Pub Date : 2024-10-23DOI: 10.1016/j.ejmech.2024.116995
Antibody-drug conjugates (ADCs) enable the precise delivery of cytotoxic agents by conjugating small-molecule drugs with monoclonal antibodies (mAbs). Over recent decades, ADCs have demonstrated substantial clinical efficacy. However, conventional ADCs often encounter various clinical challenges, including suboptimal efficacy, significant adverse effects, and the development of drug resistance, limiting their broader clinical application. Encouragingly, a next-generation approach—dual-payload ADCs—has emerged as a pioneering strategy to address these challenges. Dual-payload ADCs are characterized by the incorporation of two distinct therapeutic payloads on the same antibody, enhancing treatment efficacy by promoting synergistic effects and reducing the risk of drug resistance. However, the synthesis of dual-payload ADCs is complex due to the presence of multiple functional groups on antibodies. In this review, we comprehensively summarize the construction strategies for dual-payload ADCs, ranging from the design of ADC components to orthogonal chemistry. The subsequent sections explore current challenges and propose prospective strategies, highlighting recent advancements in dual-payload ADC research, thereby laying the foundation for the development of next-generation ADCs.
{"title":"Dual-payload antibody–drug conjugates: Taking a dual shot","authors":"","doi":"10.1016/j.ejmech.2024.116995","DOIUrl":"10.1016/j.ejmech.2024.116995","url":null,"abstract":"<div><div>Antibody-drug conjugates (ADCs) enable the precise delivery of cytotoxic agents by conjugating small-molecule drugs with monoclonal antibodies (mAbs). Over recent decades, ADCs have demonstrated substantial clinical efficacy. However, conventional ADCs often encounter various clinical challenges, including suboptimal efficacy, significant adverse effects, and the development of drug resistance, limiting their broader clinical application. Encouragingly, a next-generation approach—dual-payload ADCs—has emerged as a pioneering strategy to address these challenges. Dual-payload ADCs are characterized by the incorporation of two distinct therapeutic payloads on the same antibody, enhancing treatment efficacy by promoting synergistic effects and reducing the risk of drug resistance. However, the synthesis of dual-payload ADCs is complex due to the presence of multiple functional groups on antibodies. In this review, we comprehensively summarize the construction strategies for dual-payload ADCs, ranging from the design of ADC components to orthogonal chemistry. The subsequent sections explore current challenges and propose prospective strategies, highlighting recent advancements in dual-payload ADC research, thereby laying the foundation for the development of next-generation ADCs.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488080","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}
The authors regret an error during the organization of Fig. 14C1 – D5 in this published article, the figures (Fig. 14C1 and Fig. 14D1) were miscopied due to the same compound numbers in the simultaneous experimental projects in our previous article (https://doi.org/10.1021/acs.jmedchem.2c02036; J. Med. Chem. 2023, 66, 4868 − 4887). The corrected Fig. 14 is shown here. This correction does not change the conclusions of the article in any way. We sincerely apologize for any inconvenience caused.
Download: Download high-res image (3MB)
Download: Download full-size image
Fig. 14. H&E staining and immunohistochemical staining of Ki-67 assays. After 28-day treatment, the tumor tissues and main organs in mice were collected from various groups. H&E staining and immunohistochemical assays of Ki-67 were carried out. Tumor tissues: saline (A1, B1, 0.9 %); OXA (A2, B2, 5.0 mg/kg); 14a (A3, B3, 4.5 mg/kg); 14a + OXA (A4, B4; 4.5 + 5.0 mg/kg) or 17a (A5, B5; 9.9 mg/kg). Main organ tissues: saline (C1–C5, 0.9 %); 17a (D1–D5; 9.9 mg/kg). Representative images of three independent experiments were shown.
