European Journal of Medicinal Chemistry最新文献_第10页

Aromatic nitroolefin with inhibition efficacy in triple-negative breast cancer cells by dual targeting RXRα and tubulins

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-03-06 DOI: 10.1016/j.ejmech.2025.117486

Xiaofang Qu , Yanxia Wang , Yunqing Xu , Lin Xu , Xiaohong Ye , Hongchen Cai , Liang Bu , Zhiping Zeng , Hu Zhou

{"title":"Aromatic nitroolefin with inhibition efficacy in triple-negative breast cancer cells by dual targeting RXRα and tubulins","authors":"Xiaofang Qu , Yanxia Wang , Yunqing Xu , Lin Xu , Xiaohong Ye , Hongchen Cai , Liang Bu , Zhiping Zeng , Hu Zhou","doi":"10.1016/j.ejmech.2025.117486","DOIUrl":"10.1016/j.ejmech.2025.117486","url":null,"abstract":"<div><div>We previously identified that 1-(2-Nitrovinyl)naphthalene (Z-10) is a ligand of retinoid x receptor α (RXRα) with a potent anti-breast cancer efficacy and revealed that nitro group is an essential pharmacophore in Z-10. In this study, we defined that the double bond of the nitrovinyl group is also vital for Z-10 to bind and activate RXRα. Mechanistically, the double bond has a chemical ability to mediate Z-10's covalent binding of RXRα via the Michael addition reaction with Cys432. By retaining the nitrovinyl group, a series of Z-10 analogues with different aromatic groups and different aromatic ring-positions of nitrovinyl group and alkoxy groups were designed and synthesized. We found that some analogues including compound <strong>30</strong> show stronger ability than Z-10 in inhibiting TNFα survival signal in MDA-MB-231 breast cancer cells. Interestingly, these RXRα ligands also bind to tubulins likely through the similar covalent interaction and induce the degradation of tubulins and cell cycle arrest in MDA-MB-231 cells, of which <strong>30</strong> displays the strongest efficacy. Importantly, these analogues and TNFα exhibit synergistic effects in inducing breast cancer cell apoptosis, of which <strong>30</strong> shows greater efficacy than Z-10. Together, our study provides a theoretical basis for the RXRα and tubulin dual-targeting drug design for breast cancer treatment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117486"},"PeriodicalIF":6.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569905","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 antibacterial evaluations of novel vancomycin analogues targeting bacteria membrane to combat Gram-negative infections

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-03-05 DOI: 10.1016/j.ejmech.2025.117483

Tao Li , Ruixue Zhang , Hongzhi Gong , Ziyi Tang , Xinyu Li , Zhi Gong , Mahesh Challa , Cheng Zou , Shao-Lin Zhang , Jian Guo , Yun He

{"title":"Synthesis and antibacterial evaluations of novel vancomycin analogues targeting bacteria membrane to combat Gram-negative infections","authors":"Tao Li , Ruixue Zhang , Hongzhi Gong , Ziyi Tang , Xinyu Li , Zhi Gong , Mahesh Challa , Cheng Zou , Shao-Lin Zhang , Jian Guo , Yun He","doi":"10.1016/j.ejmech.2025.117483","DOIUrl":"10.1016/j.ejmech.2025.117483","url":null,"abstract":"<div><div>Vancomycin is primarily used to treat severe infections caused by Gram-positive bacteria and is often considered as the last-resort therapy in the life-threatening situation. However, it is inherently ineffective against Gram-negative bacteria. Herein, we report the design, synthesis, and biological evaluation of novel vancomycin analogues incorporated with lipophilic cationic groups. Through structural optimization and structure-activity relationship (SAR) studies, we identified vancomycin analogue <strong>18b</strong>, which exhibited remarkable antibacterial activity against A. baumannii ATCC 17978, with a MIC of 8 μg/mL. In contrast, vancomycin showed no activity against this strain, even at concentration as high as 128 μg/mL. Further investigations revealed that <strong>18b</strong> possesses rapid bactericidal properties, low toxicity, and a reduced propensity to induce bacterial resistance. The exceptional antibacterial performance of <strong>18b</strong> is partially attributed to the presence of membrane-targeting, lipophilic piperazine cationic groups. In a mouse model infected with A. baumannii ATCC 17978, <strong>18b</strong> exhibited excellent efficacy at a dose of 20 mg/kg, while no toxicity was observed. These findings highlight <strong>18b</strong> as a promising candidate for further development in the fight against Gram-negative bacterial infections.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117483"},"PeriodicalIF":6.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143547064","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

Corrigendum to “D-morphinan analogs with favorable pharmacokinetic profiles as dual-acting antidepressants” [Europ. J. Med. Chem. 287 (2025) 117349]

