Pub Date : 2025-01-30DOI: 10.1016/j.ejmech.2025.117330
Sheldon Sookai, Matthew Akerman, Mia Færch, Yasien Sayed, Orde Q. Munro
Topoisomerase IIα (Top II) is a critical enzyme that resolves DNA topology during transcription and replication. Inhibitors of Top II are used as anticancer agents and are classified as interfacial poisons (IFPs) or catalytic inhibitors (CICs). Here, we report a novel class of cytotoxic, stable cationic gold(III) Schiff base chelates (AuL1, AuL2, and AuL3) with DNA-intercalating properties. In the NCI-60 screen, AuL1 and AuL3 exhibited potent cytotoxicity (mean GI50 values of 11 (7) μM and 14 (9) μM, respectively), whereas AuL2 showed minimal cytotoxicity. Cluster analysis aligned AuL1 and AuL3 with the Top II poison etoposide. Mechanistic studies revealed that AuL1 acts as an IFP at concentrations between 0.5–50 μM and as a CIC at concentrations between 50–500 μM. Further investigations demonstrated that all three gold(III) chelates bind to and intercalate DNA, the main substrate for Top II. Finally, binding studies with human serum albumin (HSA) indicated that the chelates have moderate affinity for the protein. Thermodynamic analysis indicates entropically driven binding, with minimal structural disruption observed via UV-CD spectroscopy. These findings highlight the dual mode Top II inhibition mechanism delineated for the gold(III) chelates and their favourable pharmacodynamic interactions with HSA, underscoring their potential as promising anticancer agents.
{"title":"Cytotoxic pyrrole-based gold(III) chelates target human topoisomerase II as dual-mode inhibitors and interact with human serum albumin","authors":"Sheldon Sookai, Matthew Akerman, Mia Færch, Yasien Sayed, Orde Q. Munro","doi":"10.1016/j.ejmech.2025.117330","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117330","url":null,"abstract":"Topoisomerase IIα (Top II) is a critical enzyme that resolves DNA topology during transcription and replication. Inhibitors of Top II are used as anticancer agents and are classified as interfacial poisons (IFPs) or catalytic inhibitors (CICs). Here, we report a novel class of cytotoxic, stable cationic gold(III) Schiff base chelates (<strong>AuL1</strong>, <strong>AuL2</strong>, and <strong>AuL3</strong>) with DNA-intercalating properties. In the NCI-60 screen, <strong>AuL1</strong> and <strong>AuL3</strong> exhibited potent cytotoxicity (mean GI<sub>50</sub> values of 11 (7) μM and 14 (9) μM, respectively), whereas <strong>AuL2</strong> showed minimal cytotoxicity. Cluster analysis aligned <strong>AuL1</strong> and <strong>AuL3</strong> with the Top II poison etoposide. Mechanistic studies revealed that <strong>AuL1</strong> acts as an IFP at concentrations between 0.5–50 μM and as a CIC at concentrations between 50–500 μM. Further investigations demonstrated that all three gold(III) chelates bind to and intercalate DNA, the main substrate for Top II. Finally, binding studies with human serum albumin (HSA) indicated that the chelates have moderate affinity for the protein. Thermodynamic analysis indicates entropically driven binding, with minimal structural disruption observed via UV-CD spectroscopy. These findings highlight the dual mode Top II inhibition mechanism delineated for the gold(III) chelates and their favourable pharmacodynamic interactions with HSA, underscoring their potential as promising anticancer agents.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"46 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056453","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 : 2025-01-30DOI: 10.1016/j.ejmech.2025.117331
Dina H. Dawood, Manal M. Anwar
Suppression of the acetylcholinesterase (AChE) enzyme is a prevalent strategy for curing diverse mental disorders, including Alzheimer’s disease (AD) and the chronic autoimmune disease Myasthenia gravis. Acetylcholinesterase inhibitors promote cholinergic transmission via blocking AChE, which is implicated in the degradation and deficiency of acetylcholine. Various studies proved that the lack of cholinergic neurons in the central nervous system is the substantial reason for the behavioral abnormalities and cognitive retogradation that distinguish mental diseases such as dementia and AD. Moreover, thiazole scaffolds have emerged as prominent pharmacophores in drug discovery owing to their numerous outstanding therapeutic efficacy, comprising anti-acetylcholinesterase efficacy. This review presents various thiazole-based AChE inhibitors in the recent decade. In addition, the various interactions of thiazole derivatives within the active pocket of AChE have been highlighted.
