ChemMedChem最新文献_第3页

Front Cover: Corrin Ring Modification in Peptide Drug Development – a Brief History of “Corrination” (ChemMedChem 10/2025) 封面：多肽药物开发中的科林斯环修饰-“科林斯”简史（ChemMedChem 10/2025）

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-20 DOI: 10.1002/cmdc.202581001

Nancy Cham, Robert P. Doyle

引用次数: 0

Deciphering Therapeutic Targeting of Cathepsin B using Repurposed Drug Darifenacin. 利用重组药物达利那新解读组织蛋白酶B的治疗靶向性。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-20 DOI: 10.1002/cmdc.202500117

Sayantani Mukhopadhyay, Thirukumaran Kandasamy, Siddhartha S Ghosh, Parameswar Krishnan Iyer

{"title":"Deciphering Therapeutic Targeting of Cathepsin B using Repurposed Drug Darifenacin.","authors":"Sayantani Mukhopadhyay, Thirukumaran Kandasamy, Siddhartha S Ghosh, Parameswar Krishnan Iyer","doi":"10.1002/cmdc.202500117","DOIUrl":"https://doi.org/10.1002/cmdc.202500117","url":null,"abstract":"Cathepsins are lysosomal proteases with well-documented roles in the progression of various cancers. Among them, cathepsin B (CTSB), a cysteine protease, is notably involved in the development of breast cancer and neuroblastoma. In this study, we explored the potential of darifenacin as a repurposed therapeutic targeting CTSB, using molecular docking and simulation studies which demonstrated a significantly lower binding energy against CTSB (-456.268 kJ/mol) compared to its known inhibitor, aloxistatin (-36.601 kJ/mol). The cytotoxic efficacy of darifenacin was evaluated on IMR-32 (neuroblastoma) and MCF-7 (breast cancer) cells, yielding half-maximal inhibitory concentrations (IC50) of 38.14 and 39.96 µM, respectively. Darifenacin effectively inhibited CTSB enzymatic activity by ~1.82 and ~1.75-fold in IMR-32 and MCF-7 cells, respectively, triggering intracellular ROS generation, mitochondrial membrane potential depolarization, and cell cycle arrest. These events culminated in apoptosis-mediated cell death, with apoptotic populations reaching 51.39% in IMR-32 and 40.6% in MCF-7 cells, respectively. Additionally, darifenacin disrupted lipid droplet accumulation, cellular migration, and colony and sphere-forming abilities in both cell lines. Overall, this study identifies darifenacin as a promising therapeutic agent against CTSB-driven cancer progression.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500117"},"PeriodicalIF":3.6,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109239","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 Carborane-Based Halogenated Naphthyridinone-Analoga as Cannabinoid Receptor Type 2 (CB2R) Ligands. 碳硼烷基卤化萘啶酮类似物作为大麻素受体2型（CB2R）配体的研究进展。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-20 DOI: 10.1002/cmdc.202500251

Lea Ueberham, Winnie Deuther-Conrad, Peter Lönnecke, Aleksandr Kazimir, Evamarie Hey-Hawkins

{"title":"Development of Carborane-Based Halogenated Naphthyridinone-Analoga as Cannabinoid Receptor Type 2 (CB2R) Ligands.","authors":"Lea Ueberham, Winnie Deuther-Conrad, Peter Lönnecke, Aleksandr Kazimir, Evamarie Hey-Hawkins","doi":"10.1002/cmdc.202500251","DOIUrl":"https://doi.org/10.1002/cmdc.202500251","url":null,"abstract":"The cannabinoid receptor type 2 (CB2R) is overexpressed under pathological conditions. PET is a suitable non-invasive imaging technique for diagnosing disease states, but requires a radiotracer that binds to CB2R with high affinity and selectivity. Currently, there is no suitable candidate routinely used in the clinics. The naphthyridinone scaffold is a promising core structure that has been modified in the past years. The modification of naphthyridinone carboxamides with carboranes as hydrophobic surrogates for purely organic moieties could lead to a beneficial CB2R ligand with high affinity, selectivity and metabolic stability. We here report the synthesis and characterization of eight carborane-based naphthyridinone ligands, the determination of their in vitro binding affinity towards the human CB1R and CB2R and the results of in silico investigations. The meta- and para-carborane derivatives show high affinity in the low nanomolar range and a good selectivity towards CB2R. Only a minor influence of bromo- vs. iodo-substitution was observed experimentally, while in silico data suggested a stronger influence of the halogen atom, resulting in a different order of the respective carborane isomers regarding their affinity to CB2R. Although these compounds did not outperform the known organic derivatives, they extend the portfolio of potentially useful CB2R ligands.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500251"},"PeriodicalIF":3.6,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109241","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