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-03-05 DOI: 10.1016/j.ejmech.2025.117447

Jing Ji , Zhengtao Hu , Fuqiang Zheng , Jiefang Zheng , Jiaxin Cheng , Nuriddinov Zayniddin , Safomuddin Abduahadi , Guan Wang , Xudong Gong , Libiao Pan , Pengcheng Li , Jiangyu Zhao , Tianwen Hu , Weiliang Zhu , Jingshan Shen , Guanghui Tian , Haji Akber Aisa , Yang He

引用次数: 0

Discovery, synthesis, and biological mechanism evaluation of novel quinoline derivatives as potent NLRP3 inhibitors

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-03-04 DOI: 10.1016/j.ejmech.2025.117466

Ruiwen Wu , Yuyun Yan , Zhuorong Liu , Xiuxiu Zhang , Yiming Luo , Xiangting Liang , Jianhui Lin , Xulin Zeng , Dan Wu , Ping Sun , Wenhui Hu , Zhongjin Yang

{"title":"Discovery, synthesis, and biological mechanism evaluation of novel quinoline derivatives as potent NLRP3 inhibitors","authors":"Ruiwen Wu , Yuyun Yan , Zhuorong Liu , Xiuxiu Zhang , Yiming Luo , Xiangting Liang , Jianhui Lin , Xulin Zeng , Dan Wu , Ping Sun , Wenhui Hu , Zhongjin Yang","doi":"10.1016/j.ejmech.2025.117466","DOIUrl":"10.1016/j.ejmech.2025.117466","url":null,"abstract":"<div><div>Targeting NLRP3 is a highly promising strategy for treating uncontrolled inflammation, which can cause a wide range of diseases or promote disease progression. More NLRP3-targeting inhibitors with different scaffolds are needed to increase the chances of developing safe and effective NLRP3 inhibitors and treating inflammation in different tissues. Here, we discovered the novel quinoline analogues that exhibit potent inhibitory activity against the NLRP3/IL-1β pathway in J774A.1, BMDMs, and human peripheral blood cells. Mechanistic studies confirmed <strong>W16</strong> may directly target NLRP3 and block the NLRP3 inflammasome assembly and activation. <em>In vitro</em> studies demonstrated that <strong>W16</strong> has potent anti-inflammatory effects on DSS-induced ulcerative colitis model. Our findings demonstrated that <strong>W16</strong> is a potential lead compound targeting NLRP3 and deserves further investigation for the treatment of NLRP3-related inflammatory diseases.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117466"},"PeriodicalIF":6.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143547008","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

A novel Al18F-labelled NOTA-modified ubiquicidin 29-41 derivative as a bacterial infection PET imaging agent

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-03-04 DOI: 10.1016/j.ejmech.2025.117482

Yuhao Jiang , Qianna Wang , Junhong Feng , Guangxing Yin , Peiwen Han , Qing Ruan , Junbo Zhang

{"title":"A novel Al18F-labelled NOTA-modified ubiquicidin 29-41 derivative as a bacterial infection PET imaging agent","authors":"Yuhao Jiang , Qianna Wang , Junhong Feng , Guangxing Yin , Peiwen Han , Qing Ruan , Junbo Zhang","doi":"10.1016/j.ejmech.2025.117482","DOIUrl":"10.1016/j.ejmech.2025.117482","url":null,"abstract":"<div><div>The antimicrobial peptide ubiquicidin 29-41 (TGRAKRRMQYNRR) is a potential target for detecting bacterial infection. A novel UBI 29–41 derivative modified with 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) on the amino side of lysine was synthesized and radiolabelled with Al<sup>18</sup>F, named [<sup>18</sup>F]AlF-NOTA-UBI 29–41. The novel PET tracer maintained good <em>in vitro</em> stability in saline at room temperature and mouse serum at 37 °C. <em>In vitro</em> bacterial binding experiments indicated that the tracer specifically bound to <em>Staphylococcus aureus</em>. A significant difference in the uptake of [<sup>18</sup>F]AlF-NOTA-UBI 29–41 between infected muscle and inflamed muscle was observed in biodistribution. A PET imaging study in mouse models with bacterial infection and sterile inflammation showed apparent accumulation at the infection site, suggesting that the complex is a potential PET tracer for distinguishing bacterial infection from sterile inflammation.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117482"},"PeriodicalIF":6.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143547007","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

Mechanisms and therapeutic strategies for NLRP3 degradation via post-translational modifications in ubiquitin-proteasome and autophagy lysosomal pathway

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-03-04 DOI: 10.1016/j.ejmech.2025.117476

