"abstract":"<div><div>The acquired resistance of doxorubicin (DOX) significantly limits their application in breast cancer treatment. In earlier investigations, a pan-inhibitor, <strong>S07</strong>–<strong>2010</strong>, exhibiting inhibitory activity against Aldo-Keto Reductase 1C1–1C4 (AKR1C1–1C4) was discovered through virtual screening. In this study, four rounds of structural modifications were conducted, and the optimized compound <strong>29</strong> exhibited potent inhibitory activity against AKR1C1–1C4 (AKR1C1 IC<sub>50</sub> = 0.09 μM, AKR1C2 IC<sub>50</sub> = 0.28 μM, AKR1C3 IC<sub>50</sub> = 0.05 μM, AKR1C4 IC<sub>50</sub> = 0.51 μM). Molecular dynamics (MD) simulations revealed that <strong>29</strong> consistently occupied both SP2 and SP3 pockets, which may explain its pan-inhibitory activity. Utilizing highly DOX resistant MCF-7/ADR cells, <strong>29</strong> demonstrated superior potential as a therapeutic agent for re-sensitizing drug-resistant cell lines to chemotherapy both <em>in vitro</em> and <em>in vivo</em>, suggesting that pan-inhibition of AKR1C1–1C4 may serve as a more promising therapeutic strategy for drug-resistant breast cancer. In summary, Compound <strong>29</strong> may be a promising therapeutic adjuvant in the development of novel strategies to overcome drug resistance.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117413"},"PeriodicalIF":6.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452074","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 : 2025-02-20DOI: 10.1016/j.ejmech.2025.117424
Shefali Shukla , Dipankar Bagchi , Divya , Khushi , Y. Veera Manohara Reddy , Jong Pil Park
Breast cancer is the second-most common cause of cancer-related death among women worldwide, with a gradual annual increase of 0.5 % in its occurrence rate in recent years. This complex ailment exhibits considerable diversity, with a mortality rate of 2.5 %. One promising area of research for its treatment is the development of MOFs, which are intricate three-dimensional (3D) structures constructed from metal ions or clusters joined with organic ligands through coordinate bonds. MOFs have emerged as versatile platform overcoming the limitations of conventional chemotherapeutics including poor drug solubility, non-specific targeting, and multidrug resistance. These applications are attributed to their adjustable porosity, chemical makeup, dimensions, straightforward surface customization capabilities, biocompatibility, nontoxicity etc. These properties position MOFs as excellent candidates for diverse regimes of cancer therapeutics including innovative approaches such as phototherapy, chemotherapy, immunotherapy, gene therapy, sonodynamic therapy, and various combination therapies. The article emphasizes the functionalization and applications of MOFs, with a primary focus on their therapeutic capabilities, synergistic approaches, and theranostic strategies that integrate diagnostic and therapeutic functions. Strategies to improve MOF biocompatibility and stability, such as surface modifications and biocompatible coatings are also discussed. Insights on various challenges and future prospects are provided to address current limitations and inspire further research, paving the way for clinical translation of MOF-based breast cancer therapies.