Chitosan-Polymer Conjugates as Functional Coatings for Liposomal Bioactive Delivery Systems. 壳聚糖-聚合物缀合物作为脂质体生物活性递送系统的功能涂层。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-19 DOI: 10.1002/cmdc.202500191

Ngoc Thuy Trang Le, Tien-Dung Nguyen-Dinh, Anh-Minh Nguyen-Huu, Hoang Hanh Huynh, Minh-Dung Truong, Kim-Anh Phan-Dang, Dai Hai Nguyen, Cuu Khoa Nguyen

{"title":"Chitosan-Polymer Conjugates as Functional Coatings for Liposomal Bioactive Delivery Systems.","authors":"Ngoc Thuy Trang Le, Tien-Dung Nguyen-Dinh, Anh-Minh Nguyen-Huu, Hoang Hanh Huynh, Minh-Dung Truong, Kim-Anh Phan-Dang, Dai Hai Nguyen, Cuu Khoa Nguyen","doi":"10.1002/cmdc.202500191","DOIUrl":"10.1002/cmdc.202500191","url":null,"abstract":"Conventional liposomes hold promise as drug delivery systems but face challenges such as susceptibility to rapid clearance and limited targeting specificity. To address these limitations, polymer-coated liposomes have emerged as a viable solution, offering improved biocompatibility and targeted delivery capabilities. This study reports the synthesis and application of a chitosan-polyethylene glycol-folic acid (CTS-PEG-FA) conjugate as a functional liposome coating. The CTS-PEG-FA conjugate is synthesized and thoroughly characterized using spectroscopic techniques. Liposomes coated with this polymer are prepared via the thin-film hydration method and analyzed for particle size, zeta potential, and morphology through transmission electron microscopy. Using quercetin as a model drug, the system's drug-loading capacity and release kinetics are investigated. Results demonstrate that CTS-PEG-FA-coated liposomes facilitate enhanced cellular uptake and exhibit promising cytotoxic effects in cancer cells. This study highlights the potential of polymer-coated liposomes as a versatile and efficient platform for bioactive compound delivery with improved therapeutic performance.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500191"},"PeriodicalIF":3.6,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092297","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

Potent, Selective, and Drug-like G Protein-coupled Receptor Kinase 5 and 6 Inhibitors: Design, Synthesis, and X-ray Structural Studies. 强效、选择性和药物样G蛋白偶联受体激酶5和6抑制剂：设计、合成和x射线结构研究。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-19 DOI: 10.1002/cmdc.202500257

Arun K Ghosh, Ranjith Kumar Gadi, Yueyi Chen, Sandali Piladuwa Gamage, Kathryn McCauley, John J G Tesmer

{"title":"Potent, Selective, and Drug-like G Protein-coupled Receptor Kinase 5 and 6 Inhibitors: Design, Synthesis, and X-ray Structural Studies.","authors":"Arun K Ghosh, Ranjith Kumar Gadi, Yueyi Chen, Sandali Piladuwa Gamage, Kathryn McCauley, John J G Tesmer","doi":"10.1002/cmdc.202500257","DOIUrl":"https://doi.org/10.1002/cmdc.202500257","url":null,"abstract":"We report here the design, synthesis, and evaluation of small molecules, drug-like G protein-coupled receptor kinase 5 (GRK5) inhibitors. GRK5 has become an important drug development target against heart failure and cancer. GRK6, a close homolog of GRK5, is considered as a possible therapeutic target for multiple myeloma. We designed a series of drug-like GRK5 inhibitors that form noncovalent interactions in the GRK5 active site. In the design of these molecules, we utilized pyrroloindoline basic scaffold of sunitinib, an FDA approved drug and incorporated various N-heterocyclic carboxamides in the active site. Several inhibitors exhibited low nanomolar GRK5 inhibitory activity and high selectivity over GRK2. Several compounds also displayed very potent activity and selectivity for GRK6. We determined a high-resolution X-ray crystal structure of one of these small molecule inhibitors in complex with GRK5. The structure provided important molecular insights regarding ligand-binding site interactions, GRK5 inhibition, and selectivity against GRK2.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500257"},"PeriodicalIF":3.6,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101218","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

