ChemMedChem最新文献_第5页

Front Cover: Development of a NanoBRET Assay Platform to Detect Intracellular Ligands for the Chemokine Receptors CCR6 and CXCR1 (ChemMedChem 20/2024) 封面：开发用于检测趋化因子受体 CCR6 和 CXCR1 细胞内配体的 NanoBRET 检测平台（ChemMedChem 20/2024）

IF 3.6 4区医学

ChemMedChem Pub Date : 2024-10-17 DOI: 10.1002/cmdc.202482001

Max E. Huber, Silas L. Wurnig, Dr. Aurélien F. A. Moumbock, Lara Toy, Prof. Dr. Evi Kostenis, Ana Alonso Bartolomé, Dr. Martyna Szpakowska, Dr. Andy Chevigné, Prof. Dr. Stefan Günther, Prof. Dr. Finn K. Hansen, Prof. Dr. Matthias Schiedel

引用次数: 0

Targeting Tetraspanins at Cell Interfaces: Functional Modulation and Exosome-Based Drug Delivery for Precise Disease Treatment. 在细胞界面靶向四泛素：功能调节和基于外泌体的药物输送，实现精准疾病治疗。

IF 3.6 4区医学

ChemMedChem Pub Date : 2024-10-16 DOI: 10.1002/cmdc.202400664

Kun Xu, Huixia Feng, Rui Zhao, Yanyan Huang

{"title":"Targeting Tetraspanins at Cell Interfaces: Functional Modulation and Exosome-Based Drug Delivery for Precise Disease Treatment.","authors":"Kun Xu, Huixia Feng, Rui Zhao, Yanyan Huang","doi":"10.1002/cmdc.202400664","DOIUrl":"10.1002/cmdc.202400664","url":null,"abstract":"Tetraspanins are key players in various physiological and pathological processes, including malignancy, immune response, fertilization, and infectious disease. Affinity ligands targeting the interactions between tetraspanins and partner proteins are promising for modulating downstream signaling pathways, thus emerging as attractive candidates for interfering related biological functions. Due to the involvement in vesicle biogenesis and cargo trafficking, tetraspanins are also regarded as exosome markers, and become molecular targets for drug loading and delivery. Given the rapid development in these areas, this minireview focuses on recent advances in design and engineering of affinity binders toward tetraspanins including CD63, CD81, and CD9. Their mechanism of actions in modulating protein interactions at cell interfaces and treatment of malignant diseases are discussed. Strategies for constructing exosome-based drug delivery platforms are also reviewed, with emphasis on the important roles of tetraspanins and the affinity ligands. Finally, challenges and future development of tetraspanin-targeting therapy and exosomal drug delivery platforms are also discussed.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400664"},"PeriodicalIF":3.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454113","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

3'-Dehydroxypurpurogallin-4-Carboxamides as Influenza A Endonuclease Inhibitors: Synthesis, Structure-Activity Relationship Analysis, and Structural Characterization of Protein Complex. 3'-Dehydroxypurpurogallin-4-carboxamides as Influenza A Endonuclease Inhibitors：合成、SAR 分析和蛋白质复合物的结构特征。

IF 3.6 4区医学

ChemMedChem Pub Date : 2024-10-14 DOI: 10.1002/cmdc.202400577

Michal Kráľ, Tomáš Kotačka, Róbert Reiberger, Gabriela Panýrková, Kateřina Radilová, Zuzana Osifová, Miroslav Flieger, Jan Konvalinka, Pavel Majer, Milan Kožíšek, Aleš Machara

{"title":"3'-Dehydroxypurpurogallin-4-Carboxamides as Influenza A Endonuclease Inhibitors: Synthesis, Structure-Activity Relationship Analysis, and Structural Characterization of Protein Complex.","authors":"Michal Kráľ, Tomáš Kotačka, Róbert Reiberger, Gabriela Panýrková, Kateřina Radilová, Zuzana Osifová, Miroslav Flieger, Jan Konvalinka, Pavel Majer, Milan Kožíšek, Aleš Machara","doi":"10.1002/cmdc.202400577","DOIUrl":"10.1002/cmdc.202400577","url":null,"abstract":"The influenza RNA-dependent RNA polymerase harbours an endonuclease subunit characterized by a catalytic site housing two divalent metal ions. By effectively chelating both Mg2+ and Mn2+ ions, a small-molecule inhibitor with a metal-binding pharmacophore can halt endonuclease activity. Herein, two 3'-dehydroxypurpurogallin-4-carboxamide series, namely twelve C-4' unsubstituted and twelve C-4' phenyl substituted congeners were designed and prepared to be tested as inhibitors of the metal-dependent viral enzyme. These inhibitors were accessed through the chemoenzymatic reaction of gallic acid with either pyrocatechol or phenylpyrocatechol moderated by laccase, followed by amidation. Experimental IC50 values were determined using AlphaScreen technology, with the most potent inhibitors exhibiting IC50 values around 0.35 μM. Using X-ray crystallography, we analyzed structure of the endonuclease in complex with one potent 3'-dehydroxypurpurogallin-carboxamide at 2.0 Å resolution, revealing the coordination of the compound's triad of oxygen atoms with the two metal ions in the influenza A endonuclease active site.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400577"},"PeriodicalIF":3.6,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454105","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