{"title":"Multifunctional metal-organic frameworks in breast cancer therapy: Advanced nanovehicles for effective treatment","authors":"Shefali Shukla , Dipankar Bagchi , Divya , Khushi , Y. Veera Manohara Reddy , Jong Pil Park","doi":"10.1016/j.ejmech.2025.117424","DOIUrl":"10.1016/j.ejmech.2025.117424","url":null,"abstract":"<div><div>Breast cancer is the second-most common cause of cancer-related death among women worldwide, with a gradual annual increase of 0.5 % in its occurrence rate in recent years. This complex ailment exhibits considerable diversity, with a mortality rate of 2.5 %. One promising area of research for its treatment is the development of MOFs, which are intricate three-dimensional (3D) structures constructed from metal ions or clusters joined with organic ligands through coordinate bonds. MOFs have emerged as versatile platform overcoming the limitations of conventional chemotherapeutics including poor drug solubility, non-specific targeting, and multidrug resistance. These applications are attributed to their adjustable porosity, chemical makeup, dimensions, straightforward surface customization capabilities, biocompatibility, nontoxicity etc. These properties position MOFs as excellent candidates for diverse regimes of cancer therapeutics including innovative approaches such as phototherapy, chemotherapy, immunotherapy, gene therapy, sonodynamic therapy, and various combination therapies. The article emphasizes the functionalization and applications of MOFs, with a primary focus on their therapeutic capabilities, synergistic approaches, and theranostic strategies that integrate diagnostic and therapeutic functions. Strategies to improve MOF biocompatibility and stability, such as surface modifications and biocompatible coatings are also discussed. Insights on various challenges and future prospects are provided to address current limitations and inspire further research, paving the way for clinical translation of MOF-based breast cancer therapies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117424"},"PeriodicalIF":6.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452072","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 : 2025-02-20DOI: 10.1016/j.ejmech.2025.117426
Jiaxuan Chen , Xue Bai , Wen Peng , Jianru Liu , Zhongao Jia , Mingxin Cheng , Jing Li , Weiwei Guo , Yueqin Zheng
H2S as the third gasotransmitter is an important endogenous bioregulator that shows various therapeutic potentials. Herein, we present a novel thiocoumarin-based self-reporting sulfide prodrug strategy that utilizes esterase-mediated hydrolysis of thionoesters to release H2S and provide real-time fluorescence monitoring. Our key discovery is that thionoesters can be hydrolyzed by esterases to release H2S under physiological conditions, providing ample opportunities to design prodrugs based on ester-containing molecules. Thiocoumarin derivatives bearing a unique lactone structure offer advantages that simplify prodrug construction by substituting oxygen with sulfur in coumarin backbone and allow in-situ monitoring of H2S release through thiocoumarin-coumarin transformation. Our prodrug candidates are demonstrated with favorable H2S release kinetics and showed combined therapeutic effects of H2S and coumarin, making them promising for treating cerebral infarction. Fluorescent monitoring in mouse confirmed sustained H2S release and revealed the organ distribution, further validating the self-reporting system. Additionally, this approach that ensures therapeutic efficacy and reduces the hepatorenal toxicity of coumarin derivatives constitutes a facile prodrug strategy to overcome the toxicity of drug candidates.
{"title":"A thiocoumarin based self-reporting sulfide prodrug strategy with a favorable safety profile","authors":"Jiaxuan Chen , Xue Bai , Wen Peng , Jianru Liu , Zhongao Jia , Mingxin Cheng , Jing Li , Weiwei Guo , Yueqin Zheng","doi":"10.1016/j.ejmech.2025.117426","DOIUrl":"10.1016/j.ejmech.2025.117426","url":null,"abstract":"<div><div>H<sub>2</sub>S as the third gasotransmitter is an important endogenous bioregulator that shows various therapeutic potentials. Herein, we present a novel thiocoumarin-based self-reporting sulfide prodrug strategy that utilizes esterase-mediated hydrolysis of thionoesters to release H<sub>2</sub>S and provide real-time fluorescence monitoring. Our key discovery is that thionoesters can be hydrolyzed by esterases to release H<sub>2</sub>S under physiological conditions, providing ample opportunities to design prodrugs based on ester-containing molecules. Thiocoumarin derivatives bearing a unique lactone structure offer advantages that simplify prodrug construction by substituting oxygen with sulfur in coumarin backbone and allow <em>in-situ</em> monitoring of H<sub>2</sub>S release through thiocoumarin-coumarin transformation. Our prodrug candidates are demonstrated with favorable H<sub>2</sub>S release kinetics and showed combined therapeutic effects of H<sub>2</sub>S and coumarin, making them promising for treating cerebral infarction. Fluorescent monitoring in mouse confirmed sustained H<sub>2</sub>S release and revealed the organ distribution, further validating the self-reporting system. Additionally, this approach that ensures therapeutic efficacy and reduces the hepatorenal toxicity of coumarin derivatives constitutes a facile prodrug strategy to overcome the toxicity of drug candidates.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117426"},"PeriodicalIF":6.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452071","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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