Impact of Chelation on Reactivity and Cytotoxicity of Hemilabile Biphenyl Gold(III) N-Heterocyclic Carbene Complexes. 螯合对半活性联苯金（III） n杂环碳配合物反应性和细胞毒性的影响。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-16 DOI: 10.1002/cmdc.202500302

Tom Lacoma, Jérémy Forté, Régina Maruchenko, Romain Morichon, Michèle Salmain, Joëlle Sobczak-Thépot, Benoît Bertrand

{"title":"Impact of Chelation on Reactivity and Cytotoxicity of Hemilabile Biphenyl Gold(III) N-Heterocyclic Carbene Complexes.","authors":"Tom Lacoma, Jérémy Forté, Régina Maruchenko, Romain Morichon, Michèle Salmain, Joëlle Sobczak-Thépot, Benoît Bertrand","doi":"10.1002/cmdc.202500302","DOIUrl":"10.1002/cmdc.202500302","url":null,"abstract":"Although great progresses have been accomplished in the field of antineoplastic treatments, the need for chemotherapy agents with new mechanisms of action remains essential. Metal complexes presenting hemilabile ligands could combine structural toxicity upon full coordination of the ligand and reactive toxicity upon ligand partial decoordination and direct coordination of the metal center to biological targets. To investigate the relevance of hemilability in the case of Au(III) complexes, we synthesized eight open biphenyl gold(III) N-heterocyclic carbene complexes coined BGC of general formula [(C^C)Au(NHC^het)Cl] where het is a pyridine-type entity and C^C is 4,4'-diterbutylbiphenyl. Chloride abstraction afforded the chelated cationic complexes [(C^C)Au(NHC^N)]PF6 in which the pyridine arm coordinates the gold ion. Quantitative irreversible conversion of the cationic forms to the neutral ones in the presence of chloride ions was demonstrated through extensive speciation studies by 1H NMR spectroscopy on both forms in different media including DMSO/cell culture medium mixture. The BGC complexes exhibited antiproliferative activity in the low micromolar range with equivalent activities for each open neutral/chelated cationic pair. Time lapse fluorescence videomicroscopy studies demonstrated the activation of effector caspases 3/7, suggesting the induction of apoptosis. Preliminary mechanistic studies suggest that apoptotic cell death may arise partially from mitochondrial membrane depolarization.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500302"},"PeriodicalIF":3.6,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075200","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, Antimycobacterial Activity, and Computational Insight of Novel 1,4-Benzoxazin-2-one Derivatives as Promising Candidates against Multidrug-Resistant Mycobacterium Tuberculosis. 新型1,4-苯并恶嗪-2- 1衍生物的合成、抑菌活性及计算分析

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-14 DOI: 10.1002/cmdc.202500073

Maria Grazia Mamolo, Emanuele Carosati, Diletta Pasin, Alessandro De Logu, Gianluigi Cabiddu, Marko Jukič, Daniele Zampieri

引用次数: 0

Designing Cyclic Nitrogen-Bridged Sulfonamides with Anti-Cancer Activity. 具有抗癌活性的环氮桥接磺胺类化合物的设计。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-14 DOI: 10.1002/cmdc.202400936

Benedikt W Grau, Arpit Dheeraj, Irimpan I Mathews, Dhanir Tailor, Sanjay V Malhotra

引用次数: 0

Recent advances of quinoline-based small molecules as kinase inhibitors (2020-2024). 喹啉类小分子激酶抑制剂研究进展（2020-2024）。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-13 DOI: 10.1002/cmdc.202500279

Sara Sultan, Ruba A Zenati, Hanan S Anbar, Mohammed I El-Gamal, Mohammad H Semreen

