ChemMedChem最新文献_第4页

Investigating the Mechanism of Antimycobacterial and Antiproliferative Activity of (E)-N’-Benzylidenepyrazine-2-Carbohydrazides and their Derivatives (E)-N′-苄基哌嗪-2-碳酰肼及其衍生物的抑菌和抗增殖作用机制研究。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-08-29 DOI: 10.1002/cmdc.202500085

Priam-Amedeo Houngbedji, Daria Elżbieta Nawrot, Ondřej Janďourek, Klára Konečná, Martin Novák, Pavla Paterová, Pavel Bárta, Martina Hrast Rambaher, Eva Novotná, Carlo Castellano, Matteo Mori, Fiorella Meneghetti, Monika Záhorszká, Jana Korduláková, Jan Zitko

{"title":"Investigating the Mechanism of Antimycobacterial and Antiproliferative Activity of (E)-N’-Benzylidenepyrazine-2-Carbohydrazides and their Derivatives","authors":"Priam-Amedeo Houngbedji, Daria Elżbieta Nawrot, Ondřej Janďourek, Klára Konečná, Martin Novák, Pavla Paterová, Pavel Bárta, Martina Hrast Rambaher, Eva Novotná, Carlo Castellano, Matteo Mori, Fiorella Meneghetti, Monika Záhorszká, Jana Korduláková, Jan Zitko","doi":"10.1002/cmdc.202500085","DOIUrl":"10.1002/cmdc.202500085","url":null,"abstract":"A series of 33 (E)-N’-benzylidenepyrazine-2-carbohydrazides and their derivatives were synthesized and tested for biological activity. Benzylidene derivatives with 2-OH substitution on the phenyl ring (18: R = 2-OH, 21: R = 2,3-diOH, and 22: R = 2,4-diOH) exhibit various biological activities. Compounds 18 and 21 demonstrate antimycobacterial activity against Mycobacterium tuberculosis H37Ra, M. tuberculosis H37Rv, and M. aurum, with minimum inhibitory concentration values ranging from 15.625 to 62.5 μg mL−1. Compounds 18, 21, and 22 show mild cytotoxicity on several human cell lines (IC50 ranging from 70.2 to 500 μM). Crystallographic studies confirm the (E)-configuration of compound 18 and a nearly planar molecular conformation. Due to their structural similarity with salicylaldehyde isonicotinoyl hydrazone (SIH), a known iron chelator, selected compounds were tested for iron-chelating properties, revealing comparable or superior activity. Mechanistic assays targeting enoyl-[acyl carrier protein] reductase (InhA), isocitrate lyase (ICL), and lipid/mycolic acid biosynthesis show no significant inhibition, suggesting a nonspecific mechanism potentially linked to iron chelation. A correlation is observed between chelating activity and cytotoxicity, while antimycobacterial activity appears to involve additional mechanisms. Pharmacokinetic studies with compound 18 reveal no specific plasma metabolites, and no significant metabolites are detected after incubation with human liver microsomes.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 18","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202500085","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of Pyrazolo[1, 5-a]pyrimidine-Based Selective HDAC6 Inhibitors with Broad-Spectrum Antiproliferative Activity. 具有广谱抗增殖活性的吡唑啉[1,5 -a]嘧啶选择性HDAC6抑制剂的发现。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-08-29 DOI: 10.1002/cmdc.202500322

Wendeng Li, Chunhong Ma, Changchun Ye, Xiaoya Chen, Shiyuan Liu, Zilu Chen, Xin Chen, Zhengshui Xu

引用次数: 0

Multifunctional Responsive Gas-Releasing Metal Organic Framework Nanoplatform for Tumor Therapy Application. 多功能响应气体释放金属有机框架纳米平台在肿瘤治疗中的应用。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-08-28 DOI: 10.1002/cmdc.202500602

