IF 3.4 4区医学

ChemMedChem Pub Date : 2025-07-28 DOI: 10.1002/cmdc.202500532

Ziwei Gao, Jiei Sasaki, Tateki Suzuki, Shinsuke Sando, Takao Hashiguchi, Jumpei Morimoto

引用次数: 0

Design, Synthesis, and Antiproliferative and Apoptotic Assessment of Triazole-Tethered Bisnaphthalimide-Isatin Hybrids on Triple-Negative Breast and Prostate Cancers. 三唑系链双萘酰亚胺- isatin杂合体对三阴性乳腺癌和前列腺癌的设计、合成、抗增殖和凋亡评估。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-07-28 DOI: 10.1002/cmdc.202500415

Preeti, Asif Raza, Garima Arora, Amit Anand, Arun K Sharma, Vipan Kumar

{"title":"Design, Synthesis, and Antiproliferative and Apoptotic Assessment of Triazole-Tethered Bisnaphthalimide-Isatin Hybrids on Triple-Negative Breast and Prostate Cancers.","authors":"Preeti, Asif Raza, Garima Arora, Amit Anand, Arun K Sharma, Vipan Kumar","doi":"10.1002/cmdc.202500415","DOIUrl":"https://doi.org/10.1002/cmdc.202500415","url":null,"abstract":"This study reports the design, synthesis, and biological evaluation of 1H-1,2,3-triazole-tethered bisnaphthalimide-isatin hybrids as potential antiproliferative agents. The compounds are efficiently synthesized via copper-promoted azide-alkyne cycloaddition and assayed against triple-negative breast (MDA-MB-231) and prostate (DU-145) cancer cell lines. Structure-activity relationship studies reveal that halogen substitution and spacer length substantially influenced anticancer activity. The bisnaphthalimide-isatin hybrid featuring dibromo substitution and a propyl linker demonstrates IC50 values of 3.3 ± 0.1 μM (DU-145) and 4.4 ± 0.3 μM (MDA-MB-231), comparable to clinical drugs cisplatin and 5-fluorouracil. Notably, it exhibits favorable selectivity indices (2.07-2.76) against cancer versus normal keratinocytes (HaCaT). Mechanistic investigations establish that it induces caspase-mediated apoptosis and molecular docking studies confirmed its strong interaction with DNA topoisomerase II (docking score: -4.894), comparable to doxorubicin.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500415"},"PeriodicalIF":3.4,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726224","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

Unveiling Benzoxazole-Substituted Thiazolyl-Pyrazole Derivatives Inducing Apoptosis by Targeting β-Tubulin and Caspase-3. 揭示苯并恶唑取代噻唑吡唑衍生物通过靶向β-微管蛋白和Caspase-3诱导细胞凋亡。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-07-28 DOI: 10.1002/cmdc.202500320

Burak Kuzu, Mustafa Cakir, Eda Acikgoz, Mehmet Abdullah Alagoz

{"title":"Unveiling Benzoxazole-Substituted Thiazolyl-Pyrazole Derivatives Inducing Apoptosis by Targeting β-Tubulin and Caspase-3.","authors":"Burak Kuzu, Mustafa Cakir, Eda Acikgoz, Mehmet Abdullah Alagoz","doi":"10.1002/cmdc.202500320","DOIUrl":"https://doi.org/10.1002/cmdc.202500320","url":null,"abstract":"In the present study, the biological activities of novel compounds (BP-1 to BP-6), designed as antitubulin agents, were systematically evaluated, with a particular focus on their effects on the triple-negative breast cancer cell line MDA-MB-231 and non-cancerous cell line MCF-10A. BP-2 and BP-6 demonstrated micromolar-range antiproliferative activity against MDA-MB-231 cancer cells, with IC5 0 values of 8 and 4 µM, respectively, comparable to nocodazole (3 µM), and showed selective cytotoxicity over normal MCF-10A cells, with selectivity indices of approximately 3.3 and 8. In vitro analyses revealed that BP-2 and more notably BP-6 significantly inhibited cell proliferation in a time- and dose-dependent manner, disrupted microtubule organization through the downregulation of β-tubulin expression, and induced apoptosis, as evidenced by increased levels of Cleaved Caspase-3 and distinct apoptotic morphological changes. Among the tested compounds, BP-6 exhibited the most potent antiproliferative and proapoptotic activity, with an IC5 0 value close to that of NOC. Molecular docking supported these findings by showing strong binding affinities of BP-6 to both β-tubulin and Caspase-3, indicating a dual-targeted mechanism. Furthermore, molecular dynamics simulations confirmed the stable binding and dynamic integrity of BP-6 within both β-Tubulin and Caspase-3 targets, underscoring its potential as a robust candidate for anticancer drug development.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500320"},"PeriodicalIF":3.4,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726225","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

