ChemMedChem最新文献_第7页

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

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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}

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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

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Reaction of N-Ferrocenylcarbamates with Nitric Oxide: An Application for Detection of Inflammatory Sites In Vivo n -二茂铁氨基甲酸酯与一氧化氮的反应：在体内检测炎症部位的应用。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-08-22 DOI: 10.1002/cmdc.202500356

Roman Selin, Hülya Gizem Özkan, Galyna Bila, Rostyslav Bilyy, Andriy Mokhir

{"title":"Reaction of N-Ferrocenylcarbamates with Nitric Oxide: An Application for Detection of Inflammatory Sites In Vivo","authors":"Roman Selin, Hülya Gizem Özkan, Galyna Bila, Rostyslav Bilyy, Andriy Mokhir","doi":"10.1002/cmdc.202500356","DOIUrl":"10.1002/cmdc.202500356","url":null,"abstract":"Electron-deficient aminoferrocenes (edAFs) exhibit anticancer activity both in vitro and in vivo. However, their mechanism of action remains unclear. Studies using fluorogenic edAF derivatives suggest that the ferrocenyl moiety undergoes oxidation or decomposition within cells, resulting in the formation of unknown products. Interestingly, this process is not significantly facilitated by H2O2, indicating that this intracellular oxidant does not alter edAFs in the cellular environment. To identify alternative endogenous oxidants, NO is investigated as a potential candidate. Under aerobic conditions, NO is found to efficiently induce the oxidation and decomposition of edAFs. This transformation is mediated by an electrophilic nitrosation reaction, followed by nitroso-oxime tautomerism and subsequent degradation of the ferrocenyl moiety with the release of ligand-derived oxime 7 and iron ions. These findings suggest that NO may play a key role in the intracellular modification of edAFs, potentially contributing to their anticancer activity or their metabolism or both. Building on this mechanism, an effective probe is developed for detecting NO in living cells and identifying sites of inflammation in vivo. These probes are based on a modular design that enables facile substitution of the fluorescent dye, allowing straightforward customization for diverse applications both in cellulo and in vivo.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 19","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202500356","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937245","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

C1′-Branched Acyclic Nucleoside Phosphonates as Inhibitors of Plasmodium Falciparum 6-Oxopurine Phosphoribosyltransferase C1'-支链无环核苷膦酸盐作为恶性疟原虫6-氧嘌呤磷酸核糖基转移酶的抑制剂

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-08-22 DOI: 10.1002/cmdc.202500575

Jan Frydrych, Dianne T. Keough, Haojun Xia, Lenka Poštová Slavětínská, Martin Dračínský, Michal Česnek, Jye Travis, Marina Chavchich, Michael Edstein, Dana Hocková, Luke W. Guddat, Zlatko Janeba

{"title":"C1′-Branched Acyclic Nucleoside Phosphonates as Inhibitors of Plasmodium Falciparum 6-Oxopurine Phosphoribosyltransferase","authors":"Jan Frydrych, Dianne T. Keough, Haojun Xia, Lenka Poštová Slavětínská, Martin Dračínský, Michal Česnek, Jye Travis, Marina Chavchich, Michael Edstein, Dana Hocková, Luke W. Guddat, Zlatko Janeba","doi":"10.1002/cmdc.202500575","DOIUrl":"10.1002/cmdc.202500575","url":null,"abstract":"Hypoxanthine-guanine-(xanthine) phosphoribosyltransferase [HG(X)PRT] is an excellent target for the development of new drugs to treat parasitic and bacterial infections as well as MYC-dependent triple-negative breast cancer. Inhibitors include compounds that mimic the transition state of the catalytic reaction and analogs of the two products of the reaction, the nucleoside monophosphates and pyrophosphate. One type of chemistry explored here is the design of purine-based C1′-branched acyclic nucleoside phosphonates bearing diverse structural attachments (secondary linkers) on the C1′ atom. Compounds where this secondary linker has either a terminal phosphonate or a hydroxyl group are submicromolar to single-digit micromolar inhibitors of human hypoxanthine-guanine phosphoribosyltransferase and Plasmodium falciparum HGXPRT. The lowest Ki values for two of these inhibitors are 0.7 µM for the human enzyme and 0.4 µM for the parasite enzyme. The Ki values of the prepared derivatives, however, cover a wide range and depend on the chemical structure of the attachment at the C1′ atom. A phosphonodiamidate prodrug of one of the compounds has an IC50 of 4.3 µM against a drug-sensitive strain of Plasmodium falciparum grown in human erythrocytes, showing in vitro activity and the merit of these new inhibitors as potential drug leads.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 19","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202500575","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937243","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