Kaiyue Su , Minghai Tang , Jie Wu , Neng Ye , Xueqin Jiang , Min Zhao , Ruijia Zhang , Xiaoying Cai , Xinlu Zhang , Na Li , Jing Peng , Lei Lin , Wenshuang Wu , Haoyu Ye

{"title":"Mechanisms and therapeutic strategies for NLRP3 degradation via post-translational modifications in ubiquitin-proteasome and autophagy lysosomal pathway","authors":"Kaiyue Su , Minghai Tang , Jie Wu , Neng Ye , Xueqin Jiang , Min Zhao , Ruijia Zhang , Xiaoying Cai , Xinlu Zhang , Na Li , Jing Peng , Lei Lin , Wenshuang Wu , Haoyu Ye","doi":"10.1016/j.ejmech.2025.117476","DOIUrl":"10.1016/j.ejmech.2025.117476","url":null,"abstract":"<div><div>The NLRP3 inflammasome is crucial for immune responses. However, its overactivation can lead to severe inflammatory diseases, underscoring its importance as a target for therapeutic intervention. Although numerous inhibitors targeting NLRP3 exist, regulating its degradation offers an alternative and promising strategy to suppress its activation. The degradation of NLRP3 is primarily mediated by the proteasomal and autophagic pathways. The review not only elaborates on the traditional concepts of ubiquitination and NLRP3 degradation but also investigates the important roles of indirect regulatory modifications, such as phosphorylation, acetylation, ubiquitin-like modifications, and palmitoylation—key post-translational modifications (PTMs) that influence NLRP3 degradation. Additionally, we also discuss the potential targets that may affect NLRP3 degradation during the proteasomal and autophagic pathways. By unraveling these complex regulatory mechanisms, the review aims to enhance the understanding of NLRP3 regulation and its implications for developing therapeutic strategies to combat inflammatory diseases.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117476"},"PeriodicalIF":6.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538758","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

Dodecapeptides derived from human cathelicidin with potent activity against carbapenem-resistant Acinetobacter baumannii

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-03-04 DOI: 10.1016/j.ejmech.2025.117477

Yiyi Jiang , Gaomei Zhao , Yali Gong , Yin Chen , Chenwenya Li , Songling Han , Youcai Deng , Jinghong Zhao , Junping Wang , Cheng Wang

{"title":"Dodecapeptides derived from human cathelicidin with potent activity against carbapenem-resistant Acinetobacter baumannii","authors":"Yiyi Jiang , Gaomei Zhao , Yali Gong , Yin Chen , Chenwenya Li , Songling Han , Youcai Deng , Jinghong Zhao , Junping Wang , Cheng Wang","doi":"10.1016/j.ejmech.2025.117477","DOIUrl":"10.1016/j.ejmech.2025.117477","url":null,"abstract":"<div><div>The increasing infections caused by carbapenem-resistant <em>Acinetobacter baumannii</em> (CRAB) poses a serious threat to global public health. Antimicrobial peptides (AMPs) are alternatives to conventional antibiotics in combating superbugs. However, discovering AMPs with low synthesis costs and strong antibacterial effects against CRAB is challenging. In this study, we synthesized 28 dodecapeptides for bactericidal assessment by site mutation and all-hydrocarbon stapling on the basis of the antibacterial core of human cathelicidin. The linear derivative <strong>d12</strong> (Q5RD9I-KR12) and the <em>i, i + 4</em> stapled peptide <strong>d24</strong>, which was generated by substituting Val<sup>4</sup> and Lys<sup>8</sup> of <strong>d12</strong> to staples, stood out among the candidates. These short AMPs efficiently bound to bacterial membrane and penetrated it in a lipid A-dependent manner, resulting in low minimal inhibitory concentrations to inactivate CRAB clinical isolates (2.5–20 μg/mL). The CRAB infection mouse models of irradiation-assisted local pulmonary infection and intra-abdominal sepsis revealed that treatment with <strong>d12</strong> and <strong>d24</strong> significantly eliminated CRAB <em>in vivo</em> and thereby increased mouse survival. Owing to its improved proteolytic resistance, <strong>d24</strong> outperformed <strong>d12</strong> in suppressing intra-abdominal CRAB infection. The excellent antibacterial effects, good biocompatibility, and facile synthesis make <strong>d12</strong> and <strong>d24</strong> promising candidates to curb CRAB infections in different application scenarios.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117477"},"PeriodicalIF":6.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538757","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

A systematic review on the anti-microbial activities and structure-activity relationship (SAR) of quinoxaline derivatives

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-03-03 DOI: 10.1016/j.ejmech.2025.117472

Sri Mounika Bellapukonda, Rani Bandela, Anuradha Singampalli, Danaboina Srikanth, Pardeep Kumar, Srinivas Nanduri, Venkata Madhavi Yaddanapudi