Programmed Targeted Protein Degradation Via DNA Modularized Ligand. 通过DNA模块化配体的程序化靶向蛋白质降解。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-07-23 DOI: 10.1002/cmdc.202500340

Xuanming Teng, Jingyi Yang, Zhiyi Ren, Sha Yan, Jiaxin Zhai, Xinyuan Hu, Shule Hou, Yangyang Yang

{"title":"Programmed Targeted Protein Degradation Via DNA Modularized Ligand.","authors":"Xuanming Teng, Jingyi Yang, Zhiyi Ren, Sha Yan, Jiaxin Zhai, Xinyuan Hu, Shule Hou, Yangyang Yang","doi":"10.1002/cmdc.202500340","DOIUrl":"https://doi.org/10.1002/cmdc.202500340","url":null,"abstract":"Proteolysis targeting chimera (PROTAC) technology holds great promise as a protein degradation modality in therapeutic development. However, there remain challenges, including complex chemical synthesis and linker screening. To address this, a proof-of-concept of a new modularized method by constructing DNA-PROTAC is presented by identifying the valid BRD4 and Sirt2 DNA-PROTACs. These findings may provide new approaches for linker design and ligand screening for PROTACs. Herein, a ligand modularization strategy is proposed that leverages the programmability of DNA to modulate the design and construction of PROTAC molecules to facilitate the programmatic discovery of new PROTAC molecules. The bromodomain-containing protein 4 (BRD4) is selected as a target for degradation to verify the effectiveness of DNA-PROTACs. The kinetics of BRD4 degradation were assessed by performing time-course experiments in HeLa cells. In addition, to evaluate the feasibility of the DNA-PROTAC strategy for degradation of other proteins, the silent mating type information regulation 2 homolog-2 (Sirt2) is selected as the degradation target. The design and synthesis procedures of BRD4 and Sirt2 DNA-PROTACs and their mechanisms of action, are systematically introduced, and the results may provide a new method for linker design and ligand screening of PROTACs.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500340"},"PeriodicalIF":3.6,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697208","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

Front Cover: (ChemMedChem 14/2025) 封面：（ChemMedChem 14/2025）

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-07-19 DOI: 10.1002/cmdc.202581401

引用次数: 0

Estimation of In Vivo Half-Life From In Vitro Metabolic Clearance, Protein, and Cell Membrane Affinity Assays. 通过体外代谢清除率、蛋白质和细胞膜亲和力测定估算体内半衰期。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-07-19 DOI: 10.1002/cmdc.202500459

Carla Pou Miralbell, Sandrine Desrayaud, Berndt Oberhauser, John Reilly, Yves P Auberson

引用次数: 0

Identification of a New Interesting BAG3 Modulator Able to Disrupt Cancer-Related Pathways. 一种能够破坏癌症相关通路的新的BAG3调节剂的鉴定

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-07-09 DOI: 10.1002/cmdc.202500310

Dafne Ruggiero, Eleonora Boccia, Emis Ingenito, Vincenzo Vestuto, Gilda D'Urso, Alessandra Capuano, Agostino Casapullo, Stefania Terracciano, Giuseppe Bifulco, Gianluigi Lauro, Ines Bruno

引用次数: 0

Cyclin-dependent Kinase 11: Cellular Functions and Potential Therapeutic Applications. 细胞周期蛋白依赖性激酶11：细胞功能和潜在的治疗应用。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-07-08 DOI: 10.1002/cmdc.202500305

Janhabee Shrestha, Jason Blanchard, Solomon Tadesse

{"title":"Cyclin-dependent Kinase 11: Cellular Functions and Potential Therapeutic Applications.","authors":"Janhabee Shrestha, Jason Blanchard, Solomon Tadesse","doi":"10.1002/cmdc.202500305","DOIUrl":"https://doi.org/10.1002/cmdc.202500305","url":null,"abstract":"Cyclin-dependent kinase 11 (CDK11) is a multifunctional serine/threonine protein kinase that plays a pivotal role in transcription and pre-mRNA splicing. It phosphorylates serine 2 of RNA polymerase II C-terminal domain, thereby promoting transcriptional elongation and 3'-end processing of replication-dependent histone genes, as well as contributing to proper chromosome segregation during mitosis. CDK11 is essential for global pre-mRNA splicing by phosphorylating Splicing Factor 3B Subunit 1, a core U2 small nuclear ribonucleoprotein component, thereby activating the spliceosome. Since splicing is closely linked to optimal transcription and cell proliferation, inhibition of CDK11 is hypothesized to indirectly disrupt general transcription and cell cycle progression. CDK11 drives cancer cell proliferation, promotes HIV-1 mRNA 3'-end processing to enhance viral replication, and contributes to tau phosphorylation in Alzheimer's disease. Given its integral role in key cellular processes and its dysregulation in various diseases, CDK11 has emerged as a compelling therapeutic target. This review provides a comprehensive overview of the biological functions and regulatory mechanisms of CDK11, discusses its role in cancer, viral and neurodegenerative diseases, and highlights advances in the discovery and development of CDK11 inhibitors, including OTS964, which has expanded our understanding of the biological functions of CDK11 and its prospects as a cancer-specific vulnerability.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500305"},"PeriodicalIF":3.6,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582730","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 Novel Anticancer Pyrazolopyrimidinones Targeting Glioblastoma. 靶向胶质母细胞瘤的新型抗癌吡唑嘧啶类药物的研究进展。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-07-08 DOI: 10.1002/cmdc.202500337

