European Journal of Medicinal Chemistry最新文献

{"title":"Recent Progress in the Development of Peptide-Drug Conjugates (PDCs) for Cancer Therapy","authors":"Haiqi He, Xin Deng, Zhijie Wang, Jianjun Chen","doi":"10.1016/j.ejmech.2024.117204","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117204","url":null,"abstract":"Peptide-drug conjugates (PDCs) are emerging therapeutic agents composed of peptides, linkers, and payloads, which possess favorable targeting capability and can deliver enough payloads to the tumor sites with minimized impact on healthy tissues. However, only a few PDCs have been approved for clinical use so far. To advance the research on PDCs, this review summarizes the approved PDCs, and PDCs in clinical and preclinical stages based on the payload types. Additionally, the biological activity and pharmacokinetic properties of preclinical PDCs are detailedly described. Lastly, the challenges and future development directions of PDCs are discussed. This review aims to inspire insights into the development of PDCs for cancer treatment.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"23 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884499","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}

{"title":"Corrigendum to “Discovery of indazole inhibitors for heat shock protein 90 as anti-cancer agents” [Eur. J. Med. Chem. (2024) 116620]","authors":"Minh Thanh La, Van-Hai Hoang, Raghaba Sahu, Cong-Truong Nguyen, Gibeom Nam, Hyun-Ju Park, Minsu Park, Yoon-Jae Kim, Ji Young Kim, Jihyae Ann, Jae Hong Seo, Jeewoo Lee","doi":"10.1016/j.ejmech.2024.117194","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117194","url":null,"abstract":"The authors regret the omission of funding information for grant number 2023R1A2C3004010 in the Acknowledgments section of the original publication. The authors would like to amend the Acknowledgments as follows:","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"58 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879903","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}

{"title":"Discovery of Novel Bicyclic and Tricyclic Cyclohepta[b]thiophene Derivatives as Multipotent AChE and BChE Inhibitors, In-Vivo and In-Vitro Assays, ADMET and Molecular Docking Simulation","authors":"Eman A. Fayed, Samiha Ahmed El-Sebaey, Maha A. Ebrahim, Karema Abu-Elfotuh, Reda El-Sayed Mansour, Ehsan Khedre Mohamed, Ahmed M.E. Hamdan, Faleh Turki Al-subaie, Gharam Saad Albalawi, Tariq Mohammed Albalawi, Amira M. Hamdan, Asmaa A. Mohammed, Triveena M. Ramsis","doi":"10.1016/j.ejmech.2024.117201","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117201","url":null,"abstract":"Alzheimer’s disease (AD) is primarily caused by oxidative stress, hyperphosphorylated τ-protein aggregation, and amyloid-<em>β</em> deposition. Changes in dopaminergic and serotoninergic neurotransmitter pathways are linked to certain symptoms of AD. Derivatives of bicyclic and tricyclic cyclohepta[<em>b</em>]thiophene were developed to identify new potential candidates as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors for the treatment of AD. All synthesized compounds exhibited AChE inhibition with IC₅₀ values below 15 μM, while all compounds exhibited BChE inhibition with IC₅₀ values below 25 μM. Compounds <strong>9</strong> and <strong>12</strong> exhibited AChE inhibitory activities with IC₅₀ values of 0.51 μM and 0.55 μM, respectively. Compounds <strong>5</strong> and <strong>9</strong> demonstrated excellent inhibitory activity against BChE with IC₅₀ values of 2.9 μM and 2.48 μM, respectively. Compounds <strong>9</strong>, <strong>13</strong>, and <strong>14</strong> were found to be the most active in terms of the decrease in the escape latency time, with values comparable to that of Donepezil. Compounds <strong>10</strong>, <strong>11</strong>, and <strong>12</strong> exhibited promising effects on learning and memory. Compounds <strong>5</strong>, <strong>10</strong>, <strong>11</strong>, and <strong>12</strong> exhibited promising SAP values of 70.67%, 71.5%, 74.33% and 73.83%, respectively. Other biomarkers were evaluated in rat brains including TAC, MDA, SOD, BDNF, IL-<em>β</em> and TNF-<em>α</em>. Fundamental features of ADMET have been computed <em>in-silico</em> for synthesized compounds. Molecular docking was performed to confirm the binding of the novel compounds to the targets.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"11 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884495","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}