{"title":"Recent Advances in The Therapeutic Insights of Thiazole Scaffolds as Acetylcholinesterase Inhibitors","authors":"Dina H. Dawood, Manal M. Anwar","doi":"10.1016/j.ejmech.2025.117331","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117331","url":null,"abstract":"Suppression of the acetylcholinesterase (AChE) enzyme is a prevalent strategy for curing diverse mental disorders, including Alzheimer’s disease (AD) and the chronic autoimmune disease Myasthenia gravis. Acetylcholinesterase inhibitors promote cholinergic transmission via blocking AChE, which is implicated in the degradation and deficiency of acetylcholine. Various studies proved that the lack of cholinergic neurons in the central nervous system is the substantial reason for the behavioral abnormalities and cognitive retogradation that distinguish mental diseases such as dementia and AD. Moreover, thiazole scaffolds have emerged as prominent pharmacophores in drug discovery owing to their numerous outstanding therapeutic efficacy, comprising anti-acetylcholinesterase efficacy. This review presents various thiazole-based AChE inhibitors in the recent decade. In addition, the various interactions of thiazole derivatives within the active pocket of AChE have been highlighted.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"60 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056452","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 : 2025-01-30DOI: 10.1016/j.ejmech.2025.117340
Nesma M. Kahk, Fatma E.A. Mohamed, Marwa M. Abdelhakeem, Rania B. Bakr
A novel series of pyrazol-4-yl-1,2,4-triazole-3-thiol derivatives 14a-l was designed, prepared and characterized by many spectroscopic techniques. All the novel compounds were screened for their anti-proliferative activity towards breast cancer cell line (MCF-7), colon cancer cell line (HT-29) and lung cancer cell line (A-549) utilizing celecoxib, erlotinib and osimertinib as standards. Compounds 14b, 14g and 14k were the most active towards HT-29, MCF-7 and A-549 cell lines, sequentially with IC50 = 1.20-2.93 μM compared with celecoxib (IC50 = 16.47-41.45 μM), erlotinib (IC50 = 1.95-33.57 μM) and osimertinib (IC50 = 0.75-3.45 μM). These most active derivatives 14b, 14g and 14k were further investigated for their inhibitory potential against COX and EGFR enzymes. These compounds 14b, 14g and 14k suppressed COX-2 (IC50 = 0.560-4.692 μM), EGFRWT (IC50 = 0.121-0.423 μM) and EGFRT790M (IC50 = 0.076-0.764 μM) enzymes. Compounds 14b, 14g and 14k displayed apoptosis induction by up-regulating Bax and down-regulating Bcl-2 protein levels. Cell cycle analysis recorded that exposure of MFC-7 cells to compound 14g resulted in a significant increase in the percentage of cells at the G2/M to 39.15% compared to the standard erlotinib (9.87%). Docking study of the most potent candidates 14b, 14g and 14k within COX-2, EGFRWT and EGFRT790M active regions was conducted to suggest the binding mode of these compounds inside these target enzymes.