Yue Meng, Jing Lu, Xiangwei Liu, Ruixuan Liu, Ding Dai, Yuan Sun, Tiedong Sun

{"title":"Multifunctional Responsive Gas-Releasing Metal Organic Framework Nanoplatform for Tumor Therapy Application.","authors":"Yue Meng, Jing Lu, Xiangwei Liu, Ruixuan Liu, Ding Dai, Yuan Sun, Tiedong Sun","doi":"10.1002/cmdc.202500602","DOIUrl":"https://doi.org/10.1002/cmdc.202500602","url":null,"abstract":"Gas therapy (GT), which regulates the tumor microenvironment by releasing therapeutic gas molecules (e.g., O2, NO), has taken an innovative direction in tumor therapy. However, conventional gas-releasing molecules (GRMs) suffer from core problems such as uncontrollable release, poor targeting, and insufficient stability. To address these challenges, nanoplatforms represented by metal-organic frameworks (MOFs) offer an innovative solution. MOFs, with their high specific surface area, tunable porosity, and abundant active sites, are able to significantly enhance the storage and release efficiency of gases. In particular, the high specific surface area and porosity of MOFs enable efficient loading of therapeutic gases and targeted release of gases through precise regulation of porosity; their abundant active sites enhance the stability and controllability of gas release. This review focuses on the preparation and modulation of MOF, systematically describes the advantages of MOF-based GRM nanoplatforms in the efficient loading and responsive release of therapeutic gases, such as oxygen (O2), nitric oxide (NO), and hydrogen (H2), and summarizes their recent progress in the field of GT for tumor treatment. Finally, the challenges and future perspectives of GT- and MOF-based GRM nanoplatforms are discussed to provide more effective and safer therapeutic strategies for clinical applications.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500602"},"PeriodicalIF":3.4,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937210","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

Cytotoxicity of Atropisomeric [1,1'-Binaphthalene]-2,2'-Diamines (BINAM) and Analogs in Human Cancer Cells: Enantioselectivity, Structure-Activity Relationships, and Mechanism. atropisomer[1,1'-对萘]-2,2'-二胺（BINAM）及其类似物在人癌细胞中的细胞毒性：对映体选择性、构效关系及机制

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-08-27 DOI: 10.1002/cmdc.202500426

Malte Eichelbaum, Patrick J Bednarski

{"title":"Cytotoxicity of Atropisomeric [1,1'-Binaphthalene]-2,2'-Diamines (BINAM) and Analogs in Human Cancer Cells: Enantioselectivity, Structure-Activity Relationships, and Mechanism.","authors":"Malte Eichelbaum, Patrick J Bednarski","doi":"10.1002/cmdc.202500426","DOIUrl":"https://doi.org/10.1002/cmdc.202500426","url":null,"abstract":"Binaphthyls usually serve as key chiral ligands in catalysts for asymmetric syntheses, having been reported in thousands of published reactions. Herein, the discovery that atropisomeric (R)-[1,1'-binaphthalene]-2,2'-diamine (R-BINAM, 1(R)) is a moderately potent spindle poison, causing antiproliferation, depolymerization of microtubules, multipolar spindles, pericentriolar material (PCM) fragmentation, mitotic catastrophe, multinucleated cells, and apoptosis in cancer and normal human cell lines, is reported. Furthermore, the resulting abnormalities resemble those induced by microtubule-depolymerizing agents (MDAs) such as colchicine. In contrast, the enantiomer S-BINAM (1(S)) was inactive in all biological assays. Additionally, the structure-activity relationships of a selection of R- and S-BINAM derivatives with key structural differences have been studied; these studies show the same enantiomeric trend as with R-BINAM and provide insight into the structural requirements for the antiproliferative activity of this compound class. These findings should be useful for the development of more selective spindle poisons, especially due to the natural rigidity of binaphthyls and their scaffold that allows for various modifications.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500426"},"PeriodicalIF":3.4,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937254","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

Quantum Osteoimmunology: A Paradigm Shift in Understanding and Influencing Bone-Immune Crosstalk. 量子骨免疫学：理解和影响骨免疫串扰的范式转变。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-08-27 DOI: 10.1002/cmdc.202500307

Rachel Wei Li, Sara Alzaanin, Zongyou Yin, Paul N Smith

{"title":"Quantum Osteoimmunology: A Paradigm Shift in Understanding and Influencing Bone-Immune Crosstalk.","authors":"Rachel Wei Li, Sara Alzaanin, Zongyou Yin, Paul N Smith","doi":"10.1002/cmdc.202500307","DOIUrl":"https://doi.org/10.1002/cmdc.202500307","url":null,"abstract":"Despite significant advancesin osteoimmunology, the mechanistic underpinnings of immune-skeletal crosstalk remain insufficiently characterized, particularly at the molecular and submolecular scales. The present article introduces quantum osteoimmunology as a novel field of research exploring how quantum mechanical phenomena, such as coherence, tunneling, entanglement, and wavefunction superposition, may influence osteoimmune signaling dynamics. It argues that the current deterministic, temporally linear models of immune activation may overlook the probabilistic and non-linear nature of molecular events governed by quantum principles. Integrating quantum principles into osteoimmune research could offer new explanatory models for unresolved questions in bone-immune physiology and pathology. In parallel, the unique photophysical characteristics of quantum nanomaterials, such as size-tunable emission spectra, high quantum yields, and photostability, present unprecedented opportunities for high-resolution biomarker detection, enabling real-time, ultrasensitive diagnostics for osteoimmune pathologies. Moreover, these materials exhibit significant potential for the development of traceable, precision-targeted therapeutic delivery systems, as well as for high-resolution in vitro and in vivo bioimaging applications. Ultimately, quantum mechanics holds the potential to revolutionize osteoimmunology-conceptually, by reshaping one's understanding of immune-skeletal interactions at the subatomic level; and practically, by driving innovations in diagnostics, targeted therapeutics, and real-time molecular imaging.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500307"},"PeriodicalIF":3.4,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937268","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

