Hyperuricemia is a metabolic disorder syndrome caused by a disorder of purine metabolism in the body, followed by urate crystal deposition leading to gouty arthritis, urate nephropathy, and kidney stones, collectively known as gout. Promoting uric acid stone dissolution by continuously reducing blood uric acid levels and reducing acute gout attacks in patients by controlling inflammatory pain reactions are identified as a potential therapy for gout. Starting from the natural product piperine, three analogs of novel piperine derivates were designed and synthesized to improve the anti-inflammation pain efficacy. Among this, compound 39 exhibited remarkable analgesic and urate-lowering effect in formalin-induced inflammatory pain model and hyperuricemic model, respectively. Besides, compound 39 exhibited a relatively potent TRPV1 antagonistic effect with an IC50 = 33.06 ± 3.15 nM, and moderate to weak URAT1 (IC50 = 22.51 ± 5.62 μM) and GLUT9 inhibitory activities (60.25% at 50 μM). Further experiment showed that 39 exhibited high stability in vitro and in vivo, and its oral bioavailability was 34%, with a more than 8 hours T1/2. Notably, compound 39 showed high selectivity over other ion channel including hERG which indicated a high safety index. Furthermore, no significant acute damage was observed at the liver microsome, cellular and animal levels. In the long-term administration experiment of hyperuricemia model mice, it was confirmed that 39 could reverse the tissue damage and inflammation caused by high uric acid. Overall, these findings identified a promising candidate to target the pathogenesis of gout by simultaneously suppressing pian and the reabsorption of uric acid.
{"title":"Structure Optimization of Natural Product Piperine to Obtain Novel and Potent Analogs with Anti-inflammation Pain and Urate-Lowering Effect","authors":"Chunxia Liu, Wenxin Wang, Ruoyang Miao, Haoyang Chen, Ning Wang, Weiyan Cheng, Fengxin Zheng, Zheng Li, Jianxin Pang, Hai Qian, Xin Tian","doi":"10.1016/j.ejmech.2025.117649","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117649","url":null,"abstract":"Hyperuricemia is a metabolic disorder syndrome caused by a disorder of purine metabolism in the body, followed by urate crystal deposition leading to gouty arthritis, urate nephropathy, and kidney stones, collectively known as gout. Promoting uric acid stone dissolution by continuously reducing blood uric acid levels and reducing acute gout attacks in patients by controlling inflammatory pain reactions are identified as a potential therapy for gout. Starting from the natural product piperine, three analogs of novel piperine derivates were designed and synthesized to improve the anti-inflammation pain efficacy. Among this, compound <strong>39</strong> exhibited remarkable analgesic and urate-lowering effect in formalin-induced inflammatory pain model and hyperuricemic model, respectively. Besides, compound 39 exhibited a relatively potent TRPV1 antagonistic effect with an IC<sub>50</sub> = 33.06 ± 3.15 nM, and moderate to weak URAT1 (IC<sub>50</sub> = 22.51 ± 5.62 μM) and GLUT9 inhibitory activities (60.25% at 50 μM). Further experiment showed that <strong>39</strong> exhibited high stability <em>in vitro</em> and <em>in vivo</em>, and its oral bioavailability was 34%, with a more than 8 hours T<sub><em>1/2</em></sub>. Notably, compound <strong>39</strong> showed high selectivity over other ion channel including <em>hERG</em> which indicated a high safety index. Furthermore, no significant acute damage was observed at the liver microsome, cellular and animal levels. In the long-term administration experiment of hyperuricemia model mice, it was confirmed that <strong>39</strong> could reverse the tissue damage and inflammation caused by high uric acid. Overall, these findings identified a promising candidate to target the pathogenesis of gout by simultaneously suppressing pian and the reabsorption of uric acid.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"90 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846902","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 : 2025-04-17DOI: 10.1016/j.ejmech.2025.117653
Stephanie Federico, Christian Renn, Petra Brehova, Zlatko Janeba, Susanne Moschütz, Katharina Sylvester, Rasha Abu Shamleh, Helay Baburi, Herbert Zimmermann, Ali El-Tayeb, Norbert Sträter, Christa E. Müller
Ecto-5’-nucleotidase (CD73) is a novel target in cancer (immuno)therapy. Its blockade prevents the formation of immunosuppressive and cancer-promoting adenosine from AMP. Here, we report on the development of a series of small molecules that mimic adenine nucleotides, in which the ribose moiety was replaced by an alkyl chain. Its length was found to be crucial for potency. A crystal structure of the N6-disubstituted acyclic ADP analog 26 (N6-benzyl,N6-methyladenine-9-yl)pentyloxydiphosphonate) in complex with human CD73 revealed that the flexible pentyl linker adopts to interdomain rotation angles differing by up to 18.5°. The most potent CD73 inhibitor of the present series was analog 27 (N6-benzyl,N6-methyladenine-9-yl)hexyloxydiphosphonate, PSB-24000) which exhibited submicromolar potency at human CD73 (Ki 563 nM at soluble CD73; Ki 481 nM at membrane-bound CD73 of triple-negative breast cancer cells). Acyclic nucleotide analogs may be advantageous compared to the previously reported nucleotidic CD73 inhibitors due to their high chemical stability, and because less off-target effects are to be expected. The structure-activity relationships discovered in this study provide valuable insights which will be useful for the development of CD73 inhibitors as immunotherapeutic drugs.
