ChemMedChem最新文献_第2页

In vitro and in vivo photothermal and photoacoustic activities of polymeric nanoparticles loaded with Nickel, Palladium and Platinum-bis(dithiolene) complexes. 负载镍、钯和铂-双（二噻吩）配合物的聚合物纳米颗粒的体外和体内光热和光声活性

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-04-07 DOI: 10.1002/cmdc.202500121

Franck Camerel, Jean-Baptiste Pluta, Lamiaa M A Ali, Romain Guecheichia, Victorien Massé, Thiviya Parthipan, Nathalie Bellec, Sandrine Cammas-Marion, Francois Varray, Christophe Nguyen, Magali Gary-Bobo

{"title":"In vitro and in vivo photothermal and photoacoustic activities of polymeric nanoparticles loaded with Nickel, Palladium and Platinum-bis(dithiolene) complexes.","authors":"Franck Camerel, Jean-Baptiste Pluta, Lamiaa M A Ali, Romain Guecheichia, Victorien Massé, Thiviya Parthipan, Nathalie Bellec, Sandrine Cammas-Marion, Francois Varray, Christophe Nguyen, Magali Gary-Bobo","doi":"10.1002/cmdc.202500121","DOIUrl":"https://doi.org/10.1002/cmdc.202500121","url":null,"abstract":"The development of nanosystems with enhanced photothermal and photoacoustic properties is crucial for advancing theranostic applications in cancer therapy. This study explores polymeric nanoparticles constituted by a biocompatible poly(ethylene glycol)-block-poly(benzyl malate) copolymer and loaded with metal-bis(dithiolene) complexes (M = Ni, Pd, Pt). These nanoparticles, prepared via a robust nanoprecipitation method, demonstrate uniform morphology, efficient encapsulation (~70%), and tailored near-infrared (NIR) optical absorption properties. Photothermal and photoacoustic evaluations revealed superior performance of Palladium-loaded nanoparticles, offering high contrast for imaging and significant temperature increases under NIR laser irradiation. Cytotoxicity assays confirmed their non-toxicity without laser exposure, while effective cancer cell eradication was achieved upon irradiation at power densities ≥2 W/cm2. In vivo experiments on zebrafish embryos bearing human cancer xenografts showed significant tumor size reduction (20%) post-treatment with Palladium-loaded nanoparticles under 880 nm laser irradiation. These findings underscore that metal-bis(dithiolene)-loaded nanoparticles can be versatile agents for combined diagnostics and photothermal therapy, paving the way for further optimization and clinical translation.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500121"},"PeriodicalIF":3.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794268","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: Total Synthesis of Antiausterity Agent Callistrilone O Reveals Promising Antitumor Activity in a Melanoma Homograft Mouse Model (ChemMedChem 7/2025) 封面：抗肿瘤药Callistrilone O的全合成在黑色素瘤同种移植小鼠模型中显示出有希望的抗肿瘤活性（ChemMedChem 7/2025）

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-04-01 DOI: 10.1002/cmdc.202580701

Kensuke Okuda, Akira Takagi, Ryohei Shimizu, Kensuke Nishi, Narumi Hayano, Ippei Takashima, Morichika Konishi

引用次数: 0

Development of C646-based PROTAC Degraders of the Lysine Acetyltransferases CBP and p300. 基于c646的PROTAC降解赖氨酸乙酰转移酶CBP和p300的研究

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-04-01 DOI: 10.1002/cmdc.202400792

Antonello Mai, Francesco Fiorentino, Filippo Spriano, Daniela Tomaselli, Giorgia Risi, Emanuele Fabbrizi, Valeria Pecci, Simona Nanni, Francesco Bertoni, Dante Rotili