{"title":"Optimization of pyrazole/1,2,4-triazole as dual EGFR/COX-2 inhibitors: Design, synthesis, anticancer potential, apoptosis induction and cell cycle analysis","authors":"Nesma M. Kahk, Fatma E.A. Mohamed, Marwa M. Abdelhakeem, Rania B. Bakr","doi":"10.1016/j.ejmech.2025.117340","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117340","url":null,"abstract":"A novel series of pyrazol-4-yl-1,2,4-triazole-3-thiol derivatives <strong>14a-l</strong> was designed, prepared and characterized by many spectroscopic techniques. All the novel compounds were screened for their anti-proliferative activity towards breast cancer cell line (MCF-7), colon cancer cell line (HT-29) and lung cancer cell line (A-549) utilizing celecoxib, erlotinib and osimertinib as standards. Compounds <strong>14b</strong>, <strong>14g</strong> and <strong>14k</strong> were the most active towards HT-29, MCF-7 and A-549 cell lines, sequentially with IC<sub>50</sub> = 1.20-2.93 μM compared with celecoxib (IC<sub>50</sub> = 16.47-41.45 μM), erlotinib (IC<sub>50</sub> = 1.95-33.57 μM) and osimertinib (IC<sub>50</sub> = 0.75-3.45 μM). These most active derivatives <strong>14b</strong>, <strong>14g</strong> and <strong>14k</strong> were further investigated for their inhibitory potential against COX and EGFR enzymes. These compounds <strong>14b</strong>, <strong>14g</strong> and <strong>14k</strong> suppressed COX-2 (IC<sub>50</sub> = 0.560-4.692 μM), EGFR<sup>WT</sup> (IC<sub>50</sub> = 0.121-0.423 μM) and EGFR<sup>T790M</sup> (IC<sub>50</sub> = 0.076-0.764 μM) enzymes. Compounds <strong>14b</strong>, <strong>14g</strong> and <strong>14k</strong> displayed apoptosis induction by up-regulating Bax and down-regulating Bcl-2 protein levels. Cell cycle analysis recorded that exposure of MFC-7 cells to compound <strong>14g</strong> resulted in a significant increase in the percentage of cells at the G2/M to 39.15% compared to the standard erlotinib (9.87%). Docking study of the most potent candidates <strong>14b</strong>, <strong>14g</strong> and <strong>14k</strong> within COX-2, EGFR<sup>WT</sup> and EGFR<sup>T790M</sup> active regions was conducted to suggest the binding mode of these compounds inside these target enzymes.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"26 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056456","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 : 2025-01-30DOI: 10.1016/j.ejmech.2025.117338
Zhi-Chen Mao, Lei Chen, Xiao-Man Chen, Xiao-Yun Lu, Zu-Yu Mo, Yi Gou, Jian-Hua Wei, Ri-Zhen Huang, Ye Zhang
A set of diarylidenyl piperidone-ligated platinum (IV) complexes 8a‒8d with chemoimmunotherapy effects was designed and synthesized based on introduction of classic STAT3 inhibitors, diarylidenyl piperidones, into an oxaliplatin (OXA)-based skeleton. 3-(4,5)-Dimethylthiahiazo (-z-y1)-3, 5-di- phenytetrazoliumromide (MTT) assay indicated that complexes 8a‒8d exhibited obvious inhibition on T24, MDA-MB-231 and SW480 cell lines compared to OXA, with IC50 values in range of 4.96±0.14–21.1±0.35 μM. SW480 xenograft nude mice assay demonstrated that complexes 8a (2 mg/kg and 4 mg/kg), 8b (4 mg/kg) and 8c (4 mg/kg) exhibited effective inhibition on this model with tumor inhibitory rates (TIR) of 46.06%, 51.18%, 48.82% and 42.16%, respectively, compared with OXA (2 mg/kg, TIR = 31.89%/34.31%) during 21-days treatment, while CT-26 xenograft BALB/C mice assay showed that complexes 8a (10 mg/kg), 8b (5 and 10 mg/kg), 8c (5 and 10 mg/kg), and 8d (5 and 10 mg/kg) exhibited effective inhibition of with TIR values of 56.95%, 56.28%, 78.02%, 47.28 %, 63.80%, 51.90% and 70.65%, respectively, compared with OXA (5 mg/kg, TIR = 69.28% / 67.53%) during 13-days treatment. The pathology results in SW480 and CT-26 xenograft showed that complexes 8a–8d displayed limited toxicity in comparison with OXA. All these results indicated that complexes 8a–8c may be good chemoimmunotherapeutic agents with potent efficacy and safety profiles. Further mechanistic studies revealed that the representative complex 8b might exert its chemoimmunotherapeutic effect by inhibiting the expression and phosphorylation of STAT3, thus evoking CD4+ and CD8+ T lymphocyte immune responses and inducing ferroptosis and apoptosis.