{"title":"Acyclic purine and pyrimidine nucleotide analogs as ecto-5’-nucleotidase (CD73) inhibitors","authors":"Stephanie Federico, Christian Renn, Petra Brehova, Zlatko Janeba, Susanne Moschütz, Katharina Sylvester, Rasha Abu Shamleh, Helay Baburi, Herbert Zimmermann, Ali El-Tayeb, Norbert Sträter, Christa E. Müller","doi":"10.1016/j.ejmech.2025.117653","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117653","url":null,"abstract":"Ecto-5’-nucleotidase (CD73) is a novel target in cancer (immuno)therapy. Its blockade prevents the formation of immunosuppressive and cancer-promoting adenosine from AMP. Here, we report on the development of a series of small molecules that mimic adenine nucleotides, in which the ribose moiety was replaced by an alkyl chain. Its length was found to be crucial for potency. A crystal structure of the <em>N</em><sup>6</sup>-disubstituted acyclic ADP analog <strong>26</strong> (<em>N</em><sup><em>6</em></sup>-benzyl,<em>N</em><sup>6</sup>-methyladenine-9-yl)pentyloxydiphosphonate) in complex with human CD73 revealed that the flexible pentyl linker adopts to interdomain rotation angles differing by up to 18.5°. The most potent CD73 inhibitor of the present series was analog <strong>27</strong> (<em>N</em><sup><em>6</em></sup>-benzyl,<em>N</em><sup>6</sup>-methyladenine-9-yl)hexyloxydiphosphonate, PSB-24000) which exhibited submicromolar potency at human CD73 (K<sub>i</sub> 563 nM at soluble CD73; K<sub>i</sub> 481 nM at membrane-bound CD73 of triple-negative breast cancer cells). Acyclic nucleotide analogs may be advantageous compared to the previously reported nucleotidic CD73 inhibitors due to their high chemical stability, and because less off-target effects are to be expected. The structure-activity relationships discovered in this study provide valuable insights which will be useful for the development of CD73 inhibitors as immunotherapeutic drugs.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"67 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846903","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 : 2025-04-17DOI: 10.1016/j.ejmech.2025.117644
Ming Sun , Fengwei Lin , Chenchen Yue , Zijie Wei , Chang Liu , Dan Liu , Xing Chen , Qi Li , Ziyuan Liu , Jihong Han , Zichen Cui , Qing Mao , Xinyu Li , Peng Zhang , Bing Zhang , Xuefeng Fu , Han Wang , Yanhua Mou , Shaojie Wang
Hyperuricemia and monosodium urate induced nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome activation is the major pathogenesis for gouty arthritis, and urate transporter 1 (URAT1) is a proven target for hyperuricemia. In this study, scaffold hopping modification with tranilast led to the identification of HNW005, an NLRP3 inflammasome and URAT1 dual-target inhibitor, which exhibited notable inhibitory potency against NLRP3 inflammasome activation (KD = 204.6 nM, IC50 = 1.7 μM) and uric acid transmembrane transportation (IC50 = 6.4 μM). Importantly, HNW005 displayed significant in vivo efficacy with respect to anti-inflammatory, analgesic, and uric acid-lowering effects (decreasing rate = 64.8 % at 2 mg/kg). In addition, HNW005 also displayed an acceptable pharmacokinetic profile (F = 41.37 %, t1/2 = 3.07 h). Collectively, the results showed that developing dual-target inhibitors of NLRP3 inflammasomes and URAT1 is a feasible strategy for the treatment of gouty arthritis, and HNW005 is worthy of further investigation.