{"title":"Glycoconjugates of Adefovir and Tenofovir as Asialoglycoprotein-Mediated Anti-HBV Prodrugs with Enhanced Liver Targeting","authors":"Lei Chen, Mingzhenlong Deng, Wanli Yan, Ziwei Zeng, Di Chen, Yonglong Zhao, Yisong Wu, Yan Li, Bin He","doi":"10.1016/j.ejmech.2024.117207","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117207","url":null,"abstract":"Hepatitis B virus (HBV) infection remains a significant global health challenge, often leading to severe liver complications such as cirrhosis and cancer. Current treatments rely heavily on nucleos(t)ide analogs like adefovir and tenofovir due to their potent antiviral effects. However, their clinical utility is limited by insufficient liver targeting, leading to off-target side effects, particularly nephrotoxicity. To improve liver-specific drug delivery and reduce adverse effects, we designed novel liver-targeted prodrugs by conjugating adefovir and tenofovir with N-acetylgalactosamine (GalNAc) and tris-GalNAc ligands, which have high affinity for the asialoglycoprotein receptor (ASGPR) predominantly expressed in hepatocytes. Four prodrugs (<strong>A1, A2, T1, and T2</strong>) were synthesized and evaluated for cytotoxicity, maximum tolerated dose, anti-HBV activity, metabolic stability, pharmacokinetics, and liver-targeting properties. The prodrugs exhibited low cytotoxicity, robust anti-HBV activity, and enhanced selectivity compared to their parent drugs. Notably, the tris-GalNAc conjugates <strong>A2</strong> and <strong>T2</strong> demonstrated superior liver targeting, showing a threefold higher concentration in the liver compared to the kidneys, thus minimizing renal exposure. These findings suggest that GalNAc and tris-GalNAc conjugation is a promising strategy for enhancing the therapeutic efficacy and safety of adefovir and tenofovir, with potential for further optimization as liver-targeted anti-HBV prodrugs.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"14 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884497","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}

{"title":"Design, Synthesis, and Biological Evaluation of Ponatinib-based N-Phenylpyrimidine-2-amine Derivatives as Novel Fibroblast Growth Factor Receptor 4 (FGFR4) Selective Inhibitors","authors":"Lei Han, Yu Yu, Ping Deng, Shuai Wang, Junchi Hu, Shuang Wang, Jiecheng Zheng, Junhao Jiang, Yongjun Dang, Rui Long, Zongjie Gan","doi":"10.1016/j.ejmech.2024.117206","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117206","url":null,"abstract":"Fibroblast growth factor receptor 4 (FGFR4) has been proven to be a promising target for FGFR-driven HCC therapy. Great efforts have been devoted to the discovery of FGFR4 inhibitors. In this article, a new class of Ponatinib-based <em>N</em>-phenylpyridine-2-amine derivatives was designed and synthesized as covalent and irreversible FGFR4 selective inhibitors through a rational drug design strategy. The representative compound <strong>10f</strong> displayed significant FGFR4 inhibition and reasonable selectivity. Meanwhile, compound <strong>10f</strong> strongly suppressed the proliferation of FGFR4 dependent HCC cells both <em>in vitro</em> and <em>in vivo</em> by inhibiting the FGFR4 signaling pathway. Moreover, the irreversible binding to Cys552 in FGFR4 of compound <strong>10f</strong> was also characterized by LC-MS/MS. These results provide evidence of <strong>10f</strong> as a potential lead compound targeting FGFR4 for anti-HCC agent development.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"71 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884500","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}