{"title":"Design, Synthesis and Evaluation of Diarylidenyl Piperidone-Ligated Platinum (IV) Complexes as Chemoimmunotherapeutic Agents","authors":"Zhi-Chen Mao, Lei Chen, Xiao-Man Chen, Xiao-Yun Lu, Zu-Yu Mo, Yi Gou, Jian-Hua Wei, Ri-Zhen Huang, Ye Zhang","doi":"10.1016/j.ejmech.2025.117338","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117338","url":null,"abstract":"A set of diarylidenyl piperidone-ligated platinum (IV) complexes <strong>8a</strong>‒<strong>8d</strong> with chemoimmunotherapy effects was designed and synthesized based on introduction of classic STAT3 inhibitors, diarylidenyl piperidones, into an oxaliplatin (OXA)-based skeleton. 3-(4,5)-Dimethylthiahiazo (-z-y1)-3, 5-di- phenytetrazoliumromide (MTT) assay indicated that complexes <strong>8a</strong>‒<strong>8d</strong> exhibited obvious inhibition on T24, MDA-MB-231 and SW480 cell lines compared to OXA, with IC<sub>50</sub> values in range of 4.96±0.14–21.1±0.35 μM. SW480 xenograft nude mice assay demonstrated that complexes <strong>8a</strong> (2 mg/kg and 4 mg/kg), <strong>8b</strong> (4 mg/kg) and <strong>8c</strong> (4 mg/kg) exhibited effective inhibition on this model with tumor inhibitory rates (TIR) of 46.06%, 51.18%, 48.82% and 42.16%, respectively, compared with OXA (2 mg/kg, TIR = 31.89%/34.31%) during 21-days treatment, while CT-26 xenograft BALB/C mice assay showed that complexes <strong>8a</strong> (10 mg/kg), <strong>8b</strong> (5 and 10 mg/kg), <strong>8c</strong> (5 and 10 mg/kg), and <strong>8d</strong> (5 and 10 mg/kg) exhibited effective inhibition of with TIR values of 56.95%, 56.28%, 78.02%, 47.28 %, 63.80%, 51.90% and 70.65%, respectively, compared with OXA (5 mg/kg, TIR = 69.28% / 67.53%) during 13-days treatment. The pathology results in SW480 and CT-26 xenograft showed that complexes <strong>8a–8d</strong> displayed limited toxicity in comparison with OXA. All these results indicated that complexes <strong>8a–8c</strong> may be good chemoimmunotherapeutic agents with potent efficacy and safety profiles. Further mechanistic studies revealed that the representative complex <strong>8b</strong> might exert its chemoimmunotherapeutic effect by inhibiting the expression and phosphorylation of STAT3, thus evoking CD4<sup>+</sup> and CD8<sup>+</sup> T lymphocyte immune responses and inducing ferroptosis and apoptosis.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"27 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056455","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}
Carbohydrates are shown to be crucial to several biological processes. They are essential mediators of cell-cell recognition processes. Among them, Sialyl Lewis X (sLex) is a very significant structure in the human body. It is a critical tetrasaccharide that plays a pivotal role in various biological processes, including cell adhesion, immune response, and cancer metastasis. Known as the blood group antigen, sLex is also referred to as cluster of differentiation 15s (CD15s) or stage-specific embryonic antigen 1 (SSEA-1). sLex is not only a prominent blood group antigen, but also involved in the attraction of sperm to the egg during fertilization, prominently displayed at the terminus of glycolipids on the cell surface. By describing the synthetic methods and biological functions of sLex, this review underscores the importance of sLex in both fundamental and applied sciences and its potential to impact clinical practice.