{"title":"Scaffold hopping-based structural modification of tranilast led to the identification of HNW005 as a promising NLRP3 inflammasome and URAT1 dual inhibitor for the treatment of gouty arthritis","authors":"Ming Sun , Fengwei Lin , Chenchen Yue , Zijie Wei , Chang Liu , Dan Liu , Xing Chen , Qi Li , Ziyuan Liu , Jihong Han , Zichen Cui , Qing Mao , Xinyu Li , Peng Zhang , Bing Zhang , Xuefeng Fu , Han Wang , Yanhua Mou , Shaojie Wang","doi":"10.1016/j.ejmech.2025.117644","DOIUrl":"10.1016/j.ejmech.2025.117644","url":null,"abstract":"<div><div>Hyperuricemia and monosodium urate induced nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome activation is the major pathogenesis for gouty arthritis, and urate transporter 1 (URAT1) is a proven target for hyperuricemia. In this study, scaffold hopping modification with tranilast led to the identification of <strong>HNW005</strong>, an NLRP3 inflammasome and URAT1 dual-target inhibitor, which exhibited notable inhibitory potency against NLRP3 inflammasome activation (<em>K</em><sub>D</sub> = 204.6 nM, IC<sub>50</sub> = 1.7 μM) and uric acid transmembrane transportation (IC<sub>50</sub> = 6.4 μM). Importantly, <strong>HNW005</strong> displayed significant <em>in vivo</em> efficacy with respect to anti-inflammatory, analgesic, and uric acid-lowering effects (decreasing rate = 64.8 % at 2 mg/kg). In addition, <strong>HNW005</strong> also displayed an acceptable pharmacokinetic profile (F = 41.37 %, t<sub>1/2</sub> = 3.07 h). Collectively, the results showed that developing dual-target inhibitors of NLRP3 inflammasomes and URAT1 is a feasible strategy for the treatment of gouty arthritis, and <strong>HNW005</strong> is worthy of further investigation.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117644"},"PeriodicalIF":6.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842008","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 : 2025-04-17DOI: 10.1016/j.ejmech.2025.117643
Xinxin Zhao , Lin Yuan , Zheng Gong , Mengqi Li , Ye Yuan , Jin Geng
In 2024, the National Medical Products Administration (NMPA) approved 46 Class 1 or 1.1 innovative drugs, including 7 imported drugs and 39 domestically developed drugs, marking a new record in China's pharmaceutical innovation. These approvals encompassed 23 chemical drugs, 20 biological products, and 3 traditional Chinese medicines or natural products, demonstrating continuous growth in innovative drug development. Compared to 16 approvals in 2020 and the surge in 2021, when approvals equaled the total of the previous four years, the trend of increased approvals has resumed since 2024. Therapeutically, oncology drugs remained the dominant category in 2024, comprising 50 % (23/46) of approvals. Gastrointestinal and metabolic drugs, accounting for 13.04 % (6/46), surpassed other categories to rank second, followed by neurological drugs (8.7 %, 4/46). Anti-infectives, miscellaneous drugs, and traditional Chinese medicines each contributed three approvals (7.5 % each). Regulatory advancements played a significant role, with 18 drugs (39.13 %) approved via priority reviews, emergency reviews, or conditional approvals. This group included 9 chemical drugs and 9 biological products, with notable breakthrough therapies such as taletrectinib, lutetium monoclonal antibodies, and donanemab receiving special recognition. The 2024 data reflect China's growing capabilities in drug innovation and its commitment to addressing critical medical needs through accelerated regulatory pathways.