{"title":"Development of C646-based PROTAC Degraders of the Lysine Acetyltransferases CBP and p300.","authors":"Antonello Mai, Francesco Fiorentino, Filippo Spriano, Daniela Tomaselli, Giorgia Risi, Emanuele Fabbrizi, Valeria Pecci, Simona Nanni, Francesco Bertoni, Dante Rotili","doi":"10.1002/cmdc.202400792","DOIUrl":"https://doi.org/10.1002/cmdc.202400792","url":null,"abstract":"The alteration of the lysine acetyltransferase activity and protein-protein interactions of the transcriptional co-activators CBP and p300 is linked to the development of both solid and haematological cancers. To target both functions of CBP/p300, we developed two PROTAC-based chemical degraders by linking the CBP/p300 catalytic inhibitor C646 and the CRBN ligand thalidomide via PEG-based linkers. Both compounds exhibited submicromolar inhibition of CBP/p300 and decreased their levels in the SU-DHL-10 lymphoma cell line at low-micromolar concentrations. Moreover, we demonstrated that compound 1 recruits CBP/p300 and CRBN in cells and acts as a bona fide PROTAC degrader of CBP/p300 via the ubiquitin-proteasome pathway. Finally, both compounds exhibited low-micromolar antiproliferative activity in different lymphoma cell lines and were more potent than C646. Overall, we demonstrated that the PROTAC strategy is a viable option for targeting CBP/p300 in lymphoma and identified compound 1 as a promising chemical tool and lead compound for further studies.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400792"},"PeriodicalIF":3.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750638","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}

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Cover Feature: Oxidative Coupling of Guanidines and Isocyanides Catalyzed by Nickel(II): Access to Imidazoline Derivatives with Antibacterial Activity (ChemMedChem 7/2025) 封面专题：镍催化的胍类和异氰酸酯的氧化偶联（II）：获得具有抗菌活性的咪唑啉衍生物（ChemMedChem 7/2025）

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-04-01 DOI: 10.1002/cmdc.202580704

Georgii A. Gavrilov, Tuan K. Nguyen, Dr. Svetlana A. Katkova, Dr. Nikolai V. Rostovskii, Dr. Elizaveta V. Rogacheva, Dr. Liudmila A. Kraeva, Dr. Mikhail A. Kinzhalov

引用次数: 0

Co-Culture Based Screening Revealed Selective Cytostatic Effects of Pyrazol-Azepinoindoles. 基于共培养的筛选揭示了吡唑-氮平吲哚的选择性细胞抑制作用。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-03-30 DOI: 10.1002/cmdc.202500052

Dmitry Skvortsov, Irina Zhirkina, Daria Ipatova, Lilya Vasilyeva, Yan Ivanenkov, Maria Rubtsova, Victor Kartsev, Petr Sergiev, Olga Dontsova

{"title":"Co-Culture Based Screening Revealed Selective Cytostatic Effects of Pyrazol-Azepinoindoles.","authors":"Dmitry Skvortsov, Irina Zhirkina, Daria Ipatova, Lilya Vasilyeva, Yan Ivanenkov, Maria Rubtsova, Victor Kartsev, Petr Sergiev, Olga Dontsova","doi":"10.1002/cmdc.202500052","DOIUrl":"https://doi.org/10.1002/cmdc.202500052","url":null,"abstract":"This work focuses on the search for new small molecules for anticancer therapy using the Fluorescent Cells Co-Cultivation Test (FCCT). This method allows the control of the specificity of the action of compounds from the earliest stages of drug development. For the FCCT, labelled MCF7' breast cancer cells and non-cancerous breast MCF10A cells were co-cultured. Screening of 2025 compounds in the above system and previously developed co-culture of A549' with VA-13 yielded 16 selectively cytotoxic molecules. The results were confirmed by MTT assay for 7 of these molecules. Few are known as potential antitumor agents: angelicin, coumarin, and colchicine derivatives. However, the structures of macrocycle 1, pyrazole-azepinoindole derivative 2, and complex heterocyclic derivative 3 were not described as anticancer compounds according to the PubChem and SciFinder databases. Structure-activity relationships were investigated for 2, and its derivatives. The indole with a caprolactam ring (tetrahydro-azepinoindolone core) together with the pyrazolyl at the 3-position are the key elements of the pharmacophore. The optimized pyrazole-azepinoindole derivative 23 showed SI=18 for HCT116 vs VA-13 on the expanded array of cell lines. I.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500052"},"PeriodicalIF":3.6,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750637","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

AZP2006 (Ezeprogind^®): a Promising New Drug Candidate in the Battle Against Neurodegenerative Diseases. AZP2006 （Ezeprogind®）：抗神经退行性疾病的新候选药物

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-03-27 DOI: 10.1002/cmdc.202400891