{"title":"Sialyl Lewis X (sLex):Biological Functions, Synthetic Methods and Therapeutic Implications","authors":"Leyu Tang, Jiaxu Zhang, Nassima Oumata, Nathalie Mignet, Matthieu Sollogoub, Yongmin Zhang","doi":"10.1016/j.ejmech.2025.117315","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117315","url":null,"abstract":"Carbohydrates are shown to be crucial to several biological processes. They are essential mediators of cell-cell recognition processes. Among them, Sialyl Lewis X (sLe<sup>x</sup>) is a very significant structure in the human body. It is a critical tetrasaccharide that plays a pivotal role in various biological processes, including cell adhesion, immune response, and cancer metastasis. Known as the blood group antigen, sLe<sup>x</sup> is also referred to as cluster of differentiation 15s (CD15s) or stage-specific embryonic antigen 1 (SSEA-1). sLe<sup>x</sup> is not only a prominent blood group antigen, but also involved in the attraction of sperm to the egg during fertilization, prominently displayed at the terminus of glycolipids on the cell surface. By describing the synthetic methods and biological functions of sLe<sup>x</sup>, this review underscores the importance of sLe<sup>x</sup> in both fundamental and applied sciences and its potential to impact clinical practice.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"39 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056683","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 : 2025-01-30DOI: 10.1016/j.ejmech.2025.117285
Salvatore Di Maria, Raffaele Passannanti, Federica Poggialini, Chiara Vagaggini, Alessia Serafinelli, Elena Bianchi, Paolo Governa, Lorenzo Botta, Giovanni Maga, Emmanuele Crespan, Fabrizio Manetti, Elena Dreassi, Francesca Musumeci, Anna Carbone, Silvia Schenone
Table 1 showed several errors originated from the formatting issue. In addition, we noted a mistake in the structure of compound 7c reported in Fig. 3. The pyrazole nitrogen is substituted by a methyl group instead of 2-chloro-2-phenylethyl chain. We have now corrected the structure. These corrections do not alter the conclusions or the overall findings of the work. The authors would like to apologise for any inconvenience caused. The corrected version of Fig. 3 and Table 1 is shown below.
Table 1. Enzymatic activity of aminothiazoles 7a-h and imidazoles 8a,b towards Src.
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Fig. 3 Optimization study affording 7d-h.
{"title":"Corrigendum to “Applying molecular hybridization to design a new class of pyrazolo[3,4-d] pyrimidines as Src inhibitors active in hepatocellular carcinoma” [Eur. J. Med. Chem. 280 (2024) 116929]","authors":"Salvatore Di Maria, Raffaele Passannanti, Federica Poggialini, Chiara Vagaggini, Alessia Serafinelli, Elena Bianchi, Paolo Governa, Lorenzo Botta, Giovanni Maga, Emmanuele Crespan, Fabrizio Manetti, Elena Dreassi, Francesca Musumeci, Anna Carbone, Silvia Schenone","doi":"10.1016/j.ejmech.2025.117285","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117285","url":null,"abstract":"<strong>Table 1</strong> showed several errors originated from the formatting issue. In addition, we noted a mistake in the structure of compound <strong>7c</strong> reported in <strong>Fig. 3</strong>. The pyrazole nitrogen is substituted by a methyl group instead of 2-chloro-2-phenylethyl chain. We have now corrected the structure. These corrections do not alter the conclusions or the overall findings of the work. The authors would like to apologise for any inconvenience caused. The corrected version of <strong>Fig. 3</strong> and <strong>Table 1</strong> is shown below.<span><span><span><p><span>Table 1</span>. Enzymatic activity of aminothiazoles 7a-h and imidazoles 8a,b towards Src.</p></span></span><img alt=\"\" height=\"956\" src=\"https://ars.els-cdn.com/content/image/1-s2.0-S0223523425000509-fx1.jpg\"/></span><span><figure><span><img alt=\"\" aria-describedby=\"cap0015\" height=\"357\" src=\"https://ars.els-cdn.com/content/image/1-s2.0-S0223523425000509-fx2.jpg\"/><ol><li><span><span>Download: <span>Download high-res image (289KB)</span></span></span></li><li><span><span>Download: <span>Download full-size image</span></span></span></li></ol></span><span><span><p>Fig. 3 Optimization study affording <strong>7d-h</strong>.</p></span></span></figure></span>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"129 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056454","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 : 2025-01-28DOI: 10.1016/j.ejmech.2025.117333
Zhi-Ying Miao, Jing Lin, Wei-Min Chen