{"title":"New drugs approved by the NMPA in 2024: Synthesis and clinical applications","authors":"Xinxin Zhao , Lin Yuan , Zheng Gong , Mengqi Li , Ye Yuan , Jin Geng","doi":"10.1016/j.ejmech.2025.117643","DOIUrl":"10.1016/j.ejmech.2025.117643","url":null,"abstract":"<div><div>In 2024, the National Medical Products Administration (NMPA) approved 46 Class 1 or 1.1 innovative drugs, including 7 imported drugs and 39 domestically developed drugs, marking a new record in China's pharmaceutical innovation. These approvals encompassed 23 chemical drugs, 20 biological products, and 3 traditional Chinese medicines or natural products, demonstrating continuous growth in innovative drug development. Compared to 16 approvals in 2020 and the surge in 2021, when approvals equaled the total of the previous four years, the trend of increased approvals has resumed since 2024. Therapeutically, oncology drugs remained the dominant category in 2024, comprising 50 % (23/46) of approvals. Gastrointestinal and metabolic drugs, accounting for 13.04 % (6/46), surpassed other categories to rank second, followed by neurological drugs (8.7 %, 4/46). Anti-infectives, miscellaneous drugs, and traditional Chinese medicines each contributed three approvals (7.5 % each). Regulatory advancements played a significant role, with 18 drugs (39.13 %) approved via priority reviews, emergency reviews, or conditional approvals. This group included 9 chemical drugs and 9 biological products, with notable breakthrough therapies such as taletrectinib, lutetium monoclonal antibodies, and donanemab receiving special recognition. The 2024 data reflect China's growing capabilities in drug innovation and its commitment to addressing critical medical needs through accelerated regulatory pathways.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117643"},"PeriodicalIF":6.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842007","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}
Some novel benzamide derivatives with modified linker group were designed and synthesized as promising HDAC3-selective inhibitors. These compounds exerted promising antiproliferative potential compared to reference molecule CI994 while tested against several cancer cell lines. Notably, all these molecules exhibited nontoxicity towards normal human cell lines. The most promising molecule in series 7c exhibited ∼47-fold HDAC3 selectivity over HDAC2 isoform. Compound 7c induced apoptosis and cell cycle arrest in the G2/M phase in the 4T1 cell line. Moreover, compound 7c yielded a good in vivo pharmacokinetic profile. Notably, compound 7c markedly reduced tumor growth in the 4T1-Luc breast cancer xenograft model in female Balb/c mice. Compound 7c also upregulated apoptotic proteins namely caspase-3, caspase-7, and cytochrome c, and downregulated Bcl-2. The antitumor potential of compound 7c was further justified by the downregulation of EGFR and Ki-67 through Western blot analysis. Nevertheless, the HDAC3 inhibitory potency of compound 7c depicted strong and stable binding interaction at the HDAC3 active site. These findings validated that compound 7c is a promising HDAC3 inhibitor that can be further investigated for clinical translation to achieve emerging breast cancer therapeutics.
{"title":"Design and synthesis of pyridine-based benzamides as potent HDAC3 inhibitors as an armament against breast cancer with in vivo validation","authors":"Ambati Himaja , Ganesh Routholla , Tarun Patel , Suvankar Banerjee , Darakhshan Begum , Sanjeev Regula , Sravani Pulya , Swati Biswas , Nilanjan Adhikari , Balaram Ghosh","doi":"10.1016/j.ejmech.2025.117636","DOIUrl":"10.1016/j.ejmech.2025.117636","url":null,"abstract":"<div><div>Some novel benzamide derivatives with modified linker group were designed and synthesized as promising HDAC3-selective inhibitors. These compounds exerted promising antiproliferative potential compared to reference molecule CI994 while tested against several cancer cell lines. Notably, all these molecules exhibited nontoxicity towards normal human cell lines. The most promising molecule in series <strong>7c</strong> exhibited ∼47-fold HDAC3 selectivity over HDAC2 isoform. Compound <strong>7c</strong> induced apoptosis and cell cycle arrest in the G2/M phase in the 4T1 cell line. Moreover, compound <strong>7c</strong> yielded a good <em>in vivo</em> pharmacokinetic profile. Notably, compound <strong>7c</strong> markedly reduced tumor growth in the 4T1-Luc breast cancer xenograft model in female Balb/c mice. Compound <strong>7c</strong> also upregulated apoptotic proteins namely caspase-3, caspase-7, and cytochrome <em>c</em>, and downregulated Bcl-2. The antitumor potential of compound <strong>7c</strong> was further justified by the downregulation of EGFR and Ki-67 through Western blot analysis. Nevertheless, the HDAC3 inhibitory potency of compound <strong>7c</strong> depicted strong and stable binding interaction at the HDAC3 active site. These findings validated that compound <strong>7c</strong> is a promising HDAC3 inhibitor that can be further investigated for clinical translation to achieve emerging breast cancer therapeutics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117636"},"PeriodicalIF":6.