Kate Byrne, Natalia Bednarz, Ciara McEvoy, John C Stephens, James F Curtin, Gemma Kinsella

{"title":"Development of Novel Anticancer Pyrazolopyrimidinones Targeting Glioblastoma.","authors":"Kate Byrne, Natalia Bednarz, Ciara McEvoy, John C Stephens, James F Curtin, Gemma Kinsella","doi":"10.1002/cmdc.202500337","DOIUrl":"https://doi.org/10.1002/cmdc.202500337","url":null,"abstract":"Glioblastoma (GBM) is the most common and aggressive malignant grade IV brain tumour and is one of the most difficult types of brain cancer to treat with a high incidence of resistance to traditionally used chemotherapeutics. Pyrazolopyrimidinones are fused nitrogen-containing heterocyclic systems which are a scaffold in several bioactive drugs and drug candidates. Here, a structure activity relationship (SAR) study was performed where 23 substituted pyrazolo[1,5-α]pyrimidinones were screened for cytotoxicity against the GBM U-251 MG cell line and the non-cancerous embryonic kidney HEK293 cell line to assess their potential as anti-glioblastoma agents capable of selectivity for cancer cells. Through analogue synthesis of preliminary HIT compounds with varied structural substituents, a lead compound, 22, has been identified, which proved capable of inducing significant GBM cell death while having a marginal cytotoxicity against the non-cancerous cells. The mode of cell death studies suggested that the structurally varied HIT compounds induced cell death through differential mechanisms including cell membrane permeabilization and mitochondria membrane depolarization dependent mechanisms such as necrosis or apoptosis. The results highlight the potential of pyrazolo[1,5-α]pyrimidinones derivatives as a novel anti-glioblastoma therapy, capable of selectively killing cancer cells. Furthermore pyrazolo[1,5-α]pyrimidinones provide a scaffold for further development of selective glioblastoma therapies.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500337"},"PeriodicalIF":3.6,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582731","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

Adamantane Appended 1,2,3-Triazole Hybrids: Synthesis and α-Glucosidase Inhibition Studies Through Experimental and In Silico Approach. 金刚烷附加1,2,3-三唑杂化物的合成及α-葡萄糖苷酶抑制实验研究。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-07-08 DOI: 10.1002/cmdc.202500263

Aman Ragshaniya, Subhadip Maity, Lokesh Kumar, Vivek Asati, Poojita Poojita, Avijit Kumar Paul, Jayant Sindhu, Kashmiri Lal

{"title":"Adamantane Appended 1,2,3-Triazole Hybrids: Synthesis and α-Glucosidase Inhibition Studies Through Experimental and In Silico Approach.","authors":"Aman Ragshaniya, Subhadip Maity, Lokesh Kumar, Vivek Asati, Poojita Poojita, Avijit Kumar Paul, Jayant Sindhu, Kashmiri Lal","doi":"10.1002/cmdc.202500263","DOIUrl":"https://doi.org/10.1002/cmdc.202500263","url":null,"abstract":"In search of potent inhibitors of α-glucosidase, we have synthesized amide coupled adamantane derived 1,2,3-triazoles (4a-4f, 6a-6f, and 8a-8f) using Click reaction. After establishing their structure using spectral studies, all the molecular hybrids were assayed for α-glucosidase inhibition assay. Compounds 6c (IC50 = 8.30 ± 0.33 μM) and 6b (IC50 = 14.0 ± 0.16 μM) demonstrated promising inhibition of α-glucosidase in comparison to reference used (Acarbose, IC50 = 13.50 ± 0.32 μM). The role of various covalent linkers between triazole and phenyl ring has been established using structure activity relationship (SAR). The most probable mode of inhibition was studied by docking the most active compound 6c and Acarbose within the protein target (PDB ID: 3L4U). Further, 100 ns dynamics simulations were conducted to gain a detailed understanding of the complex stability. Binding energy for both the simulated complexes was calculated using MMGBSA and MMPBSA analysis, where compound 6c and Acarbose demonstrates a ΔGbind of -15.74 kcal/mol, and -46.37 kcal/mol. All compounds fit in the Lipinski rules of five, when ADME studies was carried out. This study paves the way for developing small molecule based α-glucosidase inhibitors as potential lead molecules using these frameworks.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500263"},"PeriodicalIF":3.6,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582729","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

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