{"title":"Recent advances of quinoline-based small molecules as kinase inhibitors (2020-2024).","authors":"Sara Sultan, Ruba A Zenati, Hanan S Anbar, Mohammed I El-Gamal, Mohammad H Semreen","doi":"10.1002/cmdc.202500279","DOIUrl":"https://doi.org/10.1002/cmdc.202500279","url":null,"abstract":"Quinoline-containing compounds have gained prominence in drug discovery as versatile scaffolds. These compounds have shown promise in the development of kinase inhibitors, which are crucial treatment options used in various cancer cases. This review explores the recent advances from 2020 to 2024 in the design, synthesis, and optimization of quinoline-based kinase inhibitors, focusing on their role in targeting key kinases, implicated in cancer signaling pathways. Quinoline derivatives exhibit significant inhibitory activity across a broad spectrum of kinases, highlighting their potential to disrupt aberrant signaling that drives tumor growth and progression. Several FDA-approved quinoline-containing compounds are utilized in clinical settings as kinase inhibitors, reinforcing their importance and relevance in clinical oncology. This review compiles the pharmacological profiles of these inhibitors spotlighting key compounds that have demonstrated potent inhibitory activities, excellent selectivity profiles, and promising preclinical or clinical outcomes. The review also addresses the challenges associated with their development and discusses future directions for optimizing quinoline-based kinase inhibitors, such as leveraging advanced drug design techniques, exploring novel targets, and expanding their use in combination therapies. By summarizing recent advancements, this review aims to provide insights into the evolving landscape of quinoline-based kinase inhibitors and their potential as next-generation anticancer therapies.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500279"},"PeriodicalIF":3.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956798","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

Intracellular and Extracellular Efficacy of Homoisoflavone Derivatives Against Mycobacterium Tuberculosis: Progress Toward Novel Antitubercular Agents. 同型异黄酮衍生物抗结核分枝杆菌的细胞内和细胞外功效：新型抗结核药物的研究进展。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-12 DOI: 10.1002/cmdc.202500249

Sanderson D Calixto, Juliane S Falcão, Stella S Antunes, Marlon H Araujo, Alexandre L B Cunha, David R Martins, Sarah M R Nascimento, Thatiana L B V Simão, Elena B Lasunskaia, Nelilma C Romeiro, Paulo R R Costa, Michelle F Muzitano, Guilherme S Caleffi

{"title":"Intracellular and Extracellular Efficacy of Homoisoflavone Derivatives Against Mycobacterium Tuberculosis: Progress Toward Novel Antitubercular Agents.","authors":"Sanderson D Calixto, Juliane S Falcão, Stella S Antunes, Marlon H Araujo, Alexandre L B Cunha, David R Martins, Sarah M R Nascimento, Thatiana L B V Simão, Elena B Lasunskaia, Nelilma C Romeiro, Paulo R R Costa, Michelle F Muzitano, Guilherme S Caleffi","doi":"10.1002/cmdc.202500249","DOIUrl":"10.1002/cmdc.202500249","url":null,"abstract":"Tuberculosis (TB) remains a leading cause of death among infectious diseases globally, necessitating new drug discovery due to rising drug-resistant strains. Homoisoflavones, a distinct subgroup of flavonoids characterized by their 3-benzylidenechroman-4-one skeleton, are promising natural products for new antimicrobials. This study explored 42 homoisoflavone derivatives as potential anti-TB agents. Several derivatives showed potent anti-Mycobacterium tuberculosis (Mtb) activity. Specifically, derivatives 19, 22, and 41 show good selectivity index and significantly inhibited the Mtb H37Rv strain (MIC90 2.2, 3.8, and 1.9 μM, respectively). Derivatives 22 and 41 were particularly effective against the hypervirulent clinical isolate Mtb M299 (MIC90 1.5 and 2.5 μM, respectively), surpassing the potency of rifampicin (MIC90 3.3 μM). Furthermore, these derivatives inhibited intracellular Mtb H37Rv growth in infected macrophages, with derivative 41 proving most potent (IC50 5.2 μM) due to its unique nitrofuranyl and piperidine groups. The study also established a structure-activity relationship (SAR) for the homoisoflavone scaffold. In silico analyses suggest these compounds have good oral bioavailability and low toxicity. These findings highlight homoisoflavone derivatives as promising candidates for future anti-TB drug development.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500249"},"PeriodicalIF":3.6,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954557","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