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Front Cover: (ChemMedChem 12/2025) 封面:(ChemMedChem 12/2025)
IF 3.4 4区 医学
ChemMedChem Pub Date : 2025-06-17 DOI: 10.1002/cmdc.202581201
{"title":"Front Cover: (ChemMedChem 12/2025)","authors":"","doi":"10.1002/cmdc.202581201","DOIUrl":"10.1002/cmdc.202581201","url":null,"abstract":"<p>Bringing chemistry, biology, and drug discovery together fosters innovation, increases collaboration, and accelerates science. <i>ChemMedChem</i> publishes high-impact articles showcasing the breadth of international research in medicinal chemistry, from small pharmacologically active molecules to new modalities including nanomedicine and biologics. Cover image provided courtesy of Ivan Sanchis and Dr. Álvaro Siano.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 12","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202581201","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144308928","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
Efficacy of DNA Intercalator-Conjugated Triplex-Forming Oligonucleotide as Anticancer Agent. DNA插入物偶联三聚体寡核苷酸抗癌作用的研究。
IF 3.4 4区 医学
ChemMedChem Pub Date : 2025-06-12 DOI: 10.1002/cmdc.202500325
Haruki Toyama, Akira Toriba, Atsushi Shibata, Takehiko Wada, Asako Yamayoshi, Yu Mikame
{"title":"Efficacy of DNA Intercalator-Conjugated Triplex-Forming Oligonucleotide as Anticancer Agent.","authors":"Haruki Toyama, Akira Toriba, Atsushi Shibata, Takehiko Wada, Asako Yamayoshi, Yu Mikame","doi":"10.1002/cmdc.202500325","DOIUrl":"10.1002/cmdc.202500325","url":null,"abstract":"<p><p>A triplex-forming oligonucleotide (TFO) can form a sequence-specific triple helix via Hoogsteen hydrogen bonding to polypurine tracts within a major groove side of a DNA duplex. Triplex formation can induce a double-strand break, and this phenomenon at the amplified gene loci can selectively induce the cell death of cancer cells with specific gene amplification. However, the relationship between the binding affinity of TFO for target gene loci and the cell death response remains unclear. In this study, it is aimed to develop DNA intercalator-conjugated TFOs with higher affinity for the human epidermal growth factor receptor type2 gene, which is often amplified in breast cancer cells, than the unmodified TFO. The binding affinity of the TFOs for the target DNA duplex is analyzed using nondenaturing polyacrylamide gel electrophoresis, and one of the DNA intercalator-conjugated TFOs show a higher binding affinity for the target duplex than the unmodified TFO. The cell death responses induced by these TFOs using the WST-8 assay is also evaluated suggesting that the higher binding affinity of the TFO for amplified gene loci can lead to a stronger cell death response of cancer cells with specific gene amplification.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500325"},"PeriodicalIF":3.4,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281816","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
Antiprotozoal Activity of Highly Substituted Pyrazole and Pyrimidine Derivatives 高取代吡唑和嘧啶衍生物的抗原虫活性。
IF 3.4 4区 医学
ChemMedChem Pub Date : 2025-06-12 DOI: 10.1002/cmdc.202500154
Matteo Lusardi, Nicoletta Basilico, Erika Iervasi, Chiara Brullo, Silvia Parapini, Marco Ponassi, Camillo Rosano, Andrea Spallarossa
{"title":"Antiprotozoal Activity of Highly Substituted Pyrazole and Pyrimidine Derivatives","authors":"Matteo Lusardi,&nbsp;Nicoletta Basilico,&nbsp;Erika Iervasi,&nbsp;Chiara Brullo,&nbsp;Silvia Parapini,&nbsp;Marco Ponassi,&nbsp;Camillo Rosano,&nbsp;Andrea Spallarossa","doi":"10.1002/cmdc.202500154","DOIUrl":"10.1002/cmdc.202500154","url":null,"abstract":"<p>To further extend the structure-activity relationships of previously reported antimalarial anilino-pyrazoles <b>VI</b>, trisubstituted pyrazoles <b>13–15,</b> and pyrimidines <b>16</b> and <b>17</b> are designed and synthesized. The novel derivatives are prepared thorough a divergent, chemo-selective approach starting from N,S-acetal intermediates. Compounds <b>13–17</b> are tested for their antimalarial and antileishmanial activity and their cytotoxicity is evaluated against human fibroblast. Pyrazoles <b>14 d,e</b> and pyrimidine <b>17e</b> are identified as novel and effective antiplasmodial agents being able to inhibit, at micromolar concentrations, chloroquine(CQ)-sensitive and CQ-resistant <i>Plasmodium falciparum</i> strains, as well as <i>Leishmania infatum</i> and <i>Leishmania tropica</i> protozoa. Additionally, favorable pharmacokinetics and toxicity profiles are predicted for the compounds.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 16","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202500154","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273779","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 Biological Evaluation of Evodiamine Derivatives as Antibody-Drug Conjugate (ADC) Payloads. evoloo二胺衍生物作为抗体-药物偶联物(ADC)有效载荷的设计、合成和生物学评价。
