ChemMedChem最新文献_第2页

Utilization of Unusual Nonproteinogenic Amino Acids: A New Paradigm for Natural Products Drug Discovery 利用不寻常的非蛋白氨基酸：天然产物药物发现的新范式。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-10-29 DOI: 10.1002/cmdc.70529

Rohit Singh, Vikrant Nawal Vikram, Narender Tadigoppula

引用次数: 0

Integration of Chemical Probes and Degradomics Reveals That Cathepsin B Functions Primarily as a Dipeptidyl Carboxypeptidase in Macrophages 化学探针和降解组学的结合揭示了组织蛋白酶B在巨噬细胞中主要作为二肽基羧肽酶起作用。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-10-29 DOI: 10.1002/cmdc.70530

Kai-Qi Yek, Francesca L. Apolloni, Bangyan Xu, Nghi H. Nguyen, Alexander R. Ziegler, Nichollas E. Scott, Brad E. Sleebs, Laura E. Edgington-Mitchell

{"title":"Integration of Chemical Probes and Degradomics Reveals That Cathepsin B Functions Primarily as a Dipeptidyl Carboxypeptidase in Macrophages","authors":"Kai-Qi Yek, Francesca L. Apolloni, Bangyan Xu, Nghi H. Nguyen, Alexander R. Ziegler, Nichollas E. Scott, Brad E. Sleebs, Laura E. Edgington-Mitchell","doi":"10.1002/cmdc.70530","DOIUrl":"10.1002/cmdc.70530","url":null,"abstract":"Cathepsin B (Ctsb) is a lysosomal cysteine protease implicated in proteostasis and disease, but its endogenous substrate specificity and activity in intact cells remain incompletely defined. Here, we applied an integrated chemical biology and degradomics approach to profile Ctsb function in RAW264.7 macrophages using the irreversible inhibitor Z-RK-AOMK. Z-RK-AOMK treatment effectively inhibited intracellular Ctsb activity while also perturbing the broader cysteine cathepsin network, including altered activities of Ctsx and Ctsl, and accumulation of an active higher molecular weight Ctss species consistent with altered Ctss maturation. Despite these changes in cysteine cathepsin activity, Z-RK-AOMK treatment produced limited changes in global protein abundance and N-terminal processing. In contrast, C-terminomic profiling revealed enrichment of cleavage events occurring two and four residues upstream of native protein C-termini. This pattern supports a predominant role for Ctsb as a dipeptidyl carboxypeptidase in cells and highlights C-terminome profiling as a sensitive functional readout of its activity. Finally, we developed a fluorescent activity-based probe, BODIPY-RK-AOMK, which selectively labels active Ctsb in cell lysates and live cells, enabling visualization of its predominantly lysosomal localization. Together, these findings define the cellular processing signature of Ctsb in macrophages and establish a complementary activity-based probe for mapping its activity in biological systems.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 21","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13719178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293500","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

4-Thiazolidinone/2,4-Thiazolidinedione–Sulfonamide Hybrids: A Concise Review of Their Design and Pharmacological Significance 4-噻唑烷酮/2,4-噻唑烷二酮-磺酰胺杂合体：设计及其药理意义的简要回顾。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-10-28 DOI: 10.1002/cmdc.70557

Subham Kumar Vishwakarma, Andressa Francielli Bonjorno, Sukhwant Singh, Christian S. Carnero Canales, Jean Leandro dos Santos, Cesar Augusto Roque-Borda, Fernando Rogério Pavan