The widespread emergence of multidrug-resistant (MDR) Gram-negative pathogens has posed a major challenge to clinical anti-infective therapy, and new effective treatments are urgently needed. A promising "Trojan horse" strategy involves conjugating antibiotics to siderophore molecules; the resulting siderophore-antibiotic conjugates (SACs) deliver antibiotics directly into cells by hijacking the sophisticated iron transport systems of Gram-negative bacteria, bypassing the outer membrane permeability barrier to enhance uptake and antibacterial efficacy. The clinical release of the first siderophore-antibiotic conjugate, cefiderocol, has aroused tremendous interest in the field among researchers and pharmaceutical companies. To date, most of the reported SACs have focused on the conjugation of siderophores to traditional antibacterial drugs. However, these antibacterial agents designed on the basis of the traditional antibiotic skeleton theoretically bear the risk of cross-resistance caused by shared molecular scaffolds. In this case, exploring novel natural product antibacterial conjugate scaffolds to circumvent the risk of early cross-resistance represents a presumably more sustainable approach for the development of SACs. In this review, we systematically summarize the research progress on siderophore-natural product conjugates as novel antimicrobial agents reported since 2010. Additionally, we propose challenges to be overcome and prospects for future development in this field.
{"title":"Natural sideromycins and siderophore-conjugated natural products as inspiration for novel antimicrobial agents","authors":"Zhi-Ying Miao, Jing Lin, Wei-Min Chen","doi":"10.1016/j.ejmech.2025.117333","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117333","url":null,"abstract":"The widespread emergence of multidrug-resistant (MDR) Gram-negative pathogens has posed a major challenge to clinical anti-infective therapy, and new effective treatments are urgently needed. A promising \"Trojan horse\" strategy involves conjugating antibiotics to siderophore molecules; the resulting siderophore-antibiotic conjugates (SACs) deliver antibiotics directly into cells by hijacking the sophisticated iron transport systems of Gram-negative bacteria, bypassing the outer membrane permeability barrier to enhance uptake and antibacterial efficacy. The clinical release of the first siderophore-antibiotic conjugate, cefiderocol, has aroused tremendous interest in the field among researchers and pharmaceutical companies. To date, most of the reported SACs have focused on the conjugation of siderophores to traditional antibacterial drugs. However, these antibacterial agents designed on the basis of the traditional antibiotic skeleton theoretically bear the risk of cross-resistance caused by shared molecular scaffolds. In this case, exploring novel natural product antibacterial conjugate scaffolds to circumvent the risk of early cross-resistance represents a presumably more sustainable approach for the development of SACs. In this review, we systematically summarize the research progress on siderophore-natural product conjugates as novel antimicrobial agents reported since 2010. Additionally, we propose challenges to be overcome and prospects for future development in this field.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055268","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 : 2025-01-28DOI: 10.1016/j.ejmech.2025.117324
Pengwei Liu, Zhengyang Chen, Yiting Guo, Qiaojun He, Chenghao Pan
Proteins play a pivotal role in maintaining cellular homeostasis. Their degradation primarily orchestrated through the ubiquitin-proteasome system (UPS) and cellular autophagy. Dysfunction of the UPS is associated with various human diseases, including cancer, autoimmune disorders, and neurodegenerative conditions. Consequently, the UPS has emerged as a promising therapeutic target. Deubiquitinases (DUBs) have garnered significant attention as potential targets for therapeutic intervention due to their role in modulating protein stability and function. This review focuses on recent advancements of DUBs, particularly their relevance in the UPS and their potential as drug targets. Notably, inhibitors targeting specific DUBs, such as USP1, USP7, USP14, and USP30 have shown promise in preclinical and clinical studies for cancer therapy. Additionally, DUB inhibitors have been involved in novel therapeutic approaches lately, including as targets for proteolysis-targeting chimeras (PROTACs) or as tools in deubiquitinase-targeting chimeras (DUBTACs).
