ChemMedChem最新文献_第4页

Cover Feature: Advances in Diclofenac Derivatives: Exploring Carborane-Substituted N-Methyl and Nitrile Analogs for Anticancer Therapy (ChemMedChem 11/2025) 封面专题：双氯芬酸衍生物的进展：探索碳硼烷取代的n -甲基和腈类似物用于抗癌治疗（ChemMedChem 11/2025）

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-06-03 DOI: 10.1002/cmdc.202581102

Christoph Selg, Robert Schuster, Aleksandr Kazimir, Peter Lönnecke, Mara Wolniewicz, Jonas Schädlich, Markus Laube, Jens Pietzsch, Vuk Gordić, Tamara Krajnović, Sanja Mijatović, Danijela Maksimović-Ivanić, Evamarie Hey-Hawkins

引用次数: 0

Inhibition of the Clathrin Terminal Domain-Amphiphysin Protein-Protein Interaction. Probing the Pitstop 2 Aromatic Moiety. 网格蛋白末端结构域-两性蛋白-蛋白相互作用的抑制。探测Pitstop®2芳香部分。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-06-02 DOI: 10.1002/cmdc.202500321

Kate Prichard, Mark J Robertson, Ngoc Chau, Jing Xue, Martin Neuenschwander, Uwe Fink, Andre Horatscheck, Marc Nazare, Phillip J Robinson, Volker Haucke, Adam McCluskey

{"title":"Inhibition of the Clathrin Terminal Domain-Amphiphysin Protein-Protein Interaction. Probing the Pitstop 2 Aromatic Moiety.","authors":"Kate Prichard, Mark J Robertson, Ngoc Chau, Jing Xue, Martin Neuenschwander, Uwe Fink, Andre Horatscheck, Marc Nazare, Phillip J Robinson, Volker Haucke, Adam McCluskey","doi":"10.1002/cmdc.202500321","DOIUrl":"10.1002/cmdc.202500321","url":null,"abstract":"Pitstop 2, (Z)-N-(5-(4-bromenzylidene)-4-oxo-4,5-dihydrothiazol-2-yl)naphthalene-1-sulfonamide (1) inhibits the clathrin terminal domain-amphiphysin interaction (NTD-PPI) and has been widely used to investigate endocytosis. Herein, the synthesis of 56 novel Pitstop 2 analogues via four discrete focused libraries is reported. Specific modification to the 4-bromonenzylidene moiety is explored, and their ability to inhibit the NTD-PPI interaction is examined by ELISA. In cell endocytosis, effects are measured for selective analogues as is the inhibition of dynamin, another protein involved in the endocytosis process. The most NTD-PPI active analogues retain 2- and 4-disposed substituents on the aromatic head, with 2,3,4-trihydroxy (28) the most active (IC50 0.94 μm). Catechol-free 2,3-dihydroxybenzo[b][1,4]dioxone (54) is a more promising lead with an NTD-PPI IC50 = 1.16 μm. The corresponding benzo[d][1,3]dioxole (53) is threefold less active suggesting ring size preference at this position. Nine analogues show improved or comparable NTD-PPI activity to Pitstop 2 with IC50 values from 0.94 to 2.1 μM. Heterocyclic analogues are well tolerated and potent inhibitors of CME in U2OS cells, in particular, benzofuran 67 (NTD-PPI IC50 1.5 μm and CME IC50 6.8 ± 2.7 μm). This positions 67 as one of the most cell active inhibitors of clathrin-mediated endocytosis yet reported.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500321"},"PeriodicalIF":3.6,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Machine Learning-Driven QSAR Modeling of Anticancer Activity from a Rationally Designed Synthetic Flavone Library. 合理设计的合成黄酮库抗癌活性的机器学习驱动QSAR建模。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-30 DOI: 10.1002/cmdc.202500143

Natthanan Vijara, Borwornlak Toopradab, Jantana Yahuafai, Taweesak Gulchatchai, Rita Hairani, Apinya Patigo, Thanyada Rungrotmongkol, Sumrit Wacharasindhu, Warinthorn Chavasiri, Liyi Shi, Phornphimon Maitarad, Ruchuta Ardkhean, Tanatorn Khotavivattana