De Novo Design of Tryptophan Containing Broad-Spectrum Cationic Antimicrobial Octapeptides. 从头设计含色氨酸的广谱阳离子抗菌八肽。

IF 3.6 4区医学

ChemMedChem Pub Date : 2024-10-14 DOI: 10.1002/cmdc.202400566

Tanumoy Sarkar, S R Vignesh, Pradeep Kumar Sundaravadivelu, Rajkumar P Thummer, Priyadarshi Satpati, Sunanda Chatterjee

{"title":"De Novo Design of Tryptophan Containing Broad-Spectrum Cationic Antimicrobial Octapeptides.","authors":"Tanumoy Sarkar, S R Vignesh, Pradeep Kumar Sundaravadivelu, Rajkumar P Thummer, Priyadarshi Satpati, Sunanda Chatterjee","doi":"10.1002/cmdc.202400566","DOIUrl":"10.1002/cmdc.202400566","url":null,"abstract":"With the advent of antibiotic resistant organisms, development of alternate classes of molecules other than antibiotics to combat microbial infections, have become extremely important. In this context, antimicrobial peptides have taken center stage of antimicrobial therapeutic research. In this work, we have reported two cationic antimicrobial octapeptides WRL and LWRF, with broad spectrum antimicrobial activities against several strains of ESKAPE pathogens. Both the peptides were membrane associative and induced microbial cell death through membranolysis, being selective towards microbial membranes over mammalian membranes. The AMPs were unstructured in water, adopting partial helical conformation in the presence of microbial membrane mimics. Electrostatic interaction formed the primary basis of peptide-membrane interactions. WRL was more potent, salt tolerant and faster acting of the two AMPs, owing to the presence of two tryptophan residues against that of one in LWRF. Increased tryptophan number in WRL enhanced its membrane association ability, resulting in higher antimicrobial potency but lower selectivity. This experimental and computational work, established that an optimum number of tryptophan residues and their position was critical for obtaining high antimicrobial potency and selectivity simultaneously in the designed cationic AMPs. Understanding the peptide membrane interactions in atomistic details can lead to development of better antimicrobial therapeutics in future.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400566"},"PeriodicalIF":3.6,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454108","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

Acetic Acid-Driven One-Pot Synthesis of 4,7-dihydro-[1,2,3]thiadiazolo[5,4-b]pyridine-6-carboxamides and Pharmacological Evaluations. 乙酸驱动的 4,7-二氢-[1,2,3]噻二唑并[5,4-b]吡啶-6-羧酰胺的单锅合成及药理评价。

IF 3.6 4区医学

ChemMedChem Pub Date : 2024-10-12 DOI: 10.1002/cmdc.202400595

Savan S Bhalodiya, Mehul P Parmar, Chirag D Patel, Subham G Patel, Disha P Vala, Nandhakumar Suresh, Bhuvaneshwari Jayachandran, Madan Kumar Arumugam, Mahesh Narayan, Hitendra M Patel