{"title":"Marine natural product-inspired discovery of novel BRD4 inhibitors with anti-inflammatory activity","authors":"Shuxia Chen, Jichen Yang, Xiangyu Wang, Xiaochun Liu, Xiuxue Li, Yansheng Ye, Pingyuan Wang, Zhiqing Liu, Chang-Yun Wang","doi":"10.1016/j.ejmech.2024.117193","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117193","url":null,"abstract":"Bromodomain-containing protein 4 (BRD4) has been identified as a promising target in drug discovery, and the development of novel specific BRD4 bromodomain inhibitors will benefit anti-inflammatory drug discovery as well as bromodomain function role disclose. Herein, inspired by marine quinazolinone alkaloid penipanoid C, we designed and synthesized a series of quinazolin-4(3<em>H</em>)-ones with diverse linkers between two aromatic ring systems. Among them, compound <strong>25</strong> possessed good <em>in vitro</em> BRD4 inhibitory activities (IC₅₀ = 3.64 μM for BRD4 BD1 and IC₅₀ = 0.12 μM for BRD4 BD2) and anti-inflammatory activity (IC₅₀ = 1.98 μM for NO production assay). Meantime, <strong>25</strong> obviously suppressed the expression of TNF-<em>α</em> and IL-6 in LPS-stimulated Raw 264.7 and THP-1 cells. Notablely, <strong>25</strong> displayed <em>in vivo</em> therapeutic efficacies in an acute inflammation model without obvious cytotoxicity. These findings suggest that <strong>25</strong> is a selective BRD4 BD2 inhibitor which is a promising anti-inflammatory lead compound worthy for further investigation.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"65 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879908","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}

{"title":"Design, Synthesis, and Pharmacological Evaluation of Triazine-based PI3K/mTOR Inhibitors for the Potential Treatment of Non-Small Cell Lung Cancer","authors":"Ming Zeng, Yingxuan Hu, Lan Zhao, Chengze Duan, Haifeng Wu, Yi Xu, Xiaoguang Liu, Yali Wang, Dengzhao Jiang, Shenxin Zeng","doi":"10.1016/j.ejmech.2024.117200","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117200","url":null,"abstract":"Dysregulated activation of the PI3K/AKT/mTOR pathway is crucial in the development of cancer, and disrupting it could potentially lead to cancer suppression, making it a viable strategy for cancer treatment. Here, as a consecutive work of our team, we described the identification and optimization of PI3K/mTOR inhibitors based on triazine scaffold, which exhibited potent PI3K/mTOR inhibitor activity. The systematically structure-activity relationship (SAR) results demonstrated that compound 5nh displayed high efficacy against PI3Kα and mTOR, with the IC₅₀ values of 0.45 nM and 2.9 nM, respectively. Importantly, compared to the lead compound PKI-587, 5nh demonstrated significant inhibitory activity against non-small-cell lung cancer (NSCLC) cell lines, particularly HCC-827, with a 43-fold increase (3.5 nM <em>vs</em> 150 nM). Additionally, the compound showed effective inhibition against the EGFR-resistant variant HCC-827(GR) cell line. Mechanism validation demonstrated that 5nh significantly interfered with the PI3K/AKT/mTOR signaling pathway in HCC-827 cells. Furthermore, the oral pharmacokinetic properties of 5nh had been observably improved, with AUC_0-t and C_max increasing by 13-16 times at a dose of 10 mg/kg in mice. Importantly, the <em>in vivo</em> efficacy study demonstrated that orally treatment of 5nh led to significant tumor growth suppression, with a TGI value of 84.4%. Collectively, our systematically medicinal chemistry campaigns suggested that 5nh, a novel oral available triazine derivative, held promise as a candidate for therapy of NSCLC by targeting the PI3K/AKT/mTOR cascade.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"299 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884501","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}

{"title":"Discovery of the Salicylaldehyde-Based Compound DDO-02267 as a Lysine-Targeting Covalent Inhibitor of ALKBH5","authors":"Wen-Long Fei, Ying-Zhe Wang, Qing-Lan Feng, Cui-Ting Li, Rui-Xin Jiang, Shi-Di Zhang, Yun Pan, Peng-Fei Ni, Fei-Ran Hang, Yi-Bing Huangfu, Shi-Da Zhang, Qi-Dong You, Xiao-Ke Guo","doi":"10.1016/j.ejmech.2024.117183","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117183","url":null,"abstract":"<em>N</em>⁶-methyladenosine (m⁶A) is a crucial mRNA epigenetic modification in eukaryotes, and its methylation regulation is associated with the proliferation and metastasis of diverse tumor cells. ALKBH5 functions as a demethylase for m⁶A and plays a role in the demethylation process, thus influencing tumor cell growth and migration. However, there are limited reports on selective small molecule inhibitors of ALKBH5. Herein, we designed and synthesized the ALKBH5 covalent inhibitor <strong>DDO-02267</strong> by analyzing the protein structure of ALKBH5 and introducing salicylaldehyde warhead into noncovalent small molecule ligand. <strong>DDO-02267</strong> specifically targeted Lys132 within ALKBH5, demonstrating significant selectivity for ALKBH5 <em>in vitro</em>. Additionally, <strong>DDO-02267</strong> increased m⁶A levels and targeted the <em>ALKBH5-AXL</em> signaling axis in AML cells. The compound <strong>DDO-02267</strong> can serve as a probe for investigating the biological function of mRNA demethylase and may inspire the development of future ALKBH5 inhibitors.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874662","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}

