IF 3.6 4区医学

ChemMedChem Pub Date : 2025-06-12 DOI: 10.1002/cmdc.202500154

Matteo Lusardi, Nicoletta Basilico, Erika Iervasi, Chiara Brullo, Silvia Parapini, Marco Ponassi, Camillo Rosano, Andrea Spallarossa

引用次数: 0

Design, Synthesis, and Biological Evaluation of Evodiamine Derivatives as Antibody-Drug Conjugate (ADC) Payloads. evoloo二胺衍生物作为抗体-药物偶联物（ADC）有效载荷的设计、合成和生物学评价。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-06-05 DOI: 10.1002/cmdc.202500268

Ruifeng Liu, Yanfang Duan, Jing Jiang, Weihua Bian, Meiying Zhu

{"title":"Design, Synthesis, and Biological Evaluation of Evodiamine Derivatives as Antibody-Drug Conjugate (ADC) Payloads.","authors":"Ruifeng Liu, Yanfang Duan, Jing Jiang, Weihua Bian, Meiying Zhu","doi":"10.1002/cmdc.202500268","DOIUrl":"https://doi.org/10.1002/cmdc.202500268","url":null,"abstract":"Natural product evodiamine derivatives exhibit multitarget bioactivities as dual TOPO I/II inhibitors, demonstrating remarkable potential in antitumor applications. Based on the evodiamine derivative D7-03, six derivatives were synthesized. In vitro screening showed that D7-09 had the strongest anti-tumor activity (IC50 = 9.75-26.11 nM) but poor hydrophobicity and solubility. D7-03, with nM-level cytotoxicity, better physicochemical properties, and high yield, was chosen as the core payload for ADC construction. The active molecule D7-03 was further explored as an antibody-drug conjugate (ADC) payload by constructing four linker-toxin complexes. These complexes were conjugated with trastuzumab to generate ADC candidate molecules. Notably, Ab-DL07-D7-03 exhibited superior activity (IC50 = 8.369 nM and 4.899 nM in HCC1954 and NCI-N87 cells, respectively) compared to the control group Ab-LC08-SN38. This study is the first application of evodiamine derivatives as TOPO I / II dual inhibitors in the ADC field, which not only provides a new strategy for the development of ADC payloads but also enriches the innovative application of natural product small molecules in tumor-targeted therapy.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500268"},"PeriodicalIF":3.6,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232804","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

Platinum N-Heterocyclic Carbene Complexes Based on Adenosine: Synthesis and Antiproliferative Studies. 基于腺苷的铂n -杂环卡宾配合物：合成及抗增殖研究。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-06-04 DOI: 10.1002/cmdc.202500368

Ana Petronilho, Claudia Nunes, Giulia Orsini, Andreia Marinho

引用次数: 0

Tetrahydrofuran-containing Pharmaceuticals: Targets, Pharmacological Activities, and Their SAR Studies. 含四氢呋喃的药物：靶点、药理活性及其SAR研究。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-06-04 DOI: 10.1002/cmdc.202500259

Yiou Mei, Yunfei Du

引用次数: 0

Front Cover: Carborane-Based Analogs of Celecoxib and Flurbiprofen, their COX Inhibition Potential, and COX Selectivity Index (ChemMedChem 11/2025) 封面：塞来昔布和氟比洛芬的碳硼烷类类似物，它们的COX抑制潜能和COX选择性指数（ChemMedChem 11/2025）

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-06-03 DOI: 10.1002/cmdc.202581101

Lea Ueberham, Jonas Schädlich, Kim Schramke, Sebastian Braun, Christoph Selg, Markus Laube, Peter Lönnecke, Jens Pietzsch, Evamarie Hey-Hawkins

引用次数: 0

Novel 4,5-Dihydrothiazole-phenylpiperazine Derivatives: Synthesis, Docking Studies and Pharmacological Evaluation as Serotonergic Agents. 新型4,5-二氢噻唑-苯哌嗪衍生物：合成、对接研究及作为血清素能剂的药理评价。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-06-03 DOI: 10.1002/cmdc.202500288

Giorgia Andreozzi, Natalia Karkoszka, Rosa Sparaco, Angela Corvino, Beatrice Severino, Vincenzo Santagada, Elisa Magli, Ewa Gibuła-Tarłowska, Jolanta H Kotlińska, Kinga Gawel, Raffaele Capasso, Anna Lesniak, Nataliia Semenko, Agnieszka A Kaczor, Anna Bielenica, Grażyna Biała, Giuseppe Caliendo, Ewa Kędzierska, Ferdinando Fiorino