Exploration of the Tertiary Amide Chemical Space of Dolastatin 15 Analogs Reveals New Insights into the Structure–Anticancer Activity Relationship Dolastatin 15类似物叔胺化学空间的探索揭示了结构-抗癌活性关系的新见解。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-08-22 DOI: 10.1002/cmdc.202500580

Dayana Alonso, Leslie Reguera, Robert Rennert, Ibrahim Morgan, Mohammed Saoud, Manuel G. Ricardo, Leslie Valdés, Julieta Coro-Bermello, Ludger A. Wessjohann, Daniel G. Rivera

{"title":"Exploration of the Tertiary Amide Chemical Space of Dolastatin 15 Analogs Reveals New Insights into the Structure–Anticancer Activity Relationship","authors":"Dayana Alonso, Leslie Reguera, Robert Rennert, Ibrahim Morgan, Mohammed Saoud, Manuel G. Ricardo, Leslie Valdés, Julieta Coro-Bermello, Ludger A. Wessjohann, Daniel G. Rivera","doi":"10.1002/cmdc.202500580","DOIUrl":"10.1002/cmdc.202500580","url":null,"abstract":"Dolastatins are a class of naturally occurring antimitotic peptides that have inspired the development of some of the most active and widely used anticancer agents. Here, we report on the development of synthetic methodologies for the preparation of parallel libraries of small peptides inspired by dolastatin 15 and its analogs cemadotin and tasidotin. The approaches rely on the use of either one or multiple Ugi-multicomponent reactions to generate amide N-substituted dolastatin-like skeletons, which allow the exploration of tertiary amide chemical spaces that have not been assessed previously. Evaluation of the anticancer activity in a variety of cancer cells showed that introducing a tertiary amide at the C-terminal fragment or by replacement of a proline residue does not lead to an increment in the anti-proliferative activity. The microtubule-disrupting capacity of the new dolastatin analogs was studied and compared with other potent antimitotic agents, thereby shedding light on mechanistic details of their anti-proliferative activity.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 19","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202500580","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937211","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

Design and Synthesis of Potent Ridaifen Analogues: Evaluation as Anticancer, 20S Proteasomal Inhibitors, and Antiebola Virus Agents through In vitro and In Silico Studies 高效利替芬类似物的设计和合成：通过体外和计算机研究评价其作为抗癌、20S蛋白酶体抑制剂和抗埃博拉病毒药物的作用。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-08-21 DOI: 10.1002/cmdc.202500451

Merna A. Vector, Sae Fujiwara, Yunhao Zhu, Makoto Hasegawa, Takatsugu Murata, Kaho Tsuchiya, Isamu Shiina, Ashraf H. Abadi, Nermin S. Ahmed