{"title":"Acetic Acid-Driven One-Pot Synthesis of 4,7-dihydro-[1,2,3]thiadiazolo[5,4-b]pyridine-6-carboxamides and Pharmacological Evaluations.","authors":"Savan S Bhalodiya, Mehul P Parmar, Chirag D Patel, Subham G Patel, Disha P Vala, Nandhakumar Suresh, Bhuvaneshwari Jayachandran, Madan Kumar Arumugam, Mahesh Narayan, Hitendra M Patel","doi":"10.1002/cmdc.202400595","DOIUrl":"10.1002/cmdc.202400595","url":null,"abstract":"A diverse set of 4,7-dihydro-[1,2,3]thiadiazolo[5,4-b]pyridine-6-carboxamides 4(a-o) was synthesized via a one-pot reaction of 5-amino-[1,2,3]thiadiazole, various aromatic aldehydes, and different acetoacetanilides, using glacial acetic acid. The resulting compounds were obtained in moderate to good yields. All the newly synthesized compounds were evaluated for their antimicrobial activity. Among them, compound 4 e demonstrated superior efficacy against the Salinivibrio proteolyticus strain of Gram-negative bacteria compared to ciprofloxacin. Compound 4 d exhibited the highest potency against the fungal strain Candida albicans, surpassing amphotericin B. The physicochemical characteristics of 4 d and 4 e were assessed. According to docking analysis, DHTDAPy 4 e shows a higher binding affinity of -7.2 kcal/mol in the binding cavity of the receptor. These findings illustrate the safety, tolerability, and potency of the newly synthesized DHTDAPy compounds against fungal and bacterial infections.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400595"},"PeriodicalIF":3.6,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454106","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

Adipocyte-Targeted Nanotechnology and Cell-Based Therapy for Obesity Treatment. 用于治疗肥胖症的脂肪细胞靶向纳米技术和细胞疗法。

IF 3.6 4区医学

ChemMedChem Pub Date : 2024-10-10 DOI: 10.1002/cmdc.202400611

Yue Wu, Siqi Deng, Siyu Wei, Wenqi Wei, Yunxiang He, Junling Guo

引用次数: 0

The Spanish Society of Medicinal Chemistry: Promoting Pharmaceutical R&D in Spain since 1977. 西班牙药物化学学会：自 1977 年以来一直致力于促进西班牙的医药研发。

IF 3.6 4区医学

ChemMedChem Pub Date : 2024-10-10 DOI: 10.1002/cmdc.202400511

José-Manuel Bartolomé-Nebreda, Beatriz de Pascual-Teresa, Marta Gutiérrez-Rodríguez, Mercedes Martín-Martínez

{"title":"The Spanish Society of Medicinal Chemistry: Promoting Pharmaceutical R&D in Spain since 1977.","authors":"José-Manuel Bartolomé-Nebreda, Beatriz de Pascual-Teresa, Marta Gutiérrez-Rodríguez, Mercedes Martín-Martínez","doi":"10.1002/cmdc.202400511","DOIUrl":"https://doi.org/10.1002/cmdc.202400511","url":null,"abstract":"The Spanish Society of Medicinal Chemistry (Sociedad Española de Química Terapéutica SEQT), founded in 1977, aims to advance pharmaceutical research and education in Spain, collaborating with academia, industry, and public entities. It was initially linked with the Institute of Medicinal Chemistry from Spanish National Research Council (IQM-CSIC), emphasizing the independence of medicinal chemistry as a discipline. SEQT's presidency rotates between representatives from universities, research institutes, and industry, ensuring diverse perspectives. With around 500 members, SEQT represents sectors including universities, CSIC, and industry, with a notable presence of early-career researchers. The Society actively participates in the European Federation for Medicinal chemistry and Chemical biology (EFMC). SEQT organizes conferences, summer schools, and mini symposia to facilitate networking and knowledge exchange among professionals. To support early-career scientists, SEQT organizes symposia and awards, recognizing achievements in drug discovery. It fosters mentorship opportunities and engages with international networks like EFMC-YSN. In 2023, SEQT established its Early Career Scientist (SEQT-ECS) group to provide tailored support and resources. With over 40 years of experience, SEQT continues to evolve, embracing social media and adapting to changes in medicinal chemistry and chemical biology. It remains committed to supporting its members and advancing research to address human health challenges.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400511"},"PeriodicalIF":3.6,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454114","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 Dual Action Platinum(IV) Complex with Self-assembly Property Inhibits Prostate Cancer through Mitochondrial Stress Pathway. 具有自组装特性的双效铂(IV)复合物通过线粒体应激途径抑制前列腺癌。

IF 3.6 4区医学

ChemMedChem Pub Date : 2024-10-08 DOI: 10.1002/cmdc.202400289

Muhammad Nafees, Muhammad Hanif, Raja Muhammad Asif Khan, Faisal Faiz, Piaoping Yang