{"title":"Machine Learning-Driven QSAR Modeling of Anticancer Activity from a Rationally Designed Synthetic Flavone Library.","authors":"Natthanan Vijara, Borwornlak Toopradab, Jantana Yahuafai, Taweesak Gulchatchai, Rita Hairani, Apinya Patigo, Thanyada Rungrotmongkol, Sumrit Wacharasindhu, Warinthorn Chavasiri, Liyi Shi, Phornphimon Maitarad, Ruchuta Ardkhean, Tanatorn Khotavivattana","doi":"10.1002/cmdc.202500143","DOIUrl":"10.1002/cmdc.202500143","url":null,"abstract":"Flavones, recognized as \"privileged scaffolds\" in drug discovery, hold significant promise as anticancer agents. This study develops a quantitative structure-activity relationship (QSAR) model to accelerate the optimization of lead compounds. Using pharmacophore modeling against different cancer targets, 89 flavone analogs with varied substitution patterns were designed and synthesized. Biological evaluation revealed promising candidates with enhanced cytotoxicity against breast cancer (MCF-7) and liver cancer (HepG2) cell lines, along with low toxicity toward normal Vero cells. A machine learning (ML)-driven QSAR approach was employed, comparing random forest (RF), extreme gradient boosting, and artificial neural network (ANN) models. The RF model exhibits superior performance, achieving R2 of 0.820 for (MCF-7 and 0.835 for HepG2, with cross-validation (R2cv) of 0.744 and 0.770, respectively. Validation using 27 test compounds yielded root mean square error test values of 0.573 (MCF-7) and 0.563 (HepG2). SHapley Additive exPlanations analysis highlighted key molecular descriptors influencing anticancer activity. This work presents a robust ML-driven QSAR model that supports the rational design of flavone derivatives and advances the development of selective, potent anticancer agents.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500143"},"PeriodicalIF":3.6,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis and Biological Characterization of 4,4-Difluoro-3-(phenoxymethyl)piperidine Scaffold as Dopamine 4 Receptor (D₄R) Antagonist in vitro Tool compounds. 作为多巴胺4受体（D4R）拮抗剂的4,4-二氟-3（苯氧甲基）哌啶支架体外工具化合物的合成及生物学特性

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-29 DOI: 10.1002/cmdc.202500298

Saeedeh Saeedi, Sumaiya Nahid, Anish K Vadukoot, Corey R Hopkins

引用次数: 0

Copper-Induced Supramolecular Assemblies for Biomedical Applications. 生物医学应用中的铜诱导超分子组装体。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-28 DOI: 10.1002/cmdc.202500173

Xingyao Sun, Xiangyang Zhang, Ziqi Zhao, Jie Gao

引用次数: 0

Factors Influencing the Binding of HIV-1 Protease Inhibitors: Insights from Machine Learning Models. 影响HIV-1蛋白酶抑制剂结合的因素：来自机器学习模型的见解。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-28 DOI: 10.1002/cmdc.202500277

Yaffa Shalit, Inbal Tuvi-Arad

{"title":"Factors Influencing the Binding of HIV-1 Protease Inhibitors: Insights from Machine Learning Models.","authors":"Yaffa Shalit, Inbal Tuvi-Arad","doi":"10.1002/cmdc.202500277","DOIUrl":"10.1002/cmdc.202500277","url":null,"abstract":"HIV-1 protease (PR) inhibitors are crucial for antiviral therapies targeting acquired immunodeficiency syndrome. Hundreds of PR complexes with various ligands have been resolved and deposited in the Protein Data Bank. However, binding affinity measurements for these ligands are not always available. This gap hinders a comprehensive understanding of inhibitor efficacy. To address this challenge, machine learning models are constructed and validated based on the crystallographic coordinates of 291 PR-inhibitor complexes, leveraging over 2500 molecular descriptors. The models achieved accuracy scores exceeding 0.85, and applied to predict the binding affinity of 274 additional complexes for which inhibition constants are not experimentally measured. The analysis is focused on three models, each with 8-9 features, and based on KBest with random forest, recursive feature elimination with random forest, and sequential feature selection with support vector machine. The findings revealed key predictive features, including properties of PR inhibitors like charge distribution, hydrogen-bonding capability, and 3D topology, as well as intrinsic properties of PR, such as active site symmetry and flap mutations. The study highlights the contribution of a comprehensive analysis of accumulated experimental data to enhance the structural understanding of this important molecular system.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500277"},"PeriodicalIF":3.6,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144155415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Linker Design for the Antibody Drug Conjugates: A Comprehensive Review. 抗体药物偶联物的连接设计：综述。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-27 DOI: 10.1002/cmdc.202500262

Yaxin Lei, Minglei Zheng, Peng Chen, Chen Seng Ng, Teck Peng Loh, Huitao Liu

{"title":"Linker Design for the Antibody Drug Conjugates: A Comprehensive Review.","authors":"Yaxin Lei, Minglei Zheng, Peng Chen, Chen Seng Ng, Teck Peng Loh, Huitao Liu","doi":"10.1002/cmdc.202500262","DOIUrl":"10.1002/cmdc.202500262","url":null,"abstract":"Inspired by the \"magic bullet\" concept proposed over a century ago, antibody-drug conjugates (ADCs) are developed to enhance cancer therapy by linking monoclonal antibodies to a cytotoxic payload, aiming to overcome the limitations of conventional chemotherapy. To date, 17 ADCs have received regulatory approval for treating both hematologic and solid tumors. Despite their clinical success, developing ADCs with optimal therapeutic potential remains challenging. While selecting the appropriate antibody and cytotoxin is crucial, the linker plays a pivotal role in determining plasma stability and efficient payload release at the tumor site. Over the past decade, advances in linker technology have significantly improved the pharmacokinetics, efficacy, and toxicity profiles of ADCs. This review provides an overview of clinically validated linkers and recent innovations in linker design, focusing on drug release triggers, bioconjugation strategies, the impact of spacers on hydrophilicity, traceless drug release, and linker architecture, as well as a discussion of the bystander effect, offering insights for the rational design of next-generation ADCs.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500262"},"PeriodicalIF":3.6,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144155416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of 2,9-Disubstituted Acridines as Topoisomerase IIα Inhibitors with Strong Anticancer Activity: Synthesis, Biological Evaluation, and In Silico Study. 具有强抗癌活性的2,9-二取代吖啶烷拓扑异构酶IIα抑制剂的研制——合成、生物学评价和硅研究。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-25 DOI: 10.1002/cmdc.202500267