{"title":"Corrigendum to “Novel Platinum(IV) complexes intervene oxaliplatin resistance in colon cancer via inducing ferroptosis and apoptosis” [Eur. J. Med. Chem. 263 (2024) 115968]","authors":"Zhikun Liu, Jinyuan Cai, Guiyang Jiang, Meng Wang, Chuang Wu, Kangning Su, Weiwei Hu, Yaxian Huang, Chunhao Yu, Xiaochao Huang, Guoxiu Cao, Hengshan Wang","doi":"10.1016/j.ejmech.2024.116976","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.116976","url":null,"abstract":"The authors regret an error during the organization of <span><span>Fig. 14C1 – D5</span></span> in this published article, the figures (<span><span>Fig. 14C1 and Fig. 14D1</span></span>) were miscopied due to the same compound numbers in the simultaneous experimental projects in our previous article (<span><span>https://doi.org/10.1021/acs.jmedchem.2c02036</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>; J. Med. Chem. 2023, 66, 4868 − 4887). The corrected <span><span>Fig. 14</span></span> is shown here. This correction does not change the conclusions of the article in any way. We sincerely apologize for any inconvenience caused.<span><figure><span><img alt=\"Fig. 14\" aria-describedby=\"cap0010\" height=\"516\" src=\"https://ars.els-cdn.com/content/image/1-s2.0-S0223523424008584-fx1.jpg\"/><ol><li><span><span>Download: <span>Download high-res image (3MB)</span></span></span></li><li><span><span>Download: <span>Download full-size image</span></span></span></li></ol></span><span><span><p><span>Fig. 14</span>. H&E staining and immunohistochemical staining of Ki-67 assays. After 28-day treatment, the tumor tissues and main organs in mice were collected from various groups. H&E staining and immunohistochemical assays of Ki-67 were carried out. Tumor tissues: saline (A1, B1, 0.9 %); OXA (A2, B2, 5.0 mg/kg); <strong>14a</strong> (A3, B3, 4.5 mg/kg); <strong>14a</strong> + OXA (A4, B4; 4.5 + 5.0 mg/kg) or <strong>17a</strong> (A5, B5; 9.9 mg/kg). Main organ tissues: saline (C1–C5, 0.9 %); <strong>17a</strong> (D1–D5; 9.9 mg/kg). Representative images of three independent experiments were shown.</p></span></span></figure></span>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487032","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 : 2024-10-22DOI: 10.1016/j.ejmech.2024.116991
To survive in the metal-scarce environment within the host, pathogens synthesize various small molecular metallophores to facilitate the acquisition of transition metals. The cobalt and nickel transporter (Cnt) system synthesizes and transports staphylopine, a nicotianamine-like metallophore, and serves as a primary transition metal uptake system in Gram-positive bacteria including the human pathogen Staphylococcus aureus. In this study, we report the design of the first inhibitor of the Cnt system by targeting the key aminobutanoyltransferase CntL which is involved in the biosynthesis of staphylopine. Through structure-guided fragment linking and optimization, a class of acceptor-adenosine dual-site inhibitors against S. aureus CntL (SaCntL) were designed and synthesized. The most potent inhibitor, compound 9, demonstrated a ΔTm value of 9.4 °C, a Kd value of 0.021 ± 0.004 μM, and an IC50 value of 0.06 μM against SaCntL. The detailed mechanism by which compound 9 inhibits SaCntL has been elucidated through a high-resolution co-crystal structure. Treatment with compound 9 resulted in a moderate downregulation of intracellular concentrations of iron, nickel, and cobalt ions in the S. aureus cells cultured in the metal-scarce medium, providing the first chemical validation of the important role of Cnt system in bacterial metal acquisition. Our findings pave the way for the development of CntL-based antibacterial agents in future.