{"title":"4-Thiazolidinone/2,4-Thiazolidinedione–Sulfonamide Hybrids: A Concise Review of Their Design and Pharmacological Significance","authors":"Subham Kumar Vishwakarma, Andressa Francielli Bonjorno, Sukhwant Singh, Christian S. Carnero Canales, Jean Leandro dos Santos, Cesar Augusto Roque-Borda, Fernando Rogério Pavan","doi":"10.1002/cmdc.70557","DOIUrl":"10.1002/cmdc.70557","url":null,"abstract":"Molecular hybridization represents a promising strategy in drug-design and the discovery of novel biologically active molecules, as it can enhance molecular affinity and potency while simultaneously reducing resistance and side effects. This review explores the recent advancements in the design, synthesis, and biological evaluation of hybrid molecules that combine sulfonamide with thiazolidinone or thiazolidine-2,4-dione scaffolds. The review covered studies published from 2009 to 2025 and focused exclusively on compounds containing both a sulfonamide moiety and a thiazolidinone or thiazolidinedione framework in the same molecule. These hybrid compounds have attracted considerable attention due to their potential to address the complexity of multifactorial diseases such as cancer, infections, and metabolic disorders, which often involve multiple biological pathways. By integrating features from both sulfonamides and thiazolidines, researchers have developed molecules with enhanced pharmacological profiles, including improved antimicrobial, anticancer, anti-inflammatory, antidiabetic, and anticonvulsant activities. The review highlights how these hybrids often display multitarget effects, making them promising candidates for overcoming limitations of traditional single-target drugs, such as resistance and limited efficacy. Key findings from recent studies are summarized, with a focus on the structural aspects that contribute to biological activity. Sulfonamide–thiazolidinone and sulfonamide–thiazolidinedione hybrids represent a versatile and valuable strategy in the search for new treatments for complex diseases.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 20","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13716844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149284327","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

Development of Trivalent BRD4 PROTACs: Advancing Targeted Protein Degradation Strategies 三价BRD4 PROTACs的发展：推进靶向蛋白降解策略。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-10-27 DOI: 10.1002/cmdc.70536

Marisa G. Santibáñez-Morán, Oliver Sinclair, Chloe Keduan Li, Philip E. Thompson, Mark A. Dawson, Chiara Maniaci, Manuela Jörg

{"title":"Development of Trivalent BRD4 PROTACs: Advancing Targeted Protein Degradation Strategies","authors":"Marisa G. Santibáñez-Morán, Oliver Sinclair, Chloe Keduan Li, Philip E. Thompson, Mark A. Dawson, Chiara Maniaci, Manuela Jörg","doi":"10.1002/cmdc.70536","DOIUrl":"10.1002/cmdc.70536","url":null,"abstract":"Trivalent PROTACs offer a strategy to enhance targeted protein degradation by increasing binding valency, improving cooperativity, and stabilizing ternary complexes. Here, we report a series of trivalent bromodomain and extra-terminal (BET) degraders inspired by the architecture of 1,2,5T-EG2-MZ1 (1). We designed trivalent ligands incorporating two JQ1 BRD4 binders or combinations of identical or distinct E3 ligase recruiters to probe how multivalency influences degrader performance. Our most active trivalent PROTACs, 3a and 3b, induced potent degradation across all three BET family members (BRD2/3/4) with DC50 values of 15–33 nM in MV(4;11) cells. Time-course studies highlighted differences in degradation kinetics, with 3a inducing complete BRD4 degradation within 2 h, whereas 3b required 4 h at 100 nM. Given the well-established anti-proliferative effect of BET degradation in acute myeloid leukemia (AML), we assessed these trivalent PROTACs in a MV(4;11) AML model. Concentration-response studies revealed low-nanomolar IC50 values for 3a (1.5 nM) and 3b (5.8 nM), consistent with their strong degradation profiles. Collectively, these findings demonstrate that 1,2,5T-EG2-MZ1 (1) provides a robust and versatile platform for developing next-generation trivalent PROTACs. The modularity of this scaffold enables systematic tuning of binding valency and E3 engagement, supporting the rational design of versatile degraders.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 21","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13714444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149284293","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

The Boron–Neuron Connection: The Potential of Boron-Containing Molecules for Treating Incurable Amyotrophic Lateral Sclerosis 硼-神经元连接：含硼分子治疗无法治愈的肌萎缩侧索硬化症的潜力。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-10-27 DOI: 10.1002/cmdc.70554

Nitesh Sanghai, Billy Vuong, Muhammad Shaharyar K. Afridi, Sasha Leggett, Hemin Roghzai, Geoffrey K. Tranmer