{"title":"Novel 4,5-Dihydrothiazole-phenylpiperazine Derivatives: Synthesis, Docking Studies and Pharmacological Evaluation as Serotonergic Agents.","authors":"Giorgia Andreozzi, Natalia Karkoszka, Rosa Sparaco, Angela Corvino, Beatrice Severino, Vincenzo Santagada, Elisa Magli, Ewa Gibuła-Tarłowska, Jolanta H Kotlińska, Kinga Gawel, Raffaele Capasso, Anna Lesniak, Nataliia Semenko, Agnieszka A Kaczor, Anna Bielenica, Grażyna Biała, Giuseppe Caliendo, Ewa Kędzierska, Ferdinando Fiorino","doi":"10.1002/cmdc.202500288","DOIUrl":"https://doi.org/10.1002/cmdc.202500288","url":null,"abstract":"We have described the synthesis of a new series of LCAPs (long-chain arylpiperazine) as serotoninergic ligands (FG 1-18). The combination of structural elements including heterocyclic nucleus, propyl chain and 4,5-dihydrothiazol-2-ylphenylpiperazines, led to the preparation of different derivatives tested for their affinity toward 5-HT1A, 5-HT2A and 5-HT2C receptors. The compounds with better affinity and selectivity binding profiles towards 5-HT1A and 5-HT2C (FG-1, FG-4, FG-5, FG-6, FG-7, FG-8 and FG-18) were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of pharmacological studies showed that compounds FG-1, FG-5, FG-8 and FG-6 exerted antidepressant-like effects and FG-1, FG-18, FG-6 and FG-7 revealed also significant anxiolytic properties. Among the developed derivatives, the most promising compounds seems to be FG-1 which exhibited antidepressant, anxiolytic and anticonvulsant properties, FG-7 and FG-18 which showed features as anxiolytic combine to a pro-cognitive property and notable affinity and selectivity for 5-HT2C receptor, respectively.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500288"},"PeriodicalIF":3.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207262","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

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":"https://doi.org/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. In this work we report on the synthesis of 56 novel Pitstop 2 analogues via four discrete focused libraries. Specific modification to the 4-bromonenzylidene moiety were explored, and their ability to inhibit the NTD-PPI interaction examined by an ELISA. In cell endocytosis effects were measured for select analogues as was the inhibition of dynamin, another protein involved in the endocytosis process. The most NTD-PPI active analogues retained 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 a NTD-PPI IC50 = 1.16 μM. The corresponding benzo[d][1,3]dioxole (53) was 3-fold less active suggesting ring size preference at this position. Nine analogues showed improved or comparable NTD-PPI activity to Pitstop 2 with IC50 values from 0.94 - 2.1 µM. Heterocyclic analogues were 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 in cell active inhibitors of clathrin mediated endocytosis yet reported.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500321"},"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 Anti-Cancer 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 Anti-Cancer 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":"https://doi.org/10.1002/cmdc.202500143","url":null,"abstract":"Flavones, recognized as \"privileged scaffolds\" in drug discovery, hold significant promise as anti-cancer agents. This study aimed to develop a quantitative structure-activity relationship (QSAR) model to accelerate the optimization of lead compounds. Using pharmacophore modeling against three cancer targets (PI3K, Tankyrases, and CDK-6), 89 flavone analogs were designed and synthesized with varied substitution patterns to explore potency and selectivity. Biological evaluation identified promising candidates with enhanced cytotoxicity against MCF-7 and HepG2 cells while demonstrating reduced toxicity towards normal Vero cells. A machine learning (ML)-driven QSAR approach was employed to correlate structural features with inhibitory activity. Three ML models-random forest (RF), extreme gradient boosting (XGB), and artificial neural network (ANN)-were developed and compared. The RF model exhibited 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 RMSEtest values of 0.573 (MCF-7) and 0.563 (HepG2), demonstrating model robustness. SHAP analysis identified critical molecular descriptors influencing anti-cancer activity, offering insights into key structural features. This study presents a robust QSAR model as a valuable tool for the rational design and development of potent flavone-based anti-cancer agents, contributing to the advancement of targeted cancer therapies.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500143"},"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 Vadukoot, Corey R Hopkins

引用次数: 0

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