{"title":"Structure-guided inhibitor design targeting CntL provides the first chemical validation of the staphylopine metallophore system in bacterial metal acquisition","authors":"","doi":"10.1016/j.ejmech.2024.116991","DOIUrl":"10.1016/j.ejmech.2024.116991","url":null,"abstract":"<div><div>To survive in the metal-scarce environment within the host, pathogens synthesize various small molecular metallophores to facilitate the acquisition of transition metals. The cobalt and nickel transporter (Cnt) system synthesizes and transports staphylopine, a nicotianamine-like metallophore, and serves as a primary transition metal uptake system in Gram-positive bacteria including the human pathogen <em>Staphylococcus aureus</em>. In this study, we report the design of the first inhibitor of the Cnt system by targeting the key aminobutanoyltransferase CntL which is involved in the biosynthesis of staphylopine. Through structure-guided fragment linking and optimization, a class of acceptor-adenosine dual-site inhibitors against <em>S</em>. <em>aureus</em> CntL (<em>Sa</em>CntL) were designed and synthesized. The most potent inhibitor, compound <strong>9</strong>, demonstrated a Δ<em>T</em><sub>m</sub> value of 9.4 °C, a <em>K</em><sub>d</sub> value of 0.021 ± 0.004 μM, and an IC<sub>50</sub> value of 0.06 μM against <em>Sa</em>CntL. The detailed mechanism by which compound <strong>9</strong> inhibits <em>Sa</em>CntL has been elucidated through a high-resolution co-crystal structure. Treatment with compound <strong>9</strong> resulted in a moderate downregulation of intracellular concentrations of iron, nickel, and cobalt ions in the <em>S. aureus</em> cells cultured in the metal-scarce medium, providing the first chemical validation of the important role of Cnt system in bacterial metal acquisition. Our findings pave the way for the development of CntL-based antibacterial agents in future.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486614","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 : 2024-10-22DOI: 10.1016/j.ejmech.2024.116982
The emergence of multidrug-resistant microbial species has become a global health concern, calling for novel antimicrobial agents. Peptoids, a class of synthetic peptidomimetics with unique structural properties, exhibit antimicrobial activity against a broad-spectrum of microbes, in addition to their stability to enzymatic degradation, selectivity, and relative ease of synthesis. Thus, peptoids have great potential in combating various drug-resistant pathogenic microbes. This review provides a comprehensive analysis of the recent advances in utilizing peptoids as effective antimicrobial agents against a wide range of bacteria, fungi, viruses, and parasites. In addition, some of the synthetic strategies and antimicrobial mechanisms are discussed. The imperfections of antimicrobial peptoids and the defects in current antimicrobial peptoids research are pointed out and promising directions for future development in peptoids are highlighted, to pave the way for innovating better antimicrobial peptoids to address the challenges posed by multidrug-resistant microbial species.
{"title":"Recent advances in peptoids as promising antimicrobial agents to target diverse microbial species","authors":"","doi":"10.1016/j.ejmech.2024.116982","DOIUrl":"10.1016/j.ejmech.2024.116982","url":null,"abstract":"<div><div>The emergence of multidrug-resistant microbial species has become a global health concern, calling for novel antimicrobial agents. Peptoids, a class of synthetic peptidomimetics with unique structural properties, exhibit antimicrobial activity against a broad-spectrum of microbes, in addition to their stability to enzymatic degradation, selectivity, and relative ease of synthesis. Thus, peptoids have great potential in combating various drug-resistant pathogenic microbes. This review provides a comprehensive analysis of the recent advances in utilizing peptoids as effective antimicrobial agents against a wide range of bacteria, fungi, viruses, and parasites. In addition, some of the synthetic strategies and antimicrobial mechanisms are discussed. The imperfections of antimicrobial peptoids and the defects in current antimicrobial peptoids research are pointed out and promising directions for future development in peptoids are highlighted, to pave the way for innovating better antimicrobial peptoids to address the challenges posed by multidrug-resistant microbial species.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452454","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 : 2024-10-22DOI: 10.1016/j.ejmech.2024.116957
Yingda Zang, Lei Huang, Xinyi Chen, Chuangjun Li, Jie Ma, Xiaoguang Chen, Dongming Zhang, Fangfang Lai
The authors regret < that there was an error in Fig. 4, owing to the negligence of the authors when generating the figures of this paper. Colony formation assay, the gold standard, is generally used to regulate the long-term effects of cytotoxic agents on the proliferation of cancer cells in vitro. In this experiment, MDA-MB-231 cells were used to evaluate the effect of compounds on cell colony formation. As shown in Fig. 4, compound 7a could inhibit cell colony formation in a dose-dependent manner starting from a concentration of 0.25 μM, with a stronger effect than the positive control compound CZN-13. CZN13 began to significantly inhibit cell colony formation only at a concentration of 5 μM. The results suggest that 7a inhibits cancer cell proliferation. There were no cells in the clone images at concentrations of 0.25 μM 7a and 5 μM CZN-13. So the two images look almost the same. The author accidently pasted the same image when during figure combining process. Hereby corrects the image of CZN-13 at 5 μM.