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846904","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 : 2025-04-17DOI: 10.1016/j.ejmech.2025.117628
Chunlin Ren , Qiding Xu , Qiusi Luo , Xue Qiao , Taotao Ding , Wumei Wang , Xiaodong Zeng , Cheng Chen , Yuling Xiao , Xuechuan Hong
Transient receptor potential canonical 6 (TRPC6) channels, which function as receptor-operated, non-selective cation channels, are widely expressed in the kidney, lungs, and brain. Within these organs, they play crucial roles in regulating diverse physiological processes and contribute to the pathogenesis of various disorders. The resolution of the cryo-electron microscopy structure of TRPC6 has significantly advanced our understanding of its molecular mechanisms, thereby providing a robust platform for structure-based drug design. Building upon compound 1S as a lead, we developed and synthesized a series of benzothiazole derivatives, ultimately identifying compound X26 as a potent TRPC6 antagonist with an IC50 of 0.97 μM. In vitro administration of X26 significantly suppressed TGF-β1–induced myofibroblast differentiation in HK-2 cells, as evidenced by a reduced expression of α-SMA, collagen I, and fibronectin. Furthermore, in a unilateral ureteral obstruction (UUO)–induced kidney fibrosis mouse model, treatment with X26 resulted in a substantial reduction in serum urea nitrogen, serum creatinine, and urinary protein levels, as well as a decrease in renal collagen deposition. These findings establish X26 as a promising lead for the development of TRPC6 antagonists and therapeutic interventions for kidney fibrosis.
{"title":"Benzothiazole amide analogues as antagonists of TRPC 6 channels: A therapeutic approach for kidney fibrosis","authors":"Chunlin Ren , Qiding Xu , Qiusi Luo , Xue Qiao , Taotao Ding , Wumei Wang , Xiaodong Zeng , Cheng Chen , Yuling Xiao , Xuechuan Hong","doi":"10.1016/j.ejmech.2025.117628","DOIUrl":"10.1016/j.ejmech.2025.117628","url":null,"abstract":"<div><div>Transient receptor potential canonical 6 (TRPC6) channels, which function as receptor-operated, non-selective cation channels, are widely expressed in the kidney, lungs, and brain. Within these organs, they play crucial roles in regulating diverse physiological processes and contribute to the pathogenesis of various disorders. The resolution of the cryo-electron microscopy structure of TRPC6 has significantly advanced our understanding of its molecular mechanisms, thereby providing a robust platform for structure-based drug design. Building upon compound <strong>1S</strong> as a lead, we developed and synthesized a series of benzothiazole derivatives, ultimately identifying compound <strong>X26</strong> as a potent TRPC6 antagonist with an IC<sub>50</sub> of 0.97 μM. <em>In vitro</em> administration of <strong>X26</strong> significantly suppressed TGF-β1–induced myofibroblast differentiation in HK-2 cells, as evidenced by a reduced expression of α-SMA, collagen I, and fibronectin. Furthermore, in a unilateral ureteral obstruction (UUO)–induced kidney fibrosis mouse model, treatment with <strong>X26</strong> resulted in a substantial reduction in serum urea nitrogen, serum creatinine, and urinary protein levels, as well as a decrease in renal collagen deposition. These findings establish <strong>X26</strong> as a promising lead for the development of TRPC6 antagonists and therapeutic interventions for kidney fibrosis.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117628"},"PeriodicalIF":6.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842006","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 : 2025-04-17DOI: 10.1016/j.ejmech.2025.117650
Yali Sang , Weifang Huang , Jiacheng Lin , Liu Yang , Yuge Zhou , Chang Yu , Xuehua Sun , Hong Yu , Xiaoni Kong