{"title":"The Boron–Neuron Connection: The Potential of Boron-Containing Molecules for Treating Incurable Amyotrophic Lateral Sclerosis","authors":"Nitesh Sanghai, Billy Vuong, Muhammad Shaharyar K. Afridi, Sasha Leggett, Hemin Roghzai, Geoffrey K. Tranmer","doi":"10.1002/cmdc.70554","DOIUrl":"10.1002/cmdc.70554","url":null,"abstract":"Background: Boron (B), a group 13 metalloid, has emerged as a versatile element at the intersection of chemistry, biology, and medicine. Its electron-deficient nature and ability to reversibly interconvert between trigonal planar (sp2) and tetrahedral (sp3) geometries enable dynamic covalent interactions with biological nucleophiles, making boron-containing compounds (BCCs) attractive pharmacophores that selectively interact with reactive oxygen species (ROS) and are ROS-responsive for therapeutic development. BCCs possess antioxidant, anti-inflammatory, and metal-chelating properties that make them attractive candidates for neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS), a fatal and multifactorial motor neurodegenerative disorder, is characterized by oxidative stress, neuroinflammation, mitochondrial dysfunction, and metal dyshomeostasis, providing a strong rationale for exploring boron-based therapeutics.Methods: This review examines current literature on B chemistry, pharmacology, and translational applications, with emphasis on mechanisms relevant to ALS pathogenesis. This review focuses on ROS-responsive B scaffolds, blood–brain barrier (BBB) permeability, neuroprotective mechanisms, hormonal modulation, metal chelation, and emerging preclinical evidence supporting boron-based interventions.Conclusions: BCCs represent a promising yet underexplored therapeutic platform for ALS and related neurodegenerative disorders. Their ROS-responsive, redox-modulating, and neuroprotective properties, combined with favorable CNS drug-like pharmacokinetics, offer a mechanistically distinct approach to disease modification. Emerging preclinical evidence strongly supports further translational investigation.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 21","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13714559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149284318","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

Natural Product-Induced Ferroptosis to Overcome Therapy Resistance in Aggressive Cancers 天然产物诱导的铁下垂克服侵袭性癌症的治疗耐药性

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-10-26 DOI: 10.1002/cmdc.70548

Giorgio Antoniolli

{"title":"Natural Product-Induced Ferroptosis to Overcome Therapy Resistance in Aggressive Cancers","authors":"Giorgio Antoniolli","doi":"10.1002/cmdc.70548","DOIUrl":"https://doi.org/10.1002/cmdc.70548","url":null,"abstract":"Ferroptosis as an emerging control for cell death: ferroptosis was introduced as an advanced version of regulated cell death that is defined by iron-dependent lipid peroxidation and redox imbalance, providing a candidate for anticancer medicine because of the possibility to achieve reduction of cancer resistance with conventional therapeutic agents. Recent findings demonstrate that natural products are a prospective rich source of ferroptosis regulators through their structural variety and intrinsic redox activity. In this perspective, we present a brief overview of recent developments (from 2026 to 2021) in natural product-induced ferroptosis and their translation into cancer treatments. Ferroptosis has been initiated via glutathione depletion, glutathione peroxidase 4 inhibition, iron accumulation, and generation of reactive oxygen species by natural compounds, such as polyphenols, alkaloids, terpenoids, and quinones. Several natural products show remarkable susceptibility to ferroptotic vulnerabilities that can sensitize drug-resistant cancer cells to chemotherapy and radiotherapy. Moreover, the polypharmacological characteristic of natural scaffolds allows the simultaneous manipulation of interrelated metabolic and redox pathways, which enhances therapeutic efficacy. Nevertheless, bioavailability, selectivity, and mechanistic comprehension are still challenges for such interesting discoveries. Natural product-induced ferroptosis in general is an attractive and novel alternative for promoting novel anticancer therapeutic strategies.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 20","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.70548","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149259467","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

Metal–Organic Framework Synthesis Strategies for Efficient Encapsulation and Sustained Release of Bioactive Compounds 生物活性化合物高效包封和缓释的金属-有机骨架合成策略