{"title":"Corrigendum to “Novel Nitric oxide-releasing derivatives of pyranocarbazole as antitumor agents: Design, synthesis, biological evaluation, and nitric oxide release studies” [Eur. J. Med. Chem. 244 (2022) 114832 / EJMECH-D-22-01635R2]","authors":"Yingda Zang, Lei Huang, Xinyi Chen, Chuangjun Li, Jie Ma, Xiaoguang Chen, Dongming Zhang, Fangfang Lai","doi":"10.1016/j.ejmech.2024.116957","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.116957","url":null,"abstract":"The authors regret < that there was an error in Fig. 4, owing to the negligence of the authors when generating the figures of this paper. Colony formation assay, the gold standard, is generally used to regulate the long-term effects of cytotoxic agents on the proliferation of cancer cells in vitro. In this experiment, MDA-MB-231 cells were used to evaluate the effect of compounds on cell colony formation. As shown in Fig. 4, compound 7a could inhibit cell colony formation in a dose-dependent manner starting from a concentration of 0.25 μM, with a stronger effect than the positive control compound CZN-13. CZN13 began to significantly inhibit cell colony formation only at a concentration of 5 μM. The results suggest that 7a inhibits cancer cell proliferation. There were no cells in the clone images at concentrations of 0.25 μM 7a and 5 μM CZN-13. So the two images look almost the same. The author accidently pasted the same image when during figure combining process. Hereby corrects the image of CZN-13 at 5 μM.<span><figure><span><img alt=\"Image 1\" height=\"370\" src=\"https://ars.els-cdn.com/content/image/1-s2.0-S0223523424008389-fx1.jpg\"/><ol><li><span><span>Download: <span>Download high-res image (531KB)</span></span></span></li><li><span><span>Download: <span>Download full-size image</span></span></span></li></ol></span></figure></span>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486704","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 : 2024-10-21DOI: 10.1016/j.ejmech.2024.116947
Annulated azecines, mostly partially saturated benzo[d]azecine and dibenzo[c,g]azecine fusion isomers, constitute a unique class of alkaloids and nature-inspired azaheterocyclic compounds with interesting reactivity, physicochemical and biological properties. Due to difficulties associated with the synthesis of the benzazecine (or bioisosteric) scaffold they are not the focus of organic and medicinal chemists' consideration, whereas it is worth noting the range of their pharmacological activities and their potential application in medicinal chemistry. Herein, we reviewed the synthetic methodologies of arene-fused azecine derivatives known up to date and reported about the progress in disclosing their potential in drug discovery. Indeed, their conformational restriction or liberation drives their selectivity towards diverse biological targets, making them versatile scaffolds for developing drugs, including antipsychotic and anticancer drugs, but also small molecules with potential for anti-neurodegenerative treatments, as the recent literature shows.
{"title":"Advances in synthesis of novel annulated azecines and their unique pharmacological properties","authors":"","doi":"10.1016/j.ejmech.2024.116947","DOIUrl":"10.1016/j.ejmech.2024.116947","url":null,"abstract":"<div><div>Annulated azecines, mostly partially saturated benzo[<em>d</em>]azecine and dibenzo[<em>c</em>,<em>g</em>]azecine fusion isomers, constitute a unique class of alkaloids and nature-inspired azaheterocyclic compounds with interesting reactivity, physicochemical and biological properties. Due to difficulties associated with the synthesis of the benzazecine (or bioisosteric) scaffold they are not the focus of organic and medicinal chemists' consideration, whereas it is worth noting the range of their pharmacological activities and their potential application in medicinal chemistry. Herein, we reviewed the synthetic methodologies of arene-fused azecine derivatives known up to date and reported about the progress in disclosing their potential in drug discovery. Indeed, their conformational restriction or liberation drives their selectivity towards diverse biological targets, making them versatile scaffolds for developing drugs, including antipsychotic and anticancer drugs, but also small molecules with potential for anti-neurodegenerative treatments, as the recent literature shows.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452362","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 : 2024-10-21DOI: 10.1016/j.ejmech.2024.116993
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that severely diminishes the quality of life for millions. The NLRP3 inflammasome, a critical mediator of inflammation, has emerged as a promising therapeutic target for AD. In this study, we report the development and optimization of a novel series of sulfonylurea-based NLRP3 inhibitors, with a focus on compound MC1 for the treatment of AD. Utilizing the co-crystal structure of MCC950 in complex with NLRP3 as a guide, we employed a hybrid approach of computer-aided drug design and traditional medicinal chemistry to perform two iterative optimization cycles. This strategy led to the synthesis and evaluation of 40 sulfonylurea derivatives, culminating in the identification of MC1 as the lead candidate. MC1 exhibited enhanced NLRP3 inhibitory activity and demonstrated high binding affinity to NLRP3, effectively blocking NLRP3 activation induced by diverse stimuli such as ATP and Nigericin, without perturbing upstream processes like reactive oxygen species (ROS) generation. In vivo experiments in AD mouse models revealed that MC1 significantly ameliorated cognitive deficits, surpassing the performance of MCC950. Importantly, MC1 showed no signs of hepatotoxicity or adverse effects on the central nervous system. These findings suggest that MC1 holds strong potential as a lead compound for further development in AD therapy, providing a new scaffold for NLRP3 inhibition with improved safety and efficacy profiles.