{"title":"Recent Advances in Small Molecule Inhibitors of Deubiquitinating Enzymes","authors":"Pengwei Liu, Zhengyang Chen, Yiting Guo, Qiaojun He, Chenghao Pan","doi":"10.1016/j.ejmech.2025.117324","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117324","url":null,"abstract":"Proteins play a pivotal role in maintaining cellular homeostasis. Their degradation primarily orchestrated through the ubiquitin-proteasome system (UPS) and cellular autophagy. Dysfunction of the UPS is associated with various human diseases, including cancer, autoimmune disorders, and neurodegenerative conditions. Consequently, the UPS has emerged as a promising therapeutic target. Deubiquitinases (DUBs) have garnered significant attention as potential targets for therapeutic intervention due to their role in modulating protein stability and function. This review focuses on recent advancements of DUBs, particularly their relevance in the UPS and their potential as drug targets. Notably, inhibitors targeting specific DUBs, such as USP1, USP7, USP14, and USP30 have shown promise in preclinical and clinical studies for cancer therapy. Additionally, DUB inhibitors have been involved in novel therapeutic approaches lately, including as targets for proteolysis-targeting chimeras (PROTACs) or as tools in deubiquitinase-targeting chimeras (DUBTACs).","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"40 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143050128","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}
Artemisinin and its derivatives (ARTs) are being studied for their potential anti-tumor activity. Dimerization of artemisinin has been proposed as a promising means of enhancing drug efficacy. However, the sequential progression from monomers to dimers and trimers, retaining a consistent β-configuration, has not been previously investigated in terms of its effect on compound activity. To investigate the effect of various oligomeric forms on drug potency, we synthesized β-configuration-based ARTs, namely a monomer, dimer, and trimer, and rigorously characterized their structure. We evaluated the antitumor efficacy of these compounds against MCF-7 breast cancer cells. The artemisinin trimer 6a, (β, β, β) exerted a stronger cytotoxic effects against MCF-7 breast cancer cells, with an IC50 value of 0.09 ± 0.03 μM, than did the monomer (β) or dimer (β, β), which had IC50 values of >50 and 3.14 ± 0.54 μM, respectively. This specific configuration induced alterations in nuclear morphology, inhibited colony formation, and facilitated cancer cell death. Mechanistic studies revealed that 6a (β, β, β) promoted apoptosis by modulating the Bax-caspase 3 signaling pathway and induced ferroptosis by regulating key signaling molecules, including GPX4. This study introduces an innovative methodology—a stepwise synthesis strategy progressing from monomers to dimers and trimers—to explore the relationship between oligomeric structure and drug activity. These findings provide novel insight into the architecture–activity relationship of ART derivatives, offering a foundation for advancing drug design and improving clinical applications.