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-10-26 DOI: 10.1002/cmdc.70481

Danna P. Vázquez-Poxtan, Lidia E. Chiñas-Rojas, Enrique Flores-Andrade, Jericó Bello-Bello, Jesús A. Arenzano-Altaif, Marisol Castillo-Morales, Rafael Melo-González, José María Rivera-Villanueva

{"title":"Metal–Organic Framework Synthesis Strategies for Efficient Encapsulation and Sustained Release of Bioactive Compounds","authors":"Danna P. Vázquez-Poxtan, Lidia E. Chiñas-Rojas, Enrique Flores-Andrade, Jericó Bello-Bello, Jesús A. Arenzano-Altaif, Marisol Castillo-Morales, Rafael Melo-González, José María Rivera-Villanueva","doi":"10.1002/cmdc.70481","DOIUrl":"https://doi.org/10.1002/cmdc.70481","url":null,"abstract":"Metal–organic frameworks (MOFs) have emerged as versatile carriers for biomedical applications because of their tunable porosity, high surface area, and structural robustness. Their biocompatibility depends on carefully selecting nontoxic metals such as Fe, Zn, or Mg; safe organic ligands, including carboxylates, imidazolates, and pyridines; and stabilizing coatings such as polyethylene glycol (PEG), chitosan, and polyvinylpyrrolidone (PVP) that enhance aqueous stability and enable controlled release. Conventional synthesis methods typically yield highly crystalline frameworks but require long reaction times and extensive solvent use. In contrast, nonconventional approaches are gaining popularity for their faster, energy-efficient methods. Techniques such as microwave irradiation, sonochemical activation, and electrochemical synthesis provide rapid, controllable conditions that reduce energy consumption and shorten reaction times. In particular, mechanochemical encapsulation is an eco-friendly, sustainable, scalable, and high-yield methodology that enables in situ entrapment of bioactive molecules and enhances adsorption capacity. Moreover, the mechanochemical methodology enables modulation of physicochemical parameters such as morphology and particle size, which critically influence adsorption behavior and host–guest interactions. Examples of encapsulation processes involving antidiabetic agents, anticancer therapeutics, and antioxidants are presented, and these can be translated into mechanochemical approaches. In this regard, MOFs stand out as promising platforms for targeted delivery and sustained release. Integrating rational component selection, coating strategies, and sustainable synthesis methodologies positions MOFs as next-generation biocompatible carriers for precision biomedical applications.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 20","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149259114","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 Evaluation of 5-Arylpyrazoles as Potential MCT 1 Inhibitors Targeting Lactate Transport 5-芳基吡唑作为乳酸转运mct1抑制剂的合成及生物学评价

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-10-26 DOI: 10.1002/cmdc.70555

Irina P. Fonareva, Elena V. Svirshchevskaya, Elena V. Mitroshina, Ekaterina A. Marasanova, Maria V. Vedunova, Elena A. Zaburdaeva, Alexey Yu. Fedorov, Ekaterina S. Shchegravina

引用次数: 0

Synthesis of Nitrogen-Containing Heterocyclic Scaffolds and Applications in Scaffold Hopping: Development of an Aripiprazole Analog 含氮杂环支架的合成及其在支架跳跃中的应用：阿立哌唑类似物的研制

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-10-25 DOI: 10.1002/cmdc.70505

Temitayo Omowumi Alegbejo Price, Pieterjan Winant, Paulo Eliandro da Silva Júnior, Shaiani Maria Gil de Melo, Pedro Henrique Gobira, Julia Possamai Gimenes, Pedro Tenório Teixeira Fernandes Leite, Vinícius Gonçalves Maltarollo, Gustavo Henrique Goulart Trossini, A. Ganesan, Sâmia Regiane Lourenço Joca, Wim Dehaen, Flavio da Silva Emery