Design and Synthesis of Sulfonium and Selenonium Derivatives Bearing 3',5'-O-Benzylidene Acetal Side Chains as Potent α-Glucosidase Inhibitors. 具有3′，5′-邻苯并缩醛侧链的α-葡萄糖苷酶抑制剂磺酸和硒衍生物的设计与合成。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-08-25 DOI: 10.1002/cmdc.202500299

Yaojia Li, Jiahui Zhou, Xiaoxing Wu, Wei Li, Zhe Wang, Jianchen Yang, Genzoh Tanabe, Osamu Muraoka, Weijia Xie

{"title":"Design and Synthesis of Sulfonium and Selenonium Derivatives Bearing 3',5'-O-Benzylidene Acetal Side Chains as Potent α-Glucosidase Inhibitors.","authors":"Yaojia Li, Jiahui Zhou, Xiaoxing Wu, Wei Li, Zhe Wang, Jianchen Yang, Genzoh Tanabe, Osamu Muraoka, Weijia Xie","doi":"10.1002/cmdc.202500299","DOIUrl":"https://doi.org/10.1002/cmdc.202500299","url":null,"abstract":"A series of sulfonium, selenonium, and ammonium salts featuring diverse benzylidene acetal side chain substituents are designed and synthesized. In contrast to the previous work, this study emphasized stereochemical inversion at the 3'-position and bioisosteric replacements at the sulfonium cationic center. In vitro α-glucosidase inhibition assays identified 20b, 20l, and 21b as potent inhibitors. In vivo, 20b (15.0 mg kg-1) reduced postprandial blood glucose levels in sucrose-loaded mice by 40.6% (15 min), 49.5% (30 min), and 43.6% (60 min), surpassing acarbose (20.0 mg kg- 1). Molecular docking of 20b with the N-terminal subunit of Maltase-Glucoamylase (ntMGAM) revealed an identical binding mode, where 3'-stereoinversion induced π-π stacking between the benzylidene acetal phenyl ring and Phe450 and electrostatic interactions between the ortho-nitro group and Asp203. Cytotoxicity assessments confirmed the favorable safety profile of selected compounds in normal cell lines. Enzyme kinetic studies demonstrated fully competitive inhibition of α-glucosidase by these sulfonium salts.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500299"},"PeriodicalIF":3.4,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937201","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

Novel Pyrazolo [1,5-a]-1,3,5-Triazine Derivatives as CDK7 Inhibitors: Synthesis and Biological Insights in Pancreatic Ductal Adenocarcinoma Models. 新型吡唑啉[1,5-a]-1,3,5-三嗪衍生物作为CDK7抑制剂：合成及其在胰腺导管腺癌模型中的生物学意义。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-08-25 DOI: 10.1002/cmdc.202500448

Daniela Carbone, Francesca Terrana, Ludovica Sciuto, Camilla Pecoraro, Geng Xu, Stella Cascioferro, Girolamo Cirrincione, Godefridus J Peters, Elisa Giovannetti, Barbara Parrino, Patrizia Diana