{"title":"A systematic review on the anti-microbial activities and structure-activity relationship (SAR) of quinoxaline derivatives","authors":"Sri Mounika Bellapukonda, Rani Bandela, Anuradha Singampalli, Danaboina Srikanth, Pardeep Kumar, Srinivas Nanduri, Venkata Madhavi Yaddanapudi","doi":"10.1016/j.ejmech.2025.117472","DOIUrl":"10.1016/j.ejmech.2025.117472","url":null,"abstract":"<div><div>Anti-microbial resistance has become a serious global health issue affecting millions of people worldwide. Despite extensive drug discovery efforts aimed at identifying potent molecules for effective anti-microbial treatments, the emergence of superbugs remains a significant challenge. Thus, developing novel therapeutic agents is required to combat these evolving threats. The quinoxaline scaffold emerges as a promising heterocyclic framework for developing novel anti-microbial agents. It's simple, flexible structure, coupled with its bioisosteric relationship to extensively explored quinoline and naphthalene scaffolds, offers a potential avenue for circumventing bacterial resistance developed against these established classes. Hence it has sparked interest in researchers to develop novel antibiotics based on the quinoxaline core. This review focuses on the recent advances of quinoxaline derivatives as anti-microbial agents and their structure-activity relationship studies based on the literature published from 2015 to 2024. The systematic presentation of this information will assist researchers in identifying key substitution patterns around the quinoxaline nucleus, facilitating the development of structure-activity relationship (SAR), and guiding the design of novel anti-microbial drugs to combat the growing threat of anti-microbial resistance.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117472"},"PeriodicalIF":6.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532924","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

Cross-subclass metallo-β-lactamase inhibitors: From structural and catalytic commonalities guiding design

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-03-03 DOI: 10.1016/j.ejmech.2025.117479

Yanhong Zhang, Zhenyang Liang, Shuai Wang, Renzhong Qiao, Chao Li

引用次数: 0

Synthesis and bioactivity of cyclic peptide GG-8-6 analogues as anti-hepatocellular carcinoma agents 作为抗肝细胞癌药物的环肽 GG-8-6 类似物的合成和生物活性

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-03-02 DOI: 10.1016/j.ejmech.2025.117473

Ling-Yun Li , Rong-Sheng Li , Jian Zhou , Jia Fan , Zheng-Lin Wang , Bo Hu , Qing Mu

{"title":"Synthesis and bioactivity of cyclic peptide GG-8-6 analogues as anti-hepatocellular carcinoma agents","authors":"Ling-Yun Li , Rong-Sheng Li , Jian Zhou , Jia Fan , Zheng-Lin Wang , Bo Hu , Qing Mu","doi":"10.1016/j.ejmech.2025.117473","DOIUrl":"10.1016/j.ejmech.2025.117473","url":null,"abstract":"<div><div>GG-8-6, a cyclic peptide with effective anti-hepatocellular carcinoma activity <em>in vitro</em> and <em>in vivo,</em> was synthesized based on the lead compound Grifficyclocin B, which was isolated from the plants of <em>Goniothalamus</em> species (Annonaceae family). Based on the previous study, we synthesized 17 analogues of GG-8-6 to find better potential and higher-yield cyclopeptides. Among these analogues, nine increased their yield compared to GG-8-6, and compound <strong>1</strong> reached a high yield of 14.7 %. In addition, the bioassay results showed that ten analogues exhibited significant anti-hepatocellular carcinoma activities in <em>vitro</em>, which promoted cell apoptosis and reduced intracellular ATP levels. Among them, the activity of compounds <strong>1, 2</strong> and <strong>3</strong> was significantly better than GG-8-6, while the yield of compounds <strong>1</strong> and <strong>3</strong> reached nearly five times that of GG-8-6. Compound <strong>17</strong> was obtained by deprotection from compound <strong>1</strong>, which preserved antitumor activity, and more new derivatives could be synthesized based on the hydroxyl group in its structure. A subcutaneous xenografted mice model confirmed the <em>in vivo</em> antitumor activity of compounds <strong>1</strong> and <strong>17</strong>. The results indicated that both compounds significantly inhibited the growth of tumours. At 10 mg/kg and 15 mg/kg doses for compounds <strong>1</strong> and <strong>17</strong>, the inhibition rates reached 84.3 % and 58.39 %, respectively. Furthermore, the potential mechanism of compounds <strong>1</strong> and <strong>17</strong> was analyzed by transcriptomic analysis. Our results indicated that GG-8-6 analogues as new cyclic peptides might be potential candidates for developing new drugs treating hepatocellular carcinoma.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117473"},"PeriodicalIF":6.0,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528188","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