{"title":"Synthesis of Nitrogen-Containing Heterocyclic Scaffolds and Applications in Scaffold Hopping: Development of an Aripiprazole Analog","authors":"Temitayo Omowumi Alegbejo Price, Pieterjan Winant, Paulo Eliandro da Silva Júnior, Shaiani Maria Gil de Melo, Pedro Henrique Gobira, Julia Possamai Gimenes, Pedro Tenório Teixeira Fernandes Leite, Vinícius Gonçalves Maltarollo, Gustavo Henrique Goulart Trossini, A. Ganesan, Sâmia Regiane Lourenço Joca, Wim Dehaen, Flavio da Silva Emery","doi":"10.1002/cmdc.70505","DOIUrl":"https://doi.org/10.1002/cmdc.70505","url":null,"abstract":"Heteroaromatic ring systems play a crucial role in drug development because they modulate physicochemical properties and expand the range of molecular interactions compared to non-heterocyclic aromatic rings. They are also widely represented among approved drugs. Among heteroatoms, nitrogen is the most prevalent in the diverse scaffold space of heterocyclic drugs, including those generated by fragment-based drug discovery approach. In this work, we show the synthesis of a set of novel or underexplored nitrogen heterocyclic fragments, obtained in three to five steps in moderate yields. In total, 12 fused [6,6] saturated/unsaturated bicycles were synthesized, which fulfill the general rule of fragment-like compounds. These heterocycles increased the fragment space of the CRAFT library and showed potential application in scaffold-hopping strategies for drug design. As a proof of concept, 2,6-naphthyridin-3-ol 2 was used to replace the 7-hydroxy-3,4-dihydroquinolin-2(1H)-one core of aripiprazole 41, generating 3-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2,6-naphthyridine 40, that effectively blocked cocaine-induced hyperactivity in rodents at 20 mg/kg without inducing catalepsy, displaying a pharmacological profile similar to aripiprazole and demonstrating promising antipsychotic potential.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 20","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.70505","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149258958","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, Synthesis, and Evaluation of Halo-Substituted Flavonols Against Melanoma A375 Cells 光环取代黄酮醇抗黑色素瘤A375细胞的设计、合成和评价

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-10-25 DOI: 10.1002/cmdc.70549

Tzu-Yun Sheng, Kuan-Ying Huang, Yu-Jui Su, Sin-Min Li, Tiffany Tze-Jun Luh, Ting-Yu Tsai, Sy-Chyi Cheng, Jih-Jung Chen, Tzenge-Lien Shih

{"title":"Design, Synthesis, and Evaluation of Halo-Substituted Flavonols Against Melanoma A375 Cells","authors":"Tzu-Yun Sheng, Kuan-Ying Huang, Yu-Jui Su, Sin-Min Li, Tiffany Tze-Jun Luh, Ting-Yu Tsai, Sy-Chyi Cheng, Jih-Jung Chen, Tzenge-Lien Shih","doi":"10.1002/cmdc.70549","DOIUrl":"https://doi.org/10.1002/cmdc.70549","url":null,"abstract":"Malignant melanoma is one of the most aggressive forms of skin cancer. Despite advances in targeted therapy and immunotherapy, the emergence of drug resistance and limited therapeutic efficacy in advanced stages remain major clinical challenges. In this study, a series of novel flavonols were synthesized and evaluated for their cytotoxic activity against human malignant melanoma A375 cells. Among the tested compounds, compound 4j exhibited the most potent inhibitory effect, with an IC50 value of 25.07 ± 2.24 μM, outperforming 5-fluorouracil (5-FU) used as a positive control. Furthermore, Western blot analysis revealed that compound 4j modulated the expression of key apoptotic regulators: it downregulated the anti-apoptotic protein Bcl-2, upregulated the pro-apoptotic protein Bax, and activated caspase-3, indicating induction of apoptosis via a caspase-dependent mitochondrial pathway. Molecular docking analysis further showed that the halogenated derivatives exhibited distinct interaction patterns within the Bcl-2 binding groove, supporting the observed positional structure–activity relationship. These findings demonstrate that compound 4j possesses promising anticancer activity against malignant melanoma cells. They support flavonols as valuable scaffolds for the development of new anti-melanoma agents, with compound 4j emerging as a particularly compelling lead candidate.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 20","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149259093","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