Philippe Verwaerde, Olivier Defert

{"title":"AZP2006 (Ezeprogind®): a Promising New Drug Candidate in the Battle Against Neurodegenerative Diseases.","authors":"Philippe Verwaerde, Olivier Defert","doi":"10.1002/cmdc.202400891","DOIUrl":"https://doi.org/10.1002/cmdc.202400891","url":null,"abstract":"Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disorder characterized by abnormal tau protein accumulation. This perspective article explores AZP2006 (INN: Ezeprogind), a novel small molecule targeting the Progranulin (PGRN) and Prosaposin (PSAP) axis to enhance lysosomal health in PSP treatment. AZP2006 stabilizes the PGRN-PSAP complex, improving lysosomal function and reducing tau pathology. Preclinical studies in tauopathy models demonstrated AZP2006's ability to decrease tau hyperphosphorylation, enhance neuronal survival, mitigate neuroinflammation and promote synaptogenesis. Clinical trials have shown AZP2006 to be well-tolerated in healthy volunteers and PSP patients. A Phase 2a study met its primary endpoints, as it provided valuable safety data and even encouraged further investigation of its efficacy in a larger clinical study. An upcoming Phase 2b/3 trial aims to assess long-term safety and efficacy in a larger PSP cohort. AZP2006's mechanism of action strongly suggests potential applications in other tauopathies, including Alzheimer's and Parkinson's diseases. By addressing lysosomal dysfunction and tau pathology, AZP2006 represents a promising disease-modifying approach for PSP and other neurodegenerative disorders.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400891"},"PeriodicalIF":3.6,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727288","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

Benzamide derivatives of thioacridine as DYRK2 and DYRK3 dual inhibitors. 苯甲酰胺衍生物硫代吖啶作为DYRK2和DYRK3的双重抑制剂。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-03-27 DOI: 10.1002/cmdc.202500122

Jean Roussel, Shreya Kashyap, Sourav Banerjee, Thierry Lomberget, François Hallé

{"title":"Benzamide derivatives of thioacridine as DYRK2 and DYRK3 dual inhibitors.","authors":"Jean Roussel, Shreya Kashyap, Sourav Banerjee, Thierry Lomberget, François Hallé","doi":"10.1002/cmdc.202500122","DOIUrl":"https://doi.org/10.1002/cmdc.202500122","url":null,"abstract":"DYRK2 has become a promising therapeutic target due to its involvement in various processes, including regulation of protein stability and phosphorylation events related to neurodegenerative diseases and cancers. The thioacridine derivative LDN-192960 has been widely recognized as a potent inhibitor of DYRK2. However, it also inhibits other kinases, such as DYRK3, Haspin, DYRK1A and CLK1, making it challenging to delineate the biological roles of DYRK2. In this study, we designed and synthesized a series of benzamide derivatives of the thioacridine LDN-192960, to improve selectivity and potency towards DYRK2. Several compounds demonstrated potent inhibition of DYRK2 and DYRK3, with IC50 values in the nanomolar range. Notably, the para-substituted aldehyde derivative 10f exhibited significant selectivity for DYRK2/DYRK3 against its main off-targets DYRK1A, CLK1 and Haspin, thus surpassing the selectivity profile of LDN-192960. Docking studies revealed new interactions between 10f and DYRK2, compared to LDN-192960 / DYRK2 co-crystallized structure and 10f was shown to impair proteasome activity in HEK293 cells. These findings highlight the pharmacophore study of DYRK2/DYRK3 dual inhibitors, and present compound 10f as a selective chemical probe for DYRK2 and DYRK3, that might be an essential tool for elucidating the specific biological roles of these kinases and advancing targeted therapeutic applications.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500122"},"PeriodicalIF":3.6,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717679","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

Ligand Screening and Discovery using Cocktail Soaking and Automated MicroED. 利用鸡尾酒浸泡和自动微电子显微镜筛选和发现配体。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-03-26 DOI: 10.1002/cmdc.202500156

Jieye Lin, Marc J Gallenito, Johan Hattne, Tamir Gonen

引用次数: 0

Exploiting the 5-amino-11H-indolo[3,2-c]isoquinoline Core to Achieve Better G-quadruplex Ligands for Cancer Therapy. 利用5-氨基- 11h -吲哚[3,2-c]异喹啉核心获得用于癌症治疗的更好的g -四联体配体。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-03-26 DOI: 10.1002/cmdc.202401019

Israa M Aljnadi, Barbara Bahls, Noélia Duarte, Bruno L Victor, Eduarda Mendes, Sergio P Camões, Joana P Miranda, Ermelinda Maçôas, Alexandra Paulo