{"title":"Anti-tumor Effects of Artemisinin-Based Oligomers: From Monomer to Trimer as a Novel Drug-Enhancing Strategy","authors":"Bingying Jiang, Jiaoying Wang, Lin Yue, Zejin Zhang, Jiagang Lv, Jianping Chen, Jianguo Cao, Fujiang Guo, Qingjie Zhao","doi":"10.1016/j.ejmech.2025.117313","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117313","url":null,"abstract":"Artemisinin and its derivatives (ARTs) are being studied for their potential anti-tumor activity. Dimerization of artemisinin has been proposed as a promising means of enhancing drug efficacy. However, the sequential progression from monomers to dimers and trimers, retaining a consistent <em>β</em>-configuration, has not been previously investigated in terms of its effect on compound activity. To investigate the effect of various oligomeric forms on drug potency, we synthesized <em>β</em>-configuration-based ARTs, namely a monomer, dimer, and trimer, and rigorously characterized their structure. We evaluated the antitumor efficacy of these compounds against MCF-7 breast cancer cells. The artemisinin trimer <strong>6a</strong>, (<em>β, β, β</em>) exerted a stronger cytotoxic effects against MCF-7 breast cancer cells, with an IC<sub>50</sub> value of 0.09 ± 0.03 μM, than did the monomer (<em>β</em>) or dimer (<em>β, β</em>), which had IC<sub>50</sub> values of >50 and 3.14 ± 0.54 μM, respectively. This specific configuration induced alterations in nuclear morphology, inhibited colony formation, and facilitated cancer cell death. Mechanistic studies revealed that 6a (<em>β, β, β</em>) promoted apoptosis by modulating the Bax-caspase 3 signaling pathway and induced ferroptosis by regulating key signaling molecules, including GPX4. This study introduces an innovative methodology—a stepwise synthesis strategy progressing from monomers to dimers and trimers—to explore the relationship between oligomeric structure and drug activity. These findings provide novel insight into the architecture–activity relationship of ART derivatives, offering a foundation for advancing drug design and improving clinical applications.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"40 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044386","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 : 2025-01-27DOI: 10.1016/j.ejmech.2025.117334
Tenzin Adon, Sanyukta Bhattacharya, SubbaRao V. Madhunapantula, Honnavalli Yogish Kumar
Akt, also known as protein kinase-B, is an important therapeutic target in the treatment of cancer due to its pivotal roles in the signaling pathways that regulate various hall-mark features of cancer cells such as cell growth, survival, migration, differentiation, and metabolism. The three closely related isoforms of Akt viz., Akt1, Akt2, and Akt3 exhibit distinct physiological roles that affect cellular behavior and tumor development, making isoform selectivity a crucial driving factor in the design and development of inhibitors. This review outlines key amino acids and their structural traits in Akt isoforms, potentially dictating isoform selectivity. We present an analysis of existing structure-activity relationship data of covalent-allosteric Akt inhibitors to shed light on isoform selectivity. Additionally, a brief review of potential predictive biomarkers in enhancing the therapeutic efficacy of Akt inhibitors is presented. Identifying biomarkers that can reliably predict patient response to treatment is crucial for personalizing cancer therapies and improving overall treatment outcomes. By integrating predictive biomarker identification with the ongoing development of isoform-selective Akt inhibitors, it is plausible to establish a foundation for more precise and efficacious interventions in cancer therapy.
{"title":"Structural Requirements of Isoform-Specific Inhibitors of Akt: Implications in the Development of Effective Cancer Treatment Strategies","authors":"Tenzin Adon, Sanyukta Bhattacharya, SubbaRao V. Madhunapantula, Honnavalli Yogish Kumar","doi":"10.1016/j.ejmech.2025.117334","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117334","url":null,"abstract":"Akt, also known as protein kinase-B, is an important therapeutic target in the treatment of cancer due to its pivotal roles in the signaling pathways that regulate various hall-mark features of cancer cells such as cell growth, survival, migration, differentiation, and metabolism. The three closely related isoforms of Akt viz., Akt1, Akt2, and Akt3 exhibit distinct physiological roles that affect cellular behavior and tumor development, making isoform selectivity a crucial driving factor in the design and development of inhibitors. This review outlines key amino acids and their structural traits in Akt isoforms, potentially dictating isoform selectivity. We present an analysis of existing structure-activity relationship data of covalent-allosteric Akt inhibitors to shed light on isoform selectivity. Additionally, a brief review of potential predictive biomarkers in enhancing the therapeutic efficacy of Akt inhibitors is presented. Identifying biomarkers that can reliably predict patient response to treatment is crucial for personalizing cancer therapies and improving overall treatment outcomes. By integrating predictive biomarker identification with the ongoing development of isoform-selective Akt inhibitors, it is plausible to establish a foundation for more precise and efficacious interventions in cancer therapy.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"36 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143050129","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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