{"title":"Novel Pyrazolo [1,5-a]-1,3,5-Triazine Derivatives as CDK7 Inhibitors: Synthesis and Biological Insights in Pancreatic Ductal Adenocarcinoma Models.","authors":"Daniela Carbone, Francesca Terrana, Ludovica Sciuto, Camilla Pecoraro, Geng Xu, Stella Cascioferro, Girolamo Cirrincione, Godefridus J Peters, Elisa Giovannetti, Barbara Parrino, Patrizia Diana","doi":"10.1002/cmdc.202500448","DOIUrl":"https://doi.org/10.1002/cmdc.202500448","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC), the most prevalent form of pancreatic tumor, is one of the most aggressive and lethal tumor types. Cyclin-dependent kinase 7 (CDK7) has been recently identified as a promising target in multiple human and mouse PDAC preclinical tumor models, due to significant downregulation of gene transcription and preferential inhibition of the mitotic cell cycle. With the aim of finding new CDK7 inhibitors, new indolyl and 7-aza-indolyl pyrazolo [1,5-a]-1,3,5-triazine derivatives are efficiently synthesized and screened for antiproliferative activity against three immortalized cell lines (SUIT 2.28, PATU-T, PANC-1) of PDAC. 8 out of 33 derivatives show remarkable cytotoxicity with IC50 values ranging from 0.19 to 1.58 µM and remarkable inhibition of cell migration from the earliest time point of 4 h, persisting until 24 h. The two most active compounds are further evaluated in clinically relevant models,including gemcitabine-resistant and primary cells (PATU-T GR, PDAC3), confirming their potent activity. They induce apoptosis, upregulate apoptotic gene expression, and disrupt the cell cycle, significantly reducing the viability of spheroidal PATU-T cultures. Additionally, both compounds effectively inhibit CDK7, as demonstrated by an enzyme-linked immunosorbent assay in cell extracts and by a specific enzymatic activity assay.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500448"},"PeriodicalIF":3.4,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937265","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

A Warm Welcome to MedChem: The Frontiers in Medicinal Chemistry 2025 热烈欢迎参加MedChem：药物化学前沿2025。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-08-25 DOI: 10.1002/cmdc.202500609

Matthias Schiedel, Marta Pinto, Andrea Unzue Lopez, Philipp Barbie, Felix Pape, Anika Tarasewicz, Gerhard Hessler, Peter Gmeiner, Christina Lamers, Matthias Gehringer

引用次数: 0

Covalent Conjugation Strategies for Antifungal Agents: Synthetic Approaches and Therapeutic Potential. 抗真菌药物的共价偶联策略：合成方法和治疗潜力。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-08-25 DOI: 10.1002/cmdc.202500403

Andrzej S Skwarecki, Marta Skwarecka

引用次数: 0

Towards the Use of Metabolic Volatiles in Breath for Determining Drug Response: Gstachamine as an Unlabeled Substrate to Measure CYP3A4 Activity 呼气中代谢挥发物测定药物反应的研究：gstacamine作为未标记底物测量CYP3A4活性

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-08-25 DOI: 10.1002/cmdc.202500492

Valentina Stock, Rebecca Hofer, Klaus R. Liedl, Jakob Troppmair, Thierry Langer, Hubert Gstach, Christian Dank, Sarah Kammerer, Veronika Ruzsanyi

{"title":"Towards the Use of Metabolic Volatiles in Breath for Determining Drug Response: Gstachamine as an Unlabeled Substrate to Measure CYP3A4 Activity","authors":"Valentina Stock, Rebecca Hofer, Klaus R. Liedl, Jakob Troppmair, Thierry Langer, Hubert Gstach, Christian Dank, Sarah Kammerer, Veronika Ruzsanyi","doi":"10.1002/cmdc.202500492","DOIUrl":"10.1002/cmdc.202500492","url":null,"abstract":"Breath analysis is a promising noninvasive diagnostic tool, but the clinical applicability of breath tests depends on several factors. A salient criterion pertains to the presence of substrates with the ability to produce detectable volatile metabolites during the metabolism. In this work, we evaluated the potential of two candidate compounds, namely gstachidine and gstachamine, for their use in metabolic breath analysis. Both substrates were evaluated for their toxicity and metabolic conversion in HepG2 cell clones overexpressing CYP3A4. Gstachidine was found to be toxic and did not produce any volatile metabolite. In contrast, gstachamine successfully generated butanone as a volatile metabolite, making it the first substrate to yield a stable VOC detectable exclusively at low ppbV levels in breath. To characterize its biotransformation, we conducted time-dependent analyses, as well as CYP specificity, toxicity, and inhibition investigations regarding the production of N-dealkylated gstachamine or butanone. The results demonstrated that gstachamine had a high metabolic turnover and a strong CYP3A4-dependency in the production of the specific N-dealkylated metabolite. Furthermore, a substantial reduction in the production of both metabolites was observed in HepG2-CYP3A4 cells following treatment with CYP inhibitors 1-aminobenzotriazole or ketoconazole. The results suggest that gstachamine has potential for noninvasive CYP3A4 metabolism monitoring.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 18","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202500492","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0