{"title":"A Dual Action Platinum(IV) Complex with Self-assembly Property Inhibits Prostate Cancer through Mitochondrial Stress Pathway.","authors":"Muhammad Nafees, Muhammad Hanif, Raja Muhammad Asif Khan, Faisal Faiz, Piaoping Yang","doi":"10.1002/cmdc.202400289","DOIUrl":"https://doi.org/10.1002/cmdc.202400289","url":null,"abstract":"Platinum(IV) prodrugs are highly promising anticancer agents because they can selectively target tumors and minimize the adverse effects associated with their PtII congeners. In this study, we synthesized dual action PtIV complexes by linking oxoplatin with lithocholic acid. The synthesized compounds, designated as PL-I, PL-II, and PL-III, can spontaneously self-assemble in water, resulting in the formation of spherical shape nanoparticles. Among the developed complexes, PL-III appeared to be the most potent compound against all the tested cancer cell lines, with 10 fold higher cytotoxicity compared to cisplatin in PC3 cells. The complex arrests the cell cycle in the S and G2 phases and induces DNA damage. Additional mechanistic investigations demonstrate that PL-III predominantly localizes within the mitochondria and cytoplasm. Consequently, PL-III disrupts mitochondrial membrane potential, increases ROS production, and perturbs mitochondrial bioenergetics in PC3 cells. The complex induces apoptosis through the mitochondrial pathway by upregulating pro-apoptotic protein expression and downregulating anti-apoptotic protein expression from the BCl-2 protein family. These results demonstrate that higher cellular uptake and reduction of PL-III by biological reductants in PC3 cells resulted in a synergistic effect of lithocholic acid and cisplatin, which can be easily observed due to its unique cytotoxic mechanism. This further underscores the significance of dual-action PtIV complexes in enhancing the efficacy of cancer therapy.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400289"},"PeriodicalIF":3.6,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386679","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

Programmable Intelligent DNA Nanoreactors (iDNRs) for in vivo Tumor Diagnosis and Therapy. 用于体内肿瘤诊断和治疗的可编程智能 DNA 纳米反应器 (iDNR)。

IF 3.6 4区医学

ChemMedChem Pub Date : 2024-10-08 DOI: 10.1002/cmdc.202400531

Ying Shen, Rongkai Cai, Liang Wu, Kun Han, Yu Yang, Dongsheng Mao

引用次数: 0

Exploring the Utility of Cell-Penetrating Peptides as Vehicles for the Delivery of Distinct Antimalarial Drug Cargoes. 探索细胞穿透肽作为输送不同抗疟药物载体的实用性。

IF 3.6 4区医学

ChemMedChem Pub Date : 2024-10-08 DOI: 10.1002/cmdc.202400637

Caitlin L Gare, Isabella R Palombi, Andrew M White, Marina Chavchich, Michael D Edstein, Aaron Lock, Vicky M Avery, David J Craik, Brendan J McMorran, Nicole Lawrence, Lara R Malins

{"title":"Exploring the Utility of Cell-Penetrating Peptides as Vehicles for the Delivery of Distinct Antimalarial Drug Cargoes.","authors":"Caitlin L Gare, Isabella R Palombi, Andrew M White, Marina Chavchich, Michael D Edstein, Aaron Lock, Vicky M Avery, David J Craik, Brendan J McMorran, Nicole Lawrence, Lara R Malins","doi":"10.1002/cmdc.202400637","DOIUrl":"10.1002/cmdc.202400637","url":null,"abstract":"The devastating impact of malaria includes significant mortality and illness worldwide. Increasing resistance of the causative parasite, Plasmodium, to existing antimalarial drugs underscores a need for additional compounds with distinct modes of action in the therapeutic development pipeline. Here we showcase peptide-drug conjugates (PDCs) as an attractive compound class, in which therapeutic or lead antimalarials are chemically conjugated to cell-penetrating peptides. This approach aims to enhance selective uptake into Plasmodium-infected red blood cells and impart additional cytotoxic actions on the intraerythrocytic parasite, thereby enabling targeted drug delivery and dual modes of action. We describe the development of PDCs featuring four compounds with antimalarial activity-primaquine, artesunate, tafenoquine and methotrexate-conjugated to three cell-penetrating peptide scaffolds with varied antiplasmodial activity, including active and inactive analogues of platelet factor 4 derived internalization peptide (PDIP), and a cyclic polyarginine peptide. Development of this diverse set of PDCs featured distinct and adaptable conjugation strategies, to produce conjugates with in vitro antiplasmodial activities ranging from low nanomolar to low micromolar potencies according to the drug cargo and bioactivity of the partner peptide. Overall, this study establishes a strategic and methodological framework for the further development of dual mode of action peptide-drug antimalarial therapeutics.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400637"},"PeriodicalIF":3.6,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386680","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