Nuclear factor-erythroid 2 related factor 2 (Nrf2) is a key regulator in cellular defense against oxidative stress. While flavonoids have been identified as Nrf2 activators by inhibiting Keap1-Nrf2 protein-protein interaction (PPI), their limited bioactivity presents significant challenges for therapeutic applications. To compensate for this shortcoming, 28 sulfonamide-flavonoid analogues targeting the Keap1-Nrf2 PPI were synthesized by a fragment-based approach. Among these, SG16, which incorporates a fluorine atom, exhibited potent Nrf2-activated capacity and notable anti-inflammatory properties. In AML12 hepatocytes, SG16 significantly enhanced the expression of antioxidant genes by promoting Nrf2 nuclear translocation. In an acute liver injury (ALI) mouse model, SG16 treatment led to a substantial, hundredfold upregulation of the cytoprotective gene HO-1 mRNA. Meanwhile, a dose-dependent decline in ALT, AST, and inflammatory cytokine levels was observed, reflecting improved liver function. Histopathological evaluations, including hematoxylin and eosin (HE) staining, TUNEL, myeloperoxidase (MPO) activity assessment, and F4/80 macrophage marker analysis, consistently demonstrated substantial attenuation of liver tissue damage following SG16 treatment. Moreover, Co-IP assays combined with experiments in Nrf2 knockout mice suggested that the novel sulfonamide-containing flavonoids are a promising class of Nrf2-targeted therapeutic candidates, warranting further exploration for oxidative stress-related disorders.
{"title":"Fluorinated sulfonamide-flavonoid derivatives as novel Keap1-Nrf2 inhibitors: Potent induction of cytoprotective gene HO-1 in vivo","authors":"Yali Sang , Weifang Huang , Jiacheng Lin , Liu Yang , Yuge Zhou , Chang Yu , Xuehua Sun , Hong Yu , Xiaoni Kong","doi":"10.1016/j.ejmech.2025.117650","DOIUrl":"10.1016/j.ejmech.2025.117650","url":null,"abstract":"<div><div>Nuclear factor-erythroid 2 related factor 2 (Nrf2) is a key regulator in cellular defense against oxidative stress. While flavonoids have been identified as Nrf2 activators by inhibiting Keap1-Nrf2 protein-protein interaction (PPI), their limited bioactivity presents significant challenges for therapeutic applications. To compensate for this shortcoming, 28 sulfonamide-flavonoid analogues targeting the Keap1-Nrf2 PPI were synthesized by a fragment-based approach. Among these, SG16, which incorporates a fluorine atom, exhibited potent Nrf2-activated capacity and notable anti-inflammatory properties. In AML12 hepatocytes, SG16 significantly enhanced the expression of antioxidant genes by promoting Nrf2 nuclear translocation. In an acute liver injury (ALI) mouse model, SG16 treatment led to a substantial, hundredfold upregulation of the cytoprotective gene HO-1 mRNA. Meanwhile, a dose-dependent decline in ALT, AST, and inflammatory cytokine levels was observed, reflecting improved liver function. Histopathological evaluations, including hematoxylin and eosin (HE) staining, TUNEL, myeloperoxidase (MPO) activity assessment, and F4/80 macrophage marker analysis, consistently demonstrated substantial attenuation of liver tissue damage following SG16 treatment. Moreover, Co-IP assays combined with experiments in Nrf2 knockout mice suggested that the novel sulfonamide-containing flavonoids are a promising class of Nrf2-targeted therapeutic candidates, warranting further exploration for oxidative stress-related disorders.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117650"},"PeriodicalIF":6.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846906","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}
Alzheimer's disease (AD) represents a progressive neurodegenerative disorder marked by complex pathologies. Glycogen synthase kinase-3β (GSK-3β) plays a pivotal role in AD pathogenesis, influencing key pathological processes such as hyperphosphorylation of tau and production of amyloid-beta. However, current methods for detecting GSK-3β in living cells and tissues are limited in sensitivity and real-time tracking. Herein, we reported a series of environment-sensitive fluorescent probes to detect GSK-3β in both living cells and brain slices. These probes exhibit fluorescence upon the binding of GSK-3β, providing high sensitivity and selectivity with minimal background interference. Compound 10c was further validated in an AD mouse model with elevated expression of GSK-3β, showing clear imaging in hippocampal regions. Compared to immunofluorescence, compound 10c demonstrated a lower background and faster labeling. In addition, this compound showed neuroprotective effects, supporting its potential as a theranostic tool in AD. These findings provide new tools for investigating the role of GSK-3β in AD and advancing targeted therapies.