Ladislav Janovec, Adrian Gucký, Kristína Krochtová, Radka Michalková, Katarína Kušnírová, Viktória Miškufová, Dávid Jáger, Ján Mojžiš, Mária Kožurková

{"title":"Development of 2,9-Disubstituted Acridines as Topoisomerase IIα Inhibitors with Strong Anticancer Activity: Synthesis, Biological Evaluation, and In Silico Study.","authors":"Ladislav Janovec, Adrian Gucký, Kristína Krochtová, Radka Michalková, Katarína Kušnírová, Viktória Miškufová, Dávid Jáger, Ján Mojžiš, Mária Kožurková","doi":"10.1002/cmdc.202500267","DOIUrl":"10.1002/cmdc.202500267","url":null,"abstract":"A series of 2,9-disubstituted acridines (16a-16h) is synthetized and assessed for their biological activities. The acridines feature various 9-anilino or 9-phenylalkyl substituents and are prepared via a linear sequence of six steps using commercially available starting materials. The relationship between the physicochemical properties of the 2,9-disubstituted acridines and their biological activity is studied, and the DNA binding capacities of the synthetized acridines are determined using spectroscopic (Kb 0.5-10.4 × 104 M-1) and thermal denaturation (ΔTm 4.2-9.8 °C) methods. The inhibitory potential of acridines 16a-16h toward human topoisomerase I/IIα is evaluated, and 9-phenylbutyl acridine 16h is found to inhibit human topoisomerase IIα at concentrations as low as 5 μm. Acridines 16a-16h are also subjected to in vitro screening against selected cancer cell lines; the most potent anticancer activity is observed against melanoma A2058 cell lines at IC50 values ranging from 3 to 6 μm.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500267"},"PeriodicalIF":3.6,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AMPK Activation by 2'-Hydroxy-2,4,5-Trimethoxychalcone Derivatives in Podocyte Cells. 2'-羟基-2,4,5-三甲氧基查尔酮衍生物对足细胞AMPK的激活作用。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-24 DOI: 10.1002/cmdc.202500177

Vu-Duy Nguyen, Chatchai Muanprasat, Suchada Kaewin, Wanangkan Poolsri, Warinthorn Chavasiri

{"title":"AMPK Activation by 2'-Hydroxy-2,4,5-Trimethoxychalcone Derivatives in Podocyte Cells.","authors":"Vu-Duy Nguyen, Chatchai Muanprasat, Suchada Kaewin, Wanangkan Poolsri, Warinthorn Chavasiri","doi":"10.1002/cmdc.202500177","DOIUrl":"10.1002/cmdc.202500177","url":null,"abstract":"Activating AMP-activated protein kinase (AMPK) using chalcones has emerged as a potential therapeutic strategy for managing diabetes mellitus (DM) and diabetic nephropathy. This research focuses on discovering new chalcone derivatives with a stronger ability to stimulate AMPK in podocytes compared to 2'-hydroxychalcones 1, 2, and 3 reported from the earlier research. The results show that hydrogenated products (4-6) cannot exhibit considerably improved activity. Additionally, 2'-hydroxychalcone bearing 2,4,5-triethoxy groups on the B-ring (10) and 2,4,5-trimethoxychalcones bearing 2',4'-, 2',5'-, or 2',6'-dimethoxy groups on the A-ring (17-19) demonstrate potent AMPK activation with fold changes of 2.69, 2.36, 3.22, and 2.17, respectively, surpassing both the reference compound 1 (1.28) and metformin (1.88). The structure-activity relationship shows that inserting dimethoxy groups on the A-ring can strengthen the activity better than without inserting any group or inserting other moieties such as hydroxy, methylenedioxy, amino, trifluoromethyl, bromo, acetyl, 2,3-dihydro-1,4-dioxin ring, and benzene ring. Notably, 2,4,5-trimethoxychalcone 23 possessing 2',4',5'-trimethoxy groups, bis-chalcones 35 and 36, and tris-chalcone 37 is poorly soluble in the experiments. Compound 18 exhibits more potent activity than compounds 2 and 3 (2.48 and 2.73, respectively); therefore, it would be a promising candidate for further studies on AMPK-stimulating activity.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500177"},"PeriodicalIF":3.6,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis and Bio-evaluation of Quaternized Fused-β-carbolines as anti-MRSA agents. 季铵化融合β-碳胺抗mrsa药物的合成及生物评价。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-21 DOI: 10.1002/cmdc.202500326

Adilakshmi Vutla, Deepanshi Saxena, Rahul Maitra, Sidharth Chopra, Sanjay Batra

引用次数: 0