{"title":"Exploiting the 5-amino-11H-indolo[3,2-c]isoquinoline Core to Achieve Better G-quadruplex Ligands for Cancer Therapy.","authors":"Israa M Aljnadi, Barbara Bahls, Noélia Duarte, Bruno L Victor, Eduarda Mendes, Sergio P Camões, Joana P Miranda, Ermelinda Maçôas, Alexandra Paulo","doi":"10.1002/cmdc.202401019","DOIUrl":"https://doi.org/10.1002/cmdc.202401019","url":null,"abstract":"G-quadruplexes (G4) are secondary structures that can form within guanine-rich nucleic acids and have cell proliferation regulatory functions. Targeting DNA G4 structures has emerged as a promising anticancer therapy, highlighting the need for new G4 ligands with reduced number of cationic groups to ensure lower toxicity. In this study, we report the synthesis of mono- and di-substituted 5-amino-11H-indolo[3,2-c]isoquinolines. Fluorescence spectroscopy studies indicate that substitution in position 11 dictates the preference of binding to different G4. Compound 10, which features a ethylpyrrolidine side chain, demonstrated a binding preference by one order of magnitude for parallel c-MYCG4 (Kb = 107 M-1), over parallel k-RASG4 (Kb = 106 M-1), hybrid TeloG4 and dsDNA (Kb = 105 M-1). Molecular docking studies revealed that compound 10 can bind not only to the flat G-quartets but also to bridge between two loops of c-MYCG4 through hydrogen bonds, which may explain its capacity to discriminate between G4. Moreover, compound 10 drastically reduced the cell viability of breast cancer cells at a concentration of 10 µM. Overall, herein we report the discovery of a new potent and selective G4 ligand, with reduced number of side chains and antiproliferative activity in cancer cells that deserves to be further investigated.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202401019"},"PeriodicalIF":3.6,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707851","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

Carborane-based Analogues of Celecoxib and Flurbiprofen, their COX Inhibition Potential and COX Selectivity Index. 塞来昔布和氟比洛芬碳硼烷基类似物及其COX抑制电位和COX选择性指数。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-03-24 DOI: 10.1002/cmdc.202500166

Lea Ueberham, Jonas Schädlich, Kim Schramke, Sebastian Braun, Christoph Selg, Markus Laube, Peter Lönnecke, Jens Pietzsch, Evamarie Hey-Hawkins

{"title":"Carborane-based Analogues of Celecoxib and Flurbiprofen, their COX Inhibition Potential and COX Selectivity Index.","authors":"Lea Ueberham, Jonas Schädlich, Kim Schramke, Sebastian Braun, Christoph Selg, Markus Laube, Peter Lönnecke, Jens Pietzsch, Evamarie Hey-Hawkins","doi":"10.1002/cmdc.202500166","DOIUrl":"https://doi.org/10.1002/cmdc.202500166","url":null,"abstract":"The cylcooxygenase isoforms COX-1 and COX-2 are involved in the production of prostaglandins in physiological and pathological processes. The overexpression of COX-2 under inflammatory conditions as well as its role in cancer and neurodegenerative diseases necessitates the need to develop and improve non-steroidal anti-inflammatory drugs. These COX inhibitors are used to reduce the symptoms of inflammation, with aspirin, indomethacin or flurbiprofen being prominent examples. To reduce unwanted side effects connected with unselective inhibition, the development of novel COX-2 selective inhibitors is important. We herein describe the synthesis, characterization, and in vitro biological evaluation of eight flurbiprofen- and celecoxib-based carborane analogues. Carboranes as hydrophobic surrogates are suitable substituents that can contribute to a selectivity increase towards COX-2, due to size-exclusion. The inhibitory efficacy for COX-1 and COX-2 of the four ortho- and four nido-carborane derivatives has been tested. The nido compounds are much more potent than their closo-carborane analogues. Celecoxib-based compound 10 showed an IC50 value in the sub-µM range for COX-2 and in contrast to its ortho-carborane derivative a reversed selectivity preference for COX-2 instead of COX-1. While none of these carborane derivatives outperformed their organic analogues, the flurbiprofen-based nido-carborane derivatives 14a and 14b surpassed the known carborane-based flurbiprofen analogues.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500166"},"PeriodicalIF":3.6,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699257","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