{"title":"Design, synthesis, and pharmacological characterization of sulfonylurea-based NLRP3 inhibitors: Towards an effective therapeutic strategy for Alzheimer's disease","authors":"","doi":"10.1016/j.ejmech.2024.116993","DOIUrl":"10.1016/j.ejmech.2024.116993","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that severely diminishes the quality of life for millions. The NLRP3 inflammasome, a critical mediator of inflammation, has emerged as a promising therapeutic target for AD. In this study, we report the development and optimization of a novel series of sulfonylurea-based NLRP3 inhibitors, with a focus on compound <strong>MC1</strong> for the treatment of AD. Utilizing the co-crystal structure of <strong>MCC950</strong> in complex with NLRP3 as a guide, we employed a hybrid approach of computer-aided drug design and traditional medicinal chemistry to perform two iterative optimization cycles. This strategy led to the synthesis and evaluation of 40 sulfonylurea derivatives, culminating in the identification of <strong>MC1</strong> as the lead candidate. <strong>MC1</strong> exhibited enhanced NLRP3 inhibitory activity and demonstrated high binding affinity to NLRP3, effectively blocking NLRP3 activation induced by diverse stimuli such as ATP and Nigericin, without perturbing upstream processes like reactive oxygen species (ROS) generation. In vivo experiments in AD mouse models revealed that <strong>MC1</strong> significantly ameliorated cognitive deficits, surpassing the performance of <strong>MCC950</strong>. Importantly, <strong>MC1</strong> showed no signs of hepatotoxicity or adverse effects on the central nervous system. These findings suggest that <strong>MC1</strong> holds strong potential as a lead compound for further development in AD therapy, providing a new scaffold for NLRP3 inhibition with improved safety and efficacy profiles.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452471","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 : 2024-10-20DOI: 10.1016/j.ejmech.2024.116992
Fibrosis is the terminal pathology of chronic illness in many organs, marked by excessive accumulation of extracellular matrix proteins. These changes influence organ function, ultimately resulting in organ failure. Although significant progress has been achieved in comprehending the molecular pathways responsible for fibrosis in the last decades, effective and approved clinical therapies for the condition are still lacking. Andrographolide is a diterpenoid isolated and purified mainly from the aboveground parts of the Andrographis paniculata plant, which possesses good effects of purging heat, detoxifying, antibacterial and anti-inflammatory. In-depth research has gradually confirmed the anticancer, antioxidant, antiviral and other effects of Andro so that it can play a preventive and therapeutic role in various diseases. Over the past few years, an increasing number of research findings have indicated that Andro exerts antifibrotic effects in various organs by acting on transforming growth factor-β/small mother against decapentaplegic protein, mitogen-activated protein kinases, nuclear factor-E2-related factor 2, nuclear factor kappa-B and other signalling molecules to inhibit inflammation, oxidative stress, epithelial-mesenchymal transition, fibroblast activation and collagen buildup. This review presents a compilation of findings regarding the antifibrotic impact of Andro in tissue and cell models in vitro and in vivo. Emphasis is placed on the potential therapeutic benefits of Andro in diseases related to organ fibrosis. Existing studies and cutting-edge technologies on Andro pharmacokinetics, toxicity and bioavailability are briefly discussed to provide evidence for accelerating its clinical conversion and adoption.