{"title":"Discovery of fluorescent and theranostic probes for glycogen synthase kinase-3β in living cells and brain tissues: Detection and imaging in models of Alzheimer's disease","authors":"Yu Chen , Hanyue Dong , Xiaoling Huang, Lulu Jiang, Zixing Jiang, Lanqing Li, Jinhui Hu, Wen-Hua Chen","doi":"10.1016/j.ejmech.2025.117639","DOIUrl":"10.1016/j.ejmech.2025.117639","url":null,"abstract":"<div><div>Alzheimer's disease (AD) represents a progressive neurodegenerative disorder marked by complex pathologies. Glycogen synthase kinase-3<em>β</em> (GSK-3<em>β</em>) plays a pivotal role in AD pathogenesis, influencing key pathological processes such as hyperphosphorylation of tau and production of amyloid-beta. However, current methods for detecting GSK-3<em>β</em> in living cells and tissues are limited in sensitivity and real-time tracking. Herein, we reported a series of environment-sensitive fluorescent probes to detect GSK-3<em>β</em> in both living cells and brain slices. These probes exhibit fluorescence upon the binding of GSK-3<em>β</em>, providing high sensitivity and selectivity with minimal background interference. Compound <strong>10c</strong> was further validated in an AD mouse model with elevated expression of GSK-3<em>β</em>, showing clear imaging in hippocampal regions. Compared to immunofluorescence, compound <strong>10c</strong> demonstrated a lower background and faster labeling. In addition, this compound showed neuroprotective effects, supporting its potential as a theranostic tool in AD. These findings provide new tools for investigating the role of GSK-3<em>β</em> in AD and advancing targeted therapies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117639"},"PeriodicalIF":6.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846909","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 : 2025-04-17DOI: 10.1016/j.ejmech.2025.117646
Qiu-Ge Liu , Ji Wu , Zi-Yue Wang , Bing-Bing Chen , Yi-Fei Du , Jin-Bo Niu , Jian Song , Sai-Yang Zhang
As a prevalent oncogenic driver gene in non-small cell lung cancer (NSCLC), ALK represents a crucial and efficacious therapeutic target. To date, seven ALK inhibitors have been approved for ALK fusion-positive NSCLC, with several others undergoing clinical trials. These therapies demonstrate significant efficacy in ALK fusion-positive NSCLC patients. However, acquired resistance mechanisms, including ALK kinase domain mutations, ALK gene amplification, and bypass pathway activation, significantly compromise the efficacy of targeted therapy in ALK fusion-positive NSCLC. Therefore, the discovery of novel ALK inhibitors and the development of related treatment strategies remain critical. Compared to the combination therapy strategy based on ALK inhibitors, dual-target inhibitors (targeting two distinct pathways within a single molecule) may reduce systemic toxicity and mitigate resistance mechanisms in cancer treatment. Notably, recent years have witnessed remarkable progress in dual-target ALK inhibitor development for NSCLC. Consequently, this review aims to summarize the advancements achieved through dual ALK-based inhibitors in NSCLC therapy, analyze their rational design and structure-activity relationships, and provide perspectives for overcoming resistance through next-generation inhibitors and innovative therapeutic approaches.
{"title":"ALK-based dual inhibitors: Focus on recent development for non-small cell lung cancer therapy","authors":"Qiu-Ge Liu , Ji Wu , Zi-Yue Wang , Bing-Bing Chen , Yi-Fei Du , Jin-Bo Niu , Jian Song , Sai-Yang Zhang","doi":"10.1016/j.ejmech.2025.117646","DOIUrl":"10.1016/j.ejmech.2025.117646","url":null,"abstract":"<div><div>As a prevalent oncogenic driver gene in non-small cell lung cancer (NSCLC), ALK represents a crucial and efficacious therapeutic target. To date, seven ALK inhibitors have been approved for ALK fusion-positive NSCLC, with several others undergoing clinical trials. These therapies demonstrate significant efficacy in ALK fusion-positive NSCLC patients. However, acquired resistance mechanisms, including ALK kinase domain mutations, ALK gene amplification, and bypass pathway activation, significantly compromise the efficacy of targeted therapy in ALK fusion-positive NSCLC. Therefore, the discovery of novel ALK inhibitors and the development of related treatment strategies remain critical. Compared to the combination therapy strategy based on ALK inhibitors, dual-target inhibitors (targeting two distinct pathways within a single molecule) may reduce systemic toxicity and mitigate resistance mechanisms in cancer treatment. Notably, recent years have witnessed remarkable progress in dual-target ALK inhibitor development for NSCLC. Consequently, this review aims to summarize the advancements achieved through dual ALK-based inhibitors in NSCLC therapy, analyze their rational design and structure-activity relationships, and provide perspectives for overcoming resistance through next-generation inhibitors and innovative therapeutic approaches.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117646"},"PeriodicalIF":6.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846988","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 : 2025-04-16DOI: 10.1016/j.ejmech.2025.117648
Mumen F.A. Amer , Dima Hattab , Athirah Bakhtiar
Background
Costunolide (Cos) and dehydrocostus lactone (DhC) are naturally occurring sesquiterpene lactones with potent anticancer properties. Despite their promising bioactivity, limitations such as poor solubility, metabolic instability, and off-target toxicity restrict their clinical application. To overcome these challenges, synthetic derivatives have been developed to enhance cytotoxicity, selectivity, and pharmacokinetics.
Method
ology: Following Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines, a systematic literature was conducted across PubMed, SciFinder, ScienceDirect, Scopus, and Wiley Online Library. Thirteen studies published between 2006 and 2024 met the inclusion criteria, focusing on the anticancer properties of synthetic Cos and DhC derivatives.
Results
Synthetic modifications, particularly amino and triazole conjugations, improved tumor selectivity and water solubility, while maintaining or enhancing cytotoxic potency. The most effective derivatives induced apoptosid, cell cycle arrest, and oxidative stress in various cancer cell lines. However, pharmacokinetic data remain limited, and only one study included in vivo evaluation.
Conclusion
Synthetic derivatives of Cos and DhC exhibit enhanced anticancer potential and improved pharmacokinetic properties, making them promising candidates for drug potential. However, further in vivo studies and clinical trials are necessary to validate their therapeutic efficacy and safety.
{"title":"Anticancer potential of synthetic costunolide and dehydrocostus lactone derivatives: A systematic review","authors":"Mumen F.A. Amer , Dima Hattab , Athirah Bakhtiar","doi":"10.1016/j.ejmech.2025.117648","DOIUrl":"10.1016/j.ejmech.2025.117648","url":null,"abstract":"<div><h3>Background</h3><div>Costunolide (Cos) and dehydrocostus lactone (DhC) are naturally occurring sesquiterpene lactones with potent anticancer properties. Despite their promising bioactivity, limitations such as poor solubility, metabolic instability, and off-target toxicity restrict their clinical application. To overcome these challenges, synthetic derivatives have been developed to enhance cytotoxicity, selectivity, and pharmacokinetics.</div></div><div><h3>Method</h3><div>ology: Following Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines, a systematic literature was conducted across PubMed, SciFinder, ScienceDirect, Scopus, and Wiley Online Library. Thirteen studies published between 2006 and 2024 met the inclusion criteria, focusing on the anticancer properties of synthetic Cos and DhC derivatives.</div></div><div><h3>Results</h3><div>Synthetic modifications, particularly amino and triazole conjugations, improved tumor selectivity and water solubility, while maintaining or enhancing cytotoxic potency. The most effective derivatives induced apoptosid, cell cycle arrest, and oxidative stress in various cancer cell lines. However, pharmacokinetic data remain limited, and only one study included <em>in vivo</em> evaluation.</div></div><div><h3>Conclusion</h3><div>Synthetic derivatives of Cos and DhC exhibit enhanced anticancer potential and improved pharmacokinetic properties, making them promising candidates for drug potential. However, further <em>in vivo</em> studies and clinical trials are necessary to validate their therapeutic efficacy and safety.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117648"},"PeriodicalIF":6.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842009","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：