{"title":"Photosensitizer associated with efflux pump inhibitors as a strategy for Photodynamic Therapy against bacterial resistance","authors":"Ieda Vieira da Cunha, Douglas Davison da Silva Oliveira, Gabriel Guimarães Calefi, Nagela Bernadelli Sousa Silva, Carlos Henrique Gomes Martins, Celso de Oliveira Rezende Júnior, Tayana Mazin Tsubone","doi":"10.1016/j.ejmech.2024.117197","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117197","url":null,"abstract":"Antimicrobial resistance is currently one of the biggest challenges in controlling infectious diseases and was listed among the top 10 threats to global health by the World Health Organization (WHO) in 2023. The antibiotics misuse has led to the widespread emergence of antimicrobial resistance, marking the beginning of the alarming increase in antibiotic resistance. In this context, Antimicrobial Photodynamic Therapy (aPDT) has garnered significant attention from the scientific community due to its potential to effectively eliminate multidrug-resistant pathogenic bacteria and its low propensity to induce drug resistance, which bacteria can quickly develop against traditional antibiotic treatments. However, some efflux pumps can expel diverse substrates from inside the cell, including photosensitizers used in aPDT, contributing to multidrug-resistance mechanisms. Efflux Pump Inhibitors are potential solutions to combat resistance mediated by these pumps and can play a crucial role in enhancing aPDT's effectiveness against multidrug-resistant bacteria. Therefore, combining efflux pumps inhibitors with photosensitizers can possible to eliminate the pathogen more efficiently. This review summarizes the mechanisms in which bacteria resist conventional antibiotic treatment, with a particular emphasis on efflux pump-mediated resistance, and present aPDT as a promising strategy to combat antibiotic resistance. Additionally, we highlighted several molecules of photosensitizer associated with efflux pump inhibitors as potential strategies to optimize aPDT, aiming to offer a perspective on future research directions on aPDT for overcoming the limitations of antibiotic resistance.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"14 10 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142869975","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}

{"title":"The polypharmacy combination of the BCL-2 inhibitor venetoclax (VEN) and the FLT3 inhibitor gilteritinib (GIL) is more active in acute myeloid leukemia cells than novel polypharmacologic BCL-2/FLT3 VEN–GIL hybrid single-molecule inhibitors.","authors":"Christopher C. Goodis, Christian Eberly, Alexandria M. Chan, MinJung Kim, Brandon D. Lowe, Curt I. Civin, Steven Fletcher","doi":"10.1016/j.ejmech.2024.117190","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117190","url":null,"abstract":"Current treatments for acute myeloid leukemias (AMLs) cure fewer than 30% of patients. This low efficacy is due, in part, to the inter-patient and intra-patient heterogeneity of AMLs; accordingly, all current AML treatment regimens involve drug combinations (polypharmacy). A recently-completed clinical trial in relapsed/refractory AML using a combination of two newer targeted antileukemics, the BCL-2 inhibitor venetoclax (VEN) plus the FLT3 inhibitor gilteritinib (GIL), yielded highly promising results for this two-drug polypharmacy combination. Polypharmacology – wherein a single drug molecule that inhibits two or more biological targets is created – has been proposed to offer superior therapeutic results, as compared to the corresponding polypharmacy approach. Herein, we designed and synthesized several polypharmacologic dual BCL-2/FLT3 hybrid single-molecule inhibitors by tethering VEN to GIL, through their solvent-exposed domains. While the in vitro antileukemic activity of the two-drug VEN + GIL polypharmacy combination proved superior to our focused library of VEN-GIL hybrids, alternative grafting points on GIL may yield improved results for future hybrid compounds.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"83 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142869974","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}