{"title":"Andrographolide: A promising therapeutic agent against organ fibrosis","authors":"","doi":"10.1016/j.ejmech.2024.116992","DOIUrl":"10.1016/j.ejmech.2024.116992","url":null,"abstract":"<div><div>Fibrosis is the terminal pathology of chronic illness in many organs, marked by excessive accumulation of extracellular matrix proteins. These changes influence organ function, ultimately resulting in organ failure. Although significant progress has been achieved in comprehending the molecular pathways responsible for fibrosis in the last decades, effective and approved clinical therapies for the condition are still lacking. Andrographolide is a diterpenoid isolated and purified mainly from the aboveground parts of the <em>Andrographis</em> paniculata plant, which possesses good effects of purging heat, detoxifying, antibacterial and anti-inflammatory. In-depth research has gradually confirmed the anticancer, antioxidant, antiviral and other effects of Andro so that it can play a preventive and therapeutic role in various diseases. Over the past few years, an increasing number of research findings have indicated that Andro exerts antifibrotic effects in various organs by acting on transforming growth factor-β/small mother against decapentaplegic protein, mitogen-activated protein kinases, nuclear factor-E2-related factor 2, nuclear factor kappa-B and other signalling molecules to inhibit inflammation, oxidative stress, epithelial-mesenchymal transition, fibroblast activation and collagen buildup. This review presents a compilation of findings regarding the antifibrotic impact of Andro in tissue and cell models in vitro and in vivo. Emphasis is placed on the potential therapeutic benefits of Andro in diseases related to organ fibrosis. Existing studies and cutting-edge technologies on Andro pharmacokinetics, toxicity and bioavailability are briefly discussed to provide evidence for accelerating its clinical conversion and adoption.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451530","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 : 2024-10-19DOI: 10.1016/j.ejmech.2024.116979
Leishmaniasis and trypanosomiasis rank among lethal vector-borne parasitic diseases that are endemic in tropical and sub-tropical countries. There are currently no preventive vaccines against them, and once diagnosed, a handful of less effective drugs clinically accessible are the only therapeutic options offered to treat these ailments. And although curable, the eradication and elimination of these diseases are hampered by the emergence of multidrug-resistant strains of the causal pathogens. Hence, there is accrued necessity for the development of new, effective, and affordable drugs. In recent decades, several molecular scaffolds, including nitroaromatics, endoperoxides, etc., have been attempted as building blocks to generate new effective clinical antitrypanosomatid agents with low toxicity so far to no avail. In this regard, a series of nitroindolylazine derivatives was synthesised in a three-step process involving nucleophilic substitution (SN), hydrazination and Schiff base condensation reactions, and was evaluated against various Leishmania and Trypanosoma species and strains. Several promising hits portraying leishmanicidal and trypanocidal with in vitro submicromolar activities, and devoid of toxicity on mammalian cells were uncovered. Among these, nitrofurylazine 11 (Tc IC50: 0.08 ± 0.03 μM) and nitrothienylazine 13 (Tc IC50: 0.09 ± 0.01 μM) were evaluated in vivo against Trypanosoma congolense, the causative agent of nagana, which is livestock most virulent trypanosome species in mice-infected preliminary study. However, only partial efficacy was observed as all mice succumbed due to high parasitemia within 13 days post-infection during the treatment. The translational potential of antileishmanial and antichagasic hits, as well as further identification of their molecular targets, will be assessed in future research.