IF 3.6 4区 医学
ChemMedChem Pub Date : 2025-06-05 DOI: 10.1002/cmdc.202500268
Ruifeng Liu, Yanfang Duan, Jing Jiang, Weihua Bian, Meiying Zhu
{"title":"Design, Synthesis, and Biological Evaluation of Evodiamine Derivatives as Antibody-Drug Conjugate (ADC) Payloads.","authors":"Ruifeng Liu, Yanfang Duan, Jing Jiang, Weihua Bian, Meiying Zhu","doi":"10.1002/cmdc.202500268","DOIUrl":"https://doi.org/10.1002/cmdc.202500268","url":null,"abstract":"<p><p>Natural product evodiamine derivatives exhibit multitarget bioactivities as dual TOPO I/II inhibitors, demonstrating remarkable potential in antitumor applications. Based on the evodiamine derivative D7-03, six derivatives were synthesized. In vitro screening showed that D7-09 had the strongest anti-tumor activity (IC50 = 9.75-26.11 nM) but poor hydrophobicity and solubility. D7-03, with nM-level cytotoxicity, better physicochemical properties, and high yield, was chosen as the core payload for ADC construction. The active molecule D7-03 was further explored as an antibody-drug conjugate (ADC) payload by constructing four linker-toxin complexes. These complexes were conjugated with trastuzumab to generate ADC candidate molecules. Notably, Ab-DL07-D7-03 exhibited superior activity (IC50 = 8.369 nM and 4.899 nM in HCC1954 and NCI-N87 cells, respectively) compared to the control group Ab-LC08-SN38. This study is the first application of evodiamine derivatives as TOPO I / II dual inhibitors in the ADC field, which not only provides a new strategy for the development of ADC payloads but also enriches the innovative application of natural product small molecules in tumor-targeted therapy.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500268"},"PeriodicalIF":3.6,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232804","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
Platinum N-Heterocyclic Carbene Complexes Based on Adenosine: Synthesis and Antiproliferative Studies 基于腺苷的铂n -杂环卡宾配合物:合成及抗增殖研究。
IF 3.4 4区 医学
ChemMedChem Pub Date : 2025-06-04 DOI: 10.1002/cmdc.202500368
Giulia Orsini, Andreia Marinho, Claudia Nunes, Ana Petronilho
{"title":"Platinum N-Heterocyclic Carbene Complexes Based on Adenosine: Synthesis and Antiproliferative Studies","authors":"Giulia Orsini,&nbsp;Andreia Marinho,&nbsp;Claudia Nunes,&nbsp;Ana Petronilho","doi":"10.1002/cmdc.202500368","DOIUrl":"10.1002/cmdc.202500368","url":null,"abstract":"<p>Platinum(II) N-heterocyclic carbene complexes based on 2-chloroadenosine are synthesized. The reaction of 2-chloro-2′,3′,5′-tri-<i>O</i>-acetyladenosine <b>1</b> with Pt(PPh<sub>3</sub>)<sub>4</sub> by C−Cl oxidative addition yields complex <b>2</b>, with a Pt<sup>II</sup> center bond to the C-2 of the purine ring. Complex <b>2</b> reacts with methyl iodide to yield N-heterocyclic carbene <b>3</b>, which is subsequently deprotected under basic conditions to provide N-heterocyclic carbene <b>4</b>, bearing a fully deprotected ribose. The compounds are tested for their cytotoxic activity in five different cell lines: L929, HEK293, A375, MDA-MB-231, and MCF-7. Among the platinum compounds, compound <b>2</b>, the neutral compound bearing an anionic adenosyl ligand, provides the highest cytotoxic activity, particularly against the A375 and MDA-MB-231 cell lines. Encapsulation of compound <b>2</b> with nanostructured lipid carriers does not lead to an improvement in the cytotoxic activity.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 16","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223831","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
Tetrahydrofuran-Containing Pharmaceuticals: Targets, Pharmacological Activities, and their SAR Studies 含四氢呋喃的药物:靶点、药理活性及其SAR研究。
IF 3.4 4区 医学
ChemMedChem Pub Date : 2025-06-04 DOI: 10.1002/cmdc.202500259
Yiou Mei, Yunfei Du
{"title":"Tetrahydrofuran-Containing Pharmaceuticals: Targets, Pharmacological Activities, and their SAR Studies","authors":"Yiou Mei,&nbