Pub Date : 2025-01-27DOI: 10.1016/j.ejmech.2025.117318
Kyung-Hwa Jeon, Jae-Ho Shin, Hyun-Ji Jo, Hyunjeong Kim, Seojeong Park, Seojeong Kim, Juhong Lee, Eosu Kim, Younghwa Na, Youngjoo Kwon
AMPK is a promising target for various chronic illnesses such as diabetes and Alzheimer’s disease (AD). We sought to develop a novel small molecule that directly activates AMPK, with the potential to fundamentally modulate the pathogenic mechanisms of the metabolic disorders. To identify a potent novel pharmacophore in an unbiased way, we performed structure-based virtual screening on a commercially available chemical library, and evaluated the actual AMPK activity of 118 compounds selected from 100,000 compounds based on docking scores. Additional iterative molecular docking studies and experimental evaluation of AMPK activity led us to select a hit compound, B1, with a chromone backbone. Using the hit compound and other compounds structurally similar to the hit compound, we identified the chalcone structure as a new scaffold with more efficient interactions with key residues required for AMPK activation. From the newly designed and synthesized chalcone derivatives, we discovered compound 6 as a candidate compound. Compound 6 showed the most efficient interactions with the key residues of AMPK at in silico study and demonstrated significant activation of AMPK in both in vitro and in cellular assays.
{"title":"Computer-Aided Discovery of Novel AMPK Activators through Virtual Screening and SAR-Driven Synthesis","authors":"Kyung-Hwa Jeon, Jae-Ho Shin, Hyun-Ji Jo, Hyunjeong Kim, Seojeong Park, Seojeong Kim, Juhong Lee, Eosu Kim, Younghwa Na, Youngjoo Kwon","doi":"10.1016/j.ejmech.2025.117318","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117318","url":null,"abstract":"AMPK is a promising target for various chronic illnesses such as diabetes and Alzheimer’s disease (AD). We sought to develop a novel small molecule that directly activates AMPK, with the potential to fundamentally modulate the pathogenic mechanisms of the metabolic disorders. To identify a potent novel pharmacophore in an unbiased way, we performed structure-based virtual screening on a commercially available chemical library, and evaluated the actual AMPK activity of 118 compounds selected from 100,000 compounds based on docking scores. Additional iterative molecular docking studies and experimental evaluation of AMPK activity led us to select a hit compound, B1, with a chromone backbone. Using the hit compound and other compounds structurally similar to the hit compound, we identified the chalcone structure as a new scaffold with more efficient interactions with key residues required for AMPK activation. From the newly designed and synthesized chalcone derivatives, we discovered compound <strong>6</strong> as a candidate compound. Compound <strong>6</strong> showed the most efficient interactions with the key residues of AMPK at <em>in silico</em> study and demonstrated significant activation of AMPK in both <em>in vitro</em> and in cellular assays.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"31 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-26DOI: 10.1016/j.ejmech.2025.117307
Hualong Mo, JieYing Liu, Zhengxi Su, Deng-Gao Zhao, Yan-Yan Ma, Kun Zhang, Qi Wang, Chun Fu, Yao Wang, Meiwan Chen, Burong Hu
The authors regret to inform that in Fig. 9, the same TUNEL staining image was used for the control group and the 18 (2.5 mg/kg) group. We have replaced it with the correct image. Correct forms are listed below.
Download: Download high-res image (2MB)
Download: Download full-size image
Fig. 9. H&E stain and TUNEL stain of analysis of tumor tissues after treated with PBS, SAHA, 18, and 18 NPs.
{"title":"Corrigendum to “Isoalantolactone/hydroxamic acid hybrids as potent dual STAT3/HDAC inhibitors and self-assembled nanoparticles for cancer therapy” [Euro. J. Med. Chem. (2024) 116765]","authors":"Hualong Mo, JieYing Liu, Zhengxi Su, Deng-Gao Zhao, Yan-Yan Ma, Kun Zhang, Qi Wang, Chun Fu, Yao Wang, Meiwan Chen, Burong Hu","doi":"10.1016/j.ejmech.2025.117307","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117307","url":null,"abstract":"The authors regret to inform that in <span><span>Fig. 9</span></span>, the same TUNEL staining image was used for the control group and the <strong>18</strong> (2.5 mg/kg) group. We have replaced it with the correct image. Correct forms are listed below.<span><figure><span><img alt=\"Fig. 9\" aria-describedby=\"cap0010\" height=\"233\" src=\"https://ars.els-cdn.com/content/image/1-s2.0-S0223523425000728-fx1.jpg\"/><ol><li><span><span>Download: <span>Download high-res image (2MB)</span></span></span></li><li><span><span>Download: <span>Download full-size image</span></span></span></li></ol></span><span><span><p><span>Fig. 9</span>. H&E stain and TUNEL stain of analysis of tumor tissues after treated with PBS, SAHA, <strong>18</strong>, and <strong>18</strong> NPs.</p></span></span></figure></span>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"15 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-25DOI: 10.1016/j.ejmech.2025.117323
Peng He, Haiyan Li, Zhenyu Yang, Rui Zhang, Qijun Ye, Ta Deng, Wenwen Li, Shucheng He, Guangxin Dong, Zhou Yu, Yi Li
Activating mutations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are significant oncogenic drivers in non-small cell lung cancer (NSCLC) patients. Despite several approved EGFR and ALK inhibitors, drug-resistant mutations pose a major challenge. Especially, there is currently no approved EGFR inhibitors targeting the C797S mutation, a refractory mutation resistant to the third-generation EGFR inhibitors. Furthermore, an increasing number of patients with EGFR/ALK co-mutations have been identified in clinical practice, yet there are no effective therapeutic options available for them. In this study, we report the discovery and preclinical evaluations of a new small-molecule drug candidate, DA-0157, which is capable of overcoming EGFR drug-resistant mutation C797S and EGFR/ALK co-mutations. DA-0157 demonstrated excellent in vitro efficacy, significantly inhibiting various EGFRC797S mutants resistant to the third-generation EGFR inhibitors, ALK rearrangements, and EGFR/ALK co-mutations. In vivo studies revealed that DA-0157 substantially inhibited tumor growth in the LD1-0025-200717 EGFRDel19/T790M/C797S PDX model (40 mg/kg/d, TGI: 98.3%), Ba/F3-EML-4-ALK-L1196M CDX model (40mg /kg/d, TGI: 125.2%), and NCI-H1975 EGFRDel19/T790M/C797S & NCI-H3122 (EML4-ALK) dual-side implantation CDX model (40 mg/kg/d, TGI: 89.5% & 113.9%). DA-0157 demonstrates favorable pharmacokinetic properties and safety. Currently, DA-0157 (DAJH-1050766) is undergoing Phase I/II clinical trials.
{"title":"Discovery and preclinical evaluations of drug candidate DA-0157 capable of overcoming EGFR drug-resistant mutation C797S and EGFR/ALK co-mutations","authors":"Peng He, Haiyan Li, Zhenyu Yang, Rui Zhang, Qijun Ye, Ta Deng, Wenwen Li, Shucheng He, Guangxin Dong, Zhou Yu, Yi Li","doi":"10.1016/j.ejmech.2025.117323","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117323","url":null,"abstract":"Activating mutations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are significant oncogenic drivers in non-small cell lung cancer (NSCLC) patients. Despite several approved EGFR and ALK inhibitors, drug-resistant mutations pose a major challenge. Especially, there is currently no approved EGFR inhibitors targeting the C797S mutation, a refractory mutation resistant to the third-generation EGFR inhibitors. Furthermore, an increasing number of patients with EGFR/ALK co-mutations have been identified in clinical practice, yet there are no effective therapeutic options available for them. In this study, we report the discovery and preclinical evaluations of a new small-molecule drug candidate, DA-0157, which is capable of overcoming EGFR drug-resistant mutation C797S and EGFR/ALK co-mutations. DA-0157 demonstrated excellent <em>in vitro</em> efficacy, significantly inhibiting various EGFR<sup>C797S</sup> mutants resistant to the third-generation EGFR inhibitors, ALK rearrangements, and EGFR/ALK co-mutations. <em>In vivo</em> studies revealed that DA-0157 substantially inhibited tumor growth in the LD1-0025-200717 EGFR<sup>Del19/T790M/C797S</sup> PDX model (40 mg/kg/d, TGI: 98.3%), Ba/F3-EML-4-ALK-L1196M CDX model (40mg /kg/d, TGI: 125.2%), and NCI-H1975 EGFR<sup>Del19/T790M/C797S</sup> & NCI-H3122 (EML4-ALK) dual-side implantation CDX model (40 mg/kg/d, TGI: 89.5% & 113.9%). DA-0157 demonstrates favorable pharmacokinetic properties and safety. Currently, DA-0157 (DAJH-1050766) is undergoing Phase I/II clinical trials.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"61 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-25DOI: 10.1016/j.ejmech.2025.117316
Tongtong Du, Jun Wu, Weina Wang, Wenhui Liang, Yunjie Li, Chuanlong Guo, Xiufen Li, Longjiang Huang, Haibo Yu
A novel class of 7-phenyl-[1,2,4]triazol-5(4H)-one derivatives was designed and synthesized, and their in vivo anticonvulsant activities were evaluated using subcutaneous pentylenetetrazole (Sc-PTZ) and maximal electroshock (MES) tests. Compounds 3u, 4f and 4k exhibited significant anticonvulsant activities in the Sc-PTZ model with ED50 values of 23.7, 17.1 and 18.3 mg/kg, respectively. Neurotoxicity was accessed using the rotarod assay and none of the compounds demonstrated neurotoxicity at maximum solubility, with all TD50 values exceeding 267 mg/kg. This resulted in protective indexes (PI=TD50/ED50) values of greater than 11.3, 15.6 and 14.6, respectively. Compared to control drugs such as sodium phenytoin, sodium valproate, and carbamazepine, compounds 3u, 4f and 4k displayed superior anticonvulsant activities and reduced neurotoxicity. Mechanism results indicated that compounds 4k and 4f were sensitive to the subunit configuration of synaptic α1β2γ2 GABAA receptors, while compounds 3u and 4f dose-dependently reduced the peak amplitude of Nav1.2 currents. These structural compounds may provide a foundation for the further design of novel antiepileptic molecules with low neurotoxicity.
{"title":"Design, synthesis and structure-activity relationship of novel 1,2,4-triazolopyrimidin-5-one derivatives targeting GABAA1 and Nav1.2 with antiepileptic activity","authors":"Tongtong Du, Jun Wu, Weina Wang, Wenhui Liang, Yunjie Li, Chuanlong Guo, Xiufen Li, Longjiang Huang, Haibo Yu","doi":"10.1016/j.ejmech.2025.117316","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117316","url":null,"abstract":"A novel class of 7-phenyl-[1,2,4]triazol-5(4H)-one derivatives was designed and synthesized, and their <em>in vivo</em> anticonvulsant activities were evaluated using subcutaneous pentylenetetrazole (Sc-PTZ) and maximal electroshock (MES) tests. Compounds <strong>3u</strong>, <strong>4f</strong> and <strong>4k</strong> exhibited significant anticonvulsant activities in the Sc-PTZ model with ED<sub>50</sub> values of 23.7, 17.1 and 18.3 mg/kg, respectively. Neurotoxicity was accessed using the rotarod assay and none of the compounds demonstrated neurotoxicity at maximum solubility, with all TD<sub>50</sub> values exceeding 267 mg/kg. This resulted in protective indexes (PI=TD<sub>50</sub>/ED<sub>50</sub>) values of greater than 11.3, 15.6 and 14.6, respectively. Compared to control drugs such as sodium phenytoin, sodium valproate, and carbamazepine, compounds <strong>3u</strong>, <strong>4f</strong> and <strong>4k</strong> displayed superior anticonvulsant activities and reduced neurotoxicity. Mechanism results indicated that compounds <strong>4k</strong> and <strong>4f</strong> were sensitive to the subunit configuration of synaptic α<sub>1</sub>β<sub>2</sub>γ<sub>2</sub> GABA<sub>A</sub> receptors, while compounds <strong>3u</strong> and <strong>4f</strong> dose-dependently reduced the peak amplitude of Na<sub>v</sub>1.2 currents. These structural compounds may provide a foundation for the further design of novel antiepileptic molecules with low neurotoxicity.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"15 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031227","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}
Thirty selenium-containing coumarin derivatives were synthesized and evaluated for inhibitory activity against 17 malignant tumor cell lines. Among these, compound 11i demonstrated the most potent inhibition of neuroblastoma SK-N-SH cells, with an IC50 of 2.5 ± 0.1 μM. Compound 11i notably inhibited SK-N-SH cell proliferation, migration, and invasion. Western blot and immunofluorescence analyses indicated that 11i increased the Bax/Bcl-2 protein expression ratio, promoted Cytochrome C release from mitochondria, and activated caspases 9 and 3, triggering the mitochondria-mediated apoptotic pathway and inducing endogenous tumor cell apoptosis. The compounds localized in the cytoplasm and co-localized with mitochondria, suggesting mitochondrial interaction and dysfunction. Computational docking studies revealed a strong binding affinity of 11i with Bcl-2 and mitochondrial G-quadruplexes. In a subcutaneous neuroblastoma-bearing mouse model, 11i showed notable anti-tumor efficacy with tumor inhibition rates of 79% (10 mg/kg) and 93% (20 mg/kg), exceeding that of cyclophosphamide. This study represents a novel finding on the anti-tumor activity of selenium-containing coumarin derivatives and provides a theoretical basis for developing coumarin-based therapeutics for neuroblastoma.
{"title":"Antiproliferative Activity of Selenium-Enriched Coumarin Derivatives on the SK-N-SH Neuroblastoma Cell Line: Mechanistic Insights","authors":"Ming Wang, Haoran Xu, Xuqiong Xiong, Linru Chang, Koutian Zhang, Yongnan Zhou, Feng Zhang, Annoor Awadasseid, Wen Zhang","doi":"10.1016/j.ejmech.2025.117322","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117322","url":null,"abstract":"Thirty selenium-containing coumarin derivatives were synthesized and evaluated for inhibitory activity against 17 malignant tumor cell lines. Among these, compound <strong>11i</strong> demonstrated the most potent inhibition of neuroblastoma SK-N-SH cells, with an IC<sub>50</sub> of 2.5 ± 0.1 μM. Compound <strong>11i</strong> notably inhibited SK-N-SH cell proliferation, migration, and invasion. Western blot and immunofluorescence analyses indicated that <strong>11i</strong> increased the Bax/Bcl-2 protein expression ratio, promoted Cytochrome C release from mitochondria, and activated caspases 9 and 3, triggering the mitochondria-mediated apoptotic pathway and inducing endogenous tumor cell apoptosis. The compounds localized in the cytoplasm and co-localized with mitochondria, suggesting mitochondrial interaction and dysfunction. Computational docking studies revealed a strong binding affinity of <strong>11i</strong> with Bcl-2 and mitochondrial G-quadruplexes. In a subcutaneous neuroblastoma-bearing mouse model, <strong>11i</strong> showed notable anti-tumor efficacy with tumor inhibition rates of 79% (10 mg/kg) and 93% (20 mg/kg), exceeding that of cyclophosphamide. This study represents a novel finding on the anti-tumor activity of selenium-containing coumarin derivatives and provides a theoretical basis for developing coumarin-based therapeutics for neuroblastoma.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"40 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-25DOI: 10.1016/j.ejmech.2025.117325
Jinlin Li, Lin Li, Caiyun Hou, Zhaodi Tian, Yang Zhou, Jinwei Zhang, Xiaomei Ren, Zhen Wang, Weixue Huang, Ke Ding, Fengtao Zhou
ROR1 has been identified as a pseudokinase, functioning as an allosteric regulator in tumor progression. Aberrant overexpression of ROR1 has been observed in various malignancies, highlighting its potential as therapeutic target for cancer therapy. Modulation of ROR1 by proteolysis targeting chimera degrader instead of traditional inhibitor could offer great efficiency in blocking its kinase-independent regulatory function. Here, we report the first potent ROR1 degraders constructed by connecting the E3 ligand to a ROR1 binder. One representative compound 11d exhibited remarkable efficacy in depleting ROR1 protein with a DC50 value of 40.88 nM and Dmax of 93.7%. Mechanistic investigations illuminated that compound 11d triggers ROR1 protein degradation in a ubiquitin proteasome system (UPS)-dependent manner. Additionally, compound 11d displayed a significantly enhanced ability to inhibit ROR1 signaling, induce apoptosis, and suppress proliferation in lung cell lines compared to the warhead ROR1 binder. These findings underscore the substantial potential of ROR1 degrader for the treatment of non-small cell lung cancer (NSCLC) cells.
{"title":"Discovery of the First Potent ROR1 Degrader for the Treatment of Non-Small Cell Lung Cancer","authors":"Jinlin Li, Lin Li, Caiyun Hou, Zhaodi Tian, Yang Zhou, Jinwei Zhang, Xiaomei Ren, Zhen Wang, Weixue Huang, Ke Ding, Fengtao Zhou","doi":"10.1016/j.ejmech.2025.117325","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117325","url":null,"abstract":"ROR1 has been identified as a pseudokinase, functioning as an allosteric regulator in tumor progression. Aberrant overexpression of ROR1 has been observed in various malignancies, highlighting its potential as therapeutic target for cancer therapy. Modulation of ROR1 by proteolysis targeting chimera degrader instead of traditional inhibitor could offer great efficiency in blocking its kinase-independent regulatory function. Here, we report the first potent ROR1 degraders constructed by connecting the E3 ligand to a ROR1 binder. One representative compound <strong>11d</strong> exhibited remarkable efficacy in depleting ROR1 protein with a DC<sub>50</sub> value of 40.88 nM and D<sub>max</sub> of 93.7%. Mechanistic investigations illuminated that compound <strong>11d</strong> triggers ROR1 protein degradation in a ubiquitin proteasome system (UPS)-dependent manner. Additionally, compound <strong>11d</strong> displayed a significantly enhanced ability to inhibit ROR1 signaling, induce apoptosis, and suppress proliferation in lung cell lines compared to the warhead ROR1 binder. These findings underscore the substantial potential of ROR1 degrader for the treatment of non-small cell lung cancer (NSCLC) cells.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"6 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-25DOI: 10.1016/j.ejmech.2025.117317
Rexing Yi, Yutong Shi, Xun Cao, Chengqian Pan
Actinomycetes are an important source of secondary metabolites such as antibiotics and other active natural products. Many well-known antibiotics, such as streptomycin, oxytetracycline, and tetracycline, are produced by actinomycetes. Different types of antibiotics have distinct mechanisms of action against microorganisms: inhibit protein synthesis, inhibit nucleic acid synthesis, or inhibit cell wall synthesis. For decades, actinomycetes have played a crucial role in clinical treatment for major diseases such as pathogenic bacterial infections, serving as one of the most significant sources of new discoveries. However, due to extensive use of antibiotics, the types and numbers of drug-resistant bacteria, represented by multidrug resistant (MDR) and extensively drug resistant (XDR) bacteria, have increased dramatically in clinical settings, posing a significant threat to human survival. Therefore, there is an urgent need to search for structurally novel antibacterial natural products and develop new antibiotics. In this review, a total of 170 antibacterial secondary metabolites from actinomycetes, published in the 54 literatures (2020 to September 2024) and some synthetic analogues, are discussed with emphasis on their structures and biological activities.
{"title":"Actinomycetes: Treasure Trove for Discovering Novel Antibiotic Candidates","authors":"Rexing Yi, Yutong Shi, Xun Cao, Chengqian Pan","doi":"10.1016/j.ejmech.2025.117317","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117317","url":null,"abstract":"Actinomycetes are an important source of secondary metabolites such as antibiotics and other active natural products. Many well-known antibiotics, such as streptomycin, oxytetracycline, and tetracycline, are produced by actinomycetes. Different types of antibiotics have distinct mechanisms of action against microorganisms: inhibit protein synthesis, inhibit nucleic acid synthesis, or inhibit cell wall synthesis. For decades, actinomycetes have played a crucial role in clinical treatment for major diseases such as pathogenic bacterial infections, serving as one of the most significant sources of new discoveries. However, due to extensive use of antibiotics, the types and numbers of drug-resistant bacteria, represented by multidrug resistant (MDR) and extensively drug resistant (XDR) bacteria, have increased dramatically in clinical settings, posing a significant threat to human survival. Therefore, there is an urgent need to search for structurally novel antibacterial natural products and develop new antibiotics. In this review, a total of 170 antibacterial secondary metabolites from actinomycetes, published in the 54 literatures (2020 to September 2024) and some synthetic analogues, are discussed with emphasis on their structures and biological activities.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"18 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-25DOI: 10.1016/j.ejmech.2025.117326
Jelena Kesić, Mirjana Popsavin, Goran Benedeković, Vesna Kojić, Anita Bosak, Ana Matošević, Pavol Farkaš, Romana Madelová, Velimir Popsavin, Ivana Kovačević
Herein, the modified synthesis of natural lactone (−)-cleistanolate (1) and its enantiomer (ent-1), along with the synthesis of six new analogues (3, 10, 11, 12, 13, ent-3), is presented. The antiproliferative activity of natural product 1 and its 22 analogues with lactone moiety was evaluated in vitro against eight human tumour cell lines and one normal cell line. SAR analysis revealed structural characteristics important for the activity of these types of compounds. The synthesized analogues are completely inactive toward the normal MRC-5 cell line. Their selectivity indexes (SI) range from 2.98 to 891.64. Furthermore, antimicrobial potential and inhibition of human acetyl- and butyrylcholinesterases of 1 and selected compounds have been evaluated.
{"title":"Synthesis and biological evaluation of natural cleistanolate, its enantiomer and analogues","authors":"Jelena Kesić, Mirjana Popsavin, Goran Benedeković, Vesna Kojić, Anita Bosak, Ana Matošević, Pavol Farkaš, Romana Madelová, Velimir Popsavin, Ivana Kovačević","doi":"10.1016/j.ejmech.2025.117326","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117326","url":null,"abstract":"Herein, the modified synthesis of natural lactone (−)-cleistanolate (<strong>1</strong>) and its enantiomer (<em>ent</em>-<strong>1</strong>), along with the synthesis of six new analogues (<strong>3</strong>, <strong>10</strong>, <strong>11</strong>, <strong>12</strong>, <strong>13</strong>, <em>ent</em>-<strong>3</strong>), is presented. The antiproliferative activity of natural product <strong>1</strong> and its 22 analogues with lactone moiety was evaluated <em>in vitro</em> against eight human tumour cell lines and one normal cell line. SAR analysis revealed structural characteristics important for the activity of these types of compounds. The synthesized analogues are completely inactive toward the normal MRC-5 cell line. Their selectivity indexes (SI) range from 2.98 to 891.64. Furthermore, antimicrobial potential and inhibition of human acetyl- and butyrylcholinesterases of <strong>1</strong> and selected compounds have been evaluated.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"89 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-24DOI: 10.1016/j.ejmech.2025.117308
Younghoon Kim, Eunhye Jeon, Hyunwoo Ahn, Juhee Kang, Taebo Sim
Being a primary driver in oncogenic activations of JAK-STAT signaling pathway, Janus Kinase 1 (JAK1) stands out as a promising target in anti-cancer drug discovery. We employed a scaffold morphing strategy to design and synthesize thieno[3,2-d]pyrimidine derivatives, which led to identification of 24 as a potent and highly selective JAK1 inhibitor. Kinome-wide selectivity profiling reveals that 24 exhibits a high degree of selectivity for JAK1 among the 370 kinases tested. SAR study demonstrates that both 25 and 46, improved derivatives of 24, possess higher selectivity towards JAK1 over JAK2 and JAK3 compared to AZD4205 (9). It is of note that 46 has 4-fold higher enzymatic activity against JAK1 (IC50 = 0.022 μM) relative to 9. Moreover, both 25 and 46 demonstrate over 5-fold enhancement in anti-proliferative activities on NSCLC cells with regard to 9, accompanied by significant inhibition of JAK1 signaling. Compared with 9, derivative 24, 25, and 46 induce more strongly apoptosis, cell cycle arrest, and reduction of colony formation on NSCLC cells. Our findings offer valuable insights into the design of novel selective JAK1 inhibitors.
{"title":"Identification of Thieno[3,2-d]pyrimidine Derivatives as Potent and Selective Janus Kinase 1 Inhibitors","authors":"Younghoon Kim, Eunhye Jeon, Hyunwoo Ahn, Juhee Kang, Taebo Sim","doi":"10.1016/j.ejmech.2025.117308","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117308","url":null,"abstract":"Being a primary driver in oncogenic activations of JAK-STAT signaling pathway, Janus Kinase 1 (JAK1) stands out as a promising target in anti-cancer drug discovery. We employed a scaffold morphing strategy to design and synthesize thieno[3,2-<em>d</em>]pyrimidine derivatives, which led to identification of <strong>24</strong> as a potent and highly selective JAK1 inhibitor. Kinome-wide selectivity profiling reveals that <strong>24</strong> exhibits a high degree of selectivity for JAK1 among the 370 kinases tested. SAR study demonstrates that both <strong>25</strong> and <strong>46</strong>, improved derivatives of <strong>24</strong>, possess higher selectivity towards JAK1 over JAK2 and JAK3 compared to AZD4205 (<strong>9</strong>). It is of note that <strong>46</strong> has 4-fold higher enzymatic activity against JAK1 (IC<sub>50</sub> = 0.022 <em>μ</em>M) relative to <strong>9</strong>. Moreover, both <strong>25</strong> and <strong>46</strong> demonstrate over 5-fold enhancement in anti-proliferative activities on NSCLC cells with regard to <strong>9</strong>, accompanied by significant inhibition of JAK1 signaling. Compared with <strong>9</strong>, derivative <strong>24</strong>, <strong>25</strong>, and <strong>46</strong> induce more strongly apoptosis, cell cycle arrest, and reduction of colony formation on NSCLC cells. Our findings offer valuable insights into the design of novel selective JAK1 inhibitors.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"38 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026986","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}
There is an urgent need for effective treatments targeting comorbidities of type 2 diabetes (T2DM) and obesity. Developing dual agonists of glucagon-like peptide 1 receptor (GLP-1R) and neuropeptide Y receptor type 2 (NPY2R) with combined PYY3-36 and GLP-1 bioactivity is promising. However, designing such dual agonists that effectively control glycemia and reduce weight while minimizing gastrointestinal side effects is challenging. In this study, we systematically evaluated the side effects induced by co-administering various GLP-1R agonists and PYY3-36 analogue. Our findings revealed that different GLP-1R agonist-PYY analogue combinations elicited gastrointestinal side effects of varying intensities. Among these, the co-administration of bullfrog GLP-1 analogue (bGLP-1) with PYY3-36 analogue resulted in lower gastrointestinal side effects. Thus, bGLP-1 was selected as the preferred candidate for designing dual GLP-1R/NPY2R agonists. Through stepwise structural design, optimization of linker arms, and durability enhancements, coupled with in vitro receptor screening, the novel peptide bGLP/PYY-19 emerged as the lead candidate. Notably, experimental results in mice and rats showed a significant reduction in emesis with bGLP/PYY-19 compared to semaglutide and bGLP-1 long-acting analogue (LAbGLP-1). Furthermore, bGLP/PYY-19 significantly outperformed semaglutide and LAbGLP-1 in reducing body weight in diet-induced obese (DIO) mice, without inducing nausea-associated behavior. These findings underscore the potential of dual-targeting single peptide conjugates as a promising strategy for developing glucoregulatory treatments that offer superior weight loss benefits and are better tolerated compared to treatments targeting GLP-1R alone.
{"title":"Rational design of dual-agonist peptides targeting GLP-1 and NPY2 receptors for regulating glucose homeostasis and body weight with minimal nausea and emesis","authors":"Jing Liu, Weiwen Lu, Han Wu, Zhiming Yan, Yun Liu, Chunli Tang, Yangxin Chen, Shuang Wang, Weizhong Tang, Jing Han, Changhong Wei, Neng Jiang","doi":"10.1016/j.ejmech.2025.117320","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117320","url":null,"abstract":"There is an urgent need for effective treatments targeting comorbidities of type 2 diabetes (T2DM) and obesity. Developing dual agonists of glucagon-like peptide 1 receptor (GLP-1R) and neuropeptide Y receptor type 2 (NPY2R) with combined PYY<sub>3-36</sub> and GLP-1 bioactivity is promising. However, designing such dual agonists that effectively control glycemia and reduce weight while minimizing gastrointestinal side effects is challenging. In this study, we systematically evaluated the side effects induced by co-administering various GLP-1R agonists and PYY<sub>3-36</sub> analogue. Our findings revealed that different GLP-1R agonist-PYY analogue combinations elicited gastrointestinal side effects of varying intensities. Among these, the co-administration of bullfrog GLP-1 analogue (bGLP-1) with PYY<sub>3-36</sub> analogue resulted in lower gastrointestinal side effects. Thus, bGLP-1 was selected as the preferred candidate for designing dual GLP-1R/NPY2R agonists. Through stepwise structural design, optimization of linker arms, and durability enhancements, coupled with <em>in vitro</em> receptor screening, the novel peptide bGLP/PYY-19 emerged as the lead candidate. Notably, experimental results in mice and rats showed a significant reduction in emesis with bGLP/PYY-19 compared to semaglutide and bGLP-1 long-acting analogue (LAbGLP-1). Furthermore, bGLP/PYY-19 significantly outperformed semaglutide and LAbGLP-1 in reducing body weight in diet-induced obese (DIO) mice, without inducing nausea-associated behavior. These findings underscore the potential of dual-targeting single peptide conjugates as a promising strategy for developing glucoregulatory treatments that offer superior weight loss benefits and are better tolerated compared to treatments targeting GLP-1R alone.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"74 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026952","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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