{"title":"Design, synthesis, in vitro and in vivo trypanosomaticidal efficacy of novel 5-nitroindolylazines","authors":"","doi":"10.1016/j.ejmech.2024.116979","DOIUrl":"10.1016/j.ejmech.2024.116979","url":null,"abstract":"<div><div>Leishmaniasis and trypanosomiasis rank among lethal vector-borne parasitic diseases that are endemic in tropical and sub-tropical countries. There are currently no preventive vaccines against them, and once diagnosed, a handful of less effective drugs clinically accessible are the only therapeutic options offered to treat these ailments. And although curable, the eradication and elimination of these diseases are hampered by the emergence of multidrug-resistant strains of the causal pathogens. Hence, there is accrued necessity for the development of new, effective, and affordable drugs. In recent decades, several molecular scaffolds, including nitroaromatics, endoperoxides, etc., have been attempted as building blocks to generate new effective clinical antitrypanosomatid agents with low toxicity so far to no avail. In this regard, a series of nitroindolylazine derivatives was synthesised in a three-step process involving nucleophilic substitution (S<sub>N</sub>), hydrazination and Schiff base condensation reactions, and was evaluated against various <em>Leishmania</em> and <em>Trypanosoma</em> species and strains. Several promising hits portraying leishmanicidal and trypanocidal with <em>in vitro</em> submicromolar activities, and devoid of toxicity on mammalian cells were uncovered. Among these, nitrofurylazine <strong>11</strong> (<em>Tc</em> IC<sub>50</sub>: 0.08 ± 0.03 μM) and nitrothienylazine <strong>13</strong> (<em>Tc</em> IC<sub>50</sub>: 0.09 ± 0.01 μM) were evaluated <em>in vivo</em> against <em>Trypanosoma congolense</em>, the causative agent of <em>nagana</em>, which is livestock most virulent trypanosome species in mice-infected preliminary study. However, only partial efficacy was observed as all mice succumbed due to high parasitemia within 13 days post-infection during the treatment. The translational potential of antileishmanial and antichagasic hits, as well as further identification of their molecular targets, will be assessed in future research.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450151","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 : 2024-10-19DOI: 10.1016/j.ejmech.2024.116970
The protein arginine methyltransferase 5 (PRMT5) has emerged as potential target for the treatment of cancer. Many efforts have been made to develop potent and selective PRMT5 inhibitors targeting either S-adenosyl methionine (SAM) pocket or substrate binding pocket. Here, we rationally designed a series of nucleoside derivatives incorporated with piperazine as novel PRMT5 inhibitors occupying both pockets. The representative compound 36 exhibited highly potent PRMT5 inhibition activity as well as good selectivity over other methyltransferases. Further cellular experiments revealed that compound 36 potently reduced the level of symmetric dimethylarginines (sDMA) and inhibited the proliferation of MOLM-13 cell lines by inducing apoptosis and cell cycle arrest. Moreover, compound 36 had more favorable metabolic stability and aqueous solubility than JNJ64619178 (9). Meanwhile, it obviously suppressed the tumor growth in a MOLM-13 tumor xenograft model. These results clearly indicate that 36 is a highly potent and selective PRMT5 inhibitor worthy for further development.
{"title":"One stone two birds: Introducing piperazine into a series of nucleoside derivatives as potent and selective PRMT5 inhibitors","authors":"","doi":"10.1016/j.ejmech.2024.116970","DOIUrl":"10.1016/j.ejmech.2024.116970","url":null,"abstract":"<div><div>The protein arginine methyltransferase 5 (PRMT5) has emerged as potential target for the treatment of cancer. Many efforts have been made to develop potent and selective PRMT5 inhibitors targeting either S-adenosyl methionine (SAM) pocket or substrate binding pocket. Here, we rationally designed a series of nucleoside derivatives incorporated with piperazine as novel PRMT5 inhibitors occupying both pockets. The representative compound <strong>36</strong> exhibited highly potent PRMT5 inhibition activity as well as good selectivity over other methyltransferases. Further cellular experiments revealed that compound <strong>36</strong> potently reduced the level of symmetric dimethylarginines (sDMA) and inhibited the proliferation of MOLM-13 cell lines by inducing apoptosis and cell cycle arrest. Moreover, compound <strong>36</strong> had more favorable metabolic stability and aqueous solubility than JNJ64619178 (<strong>9</strong>). Meanwhile, it obviously suppressed the tumor growth in a MOLM-13 tumor xenograft model. These results clearly indicate that <strong>36</strong> is a highly potent and selective PRMT5 inhibitor worthy for further development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450152","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号