{"title":"Design and Synthesis of Potent Ridaifen Analogues: Evaluation as Anticancer, 20S Proteasomal Inhibitors, and Antiebola Virus Agents through In vitro and In Silico Studies","authors":"Merna A. Vector, Sae Fujiwara, Yunhao Zhu, Makoto Hasegawa, Takatsugu Murata, Kaho Tsuchiya, Isamu Shiina, Ashraf H. Abadi, Nermin S. Ahmed","doi":"10.1002/cmdc.202500451","DOIUrl":"10.1002/cmdc.202500451","url":null,"abstract":"Ridaifen (RID) analogues are identified as nonpeptide, noncovalent inhibitors of the catalytic subunits of the human 20S proteasome. They demonstrated effectiveness against both multiple myeloma and solid tumors. Herein, the synthesis and biological evaluation of 20 novel RID analogs that exhibit inhibitory effects on the three catalytic subunits of the 20S proteasome are reported. All the compounds were tested on the National Cancer Institute (NCI) 60 cancerous cell lines. The compounds bear symmetric aminoalkoxy groups on rings B and C, different substituents on ring A, and the terminal side chain on the ethylene backbone was modified to methyl and cyclopentyl groups.Compound 43 was the most potent inhibitor for both CT-L and PGPH (IC50 = 0.22, 0.05 μM), which is threefold more potent for CT-L and tenfold more potent on PGPH than RID-F. Most of the analogs showed pan activity toward different cancer cell lines, and compound 20 was more potent than tamoxifen. Compound 20 showed submicromolar IC50 values for CT-L and PGPH activities, indicating that it mediates its cytotoxic activity via proteasomal inhibition. Selected compounds were tested against Ebolavirus, and compound 36 showed the highest antiviral activity, surpassing the EC50 of the reference compound favipiravir.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 18","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937252","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

Modified Nucleotides in Bifunctional Antisense Oligonucleotides: Exploring their Anticancer Potential 双功能反义寡核苷酸中的修饰核苷酸：探索其抗癌潜力。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-08-21 DOI: 10.1002/cmdc.202500220

Natalia Bartyś, Anna Pasternak, Jolanta Lisowiec-Wąchnicka

引用次数: 0

Front Cover: Inhibition of the Clathrin Terminal Domain—Amphiphysin Protein–Protein Interaction. Probing the Pitstop 2 Aromatic Moiety (ChemMedChem 16/2025) 封面：网格蛋白末端结构域- amphiphysin蛋白-蛋白相互作用的抑制。探测Pitstop 2芳香部分（ChemMedChem 16/2025）

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-08-21 DOI: 10.1002/cmdc.70019

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

引用次数: 0

Development of a Tumor Microenvironment-Responsive Co(III)-Chrysin Prodrug: Synthesis, Activation Profiling, and In Vitro Antineoplastic Evaluation 肿瘤微环境响应型Co(III)-Chrysin前药的开发：合成、激活分析和体外抗肿瘤评价。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-08-20 DOI: 10.1002/cmdc.202500232

Prakash Shukla, Krishna Kanta Choudhury, Kajol, Subhrata Behera, Janhabi Panigrahy, Rakesh Kumar Pathak

{"title":"Development of a Tumor Microenvironment-Responsive Co(III)-Chrysin Prodrug: Synthesis, Activation Profiling, and In Vitro Antineoplastic Evaluation","authors":"Prakash Shukla, Krishna Kanta Choudhury,  Kajol, Subhrata Behera, Janhabi Panigrahy, Rakesh Kumar Pathak","doi":"10.1002/cmdc.202500232","DOIUrl":"10.1002/cmdc.202500232","url":null,"abstract":"Chrysin, a bioactive flavonoid with significant anticancer potential, is limited by its nonspecific toxicity and poor targetability. To overcome these challenges, we developed a cobalt(III)-chrysin prodrug (CCP) designed for selective activation in the hypoxic and reducing tumor microenvironment. The CCP was synthesized and characterized using spectroscopic and analytical techniques, demonstrating stability under physiological conditions and controlled release of chrysin in reducing environments, as confirmed by HPLC, LC-MS, and 1H NMR studies. Biomolecular interaction studies demonstrated its binding to BSA and ctDNA. In vitro cytotoxicity assays in HeLa cells revealed that CCP effectively masked chrysin's activity, exhibiting an IC50 value > 100 µM compared to free chrysin (IC50 = 15 ± 2 µM). The activation of CCP with sodium ascorbate reduced its IC50, confirming its ability to release chrysin in a biologically relevant context. Live-dead assays validated the selective cytotoxicity of activated CCP, with increased cell death observed under reducing conditions. These findings highlight CCP as a promising prodrug system, combining the pharmacological benefits of chrysin with the advantages of metal-drug conjugates for hypoxia-activated cancer therapy.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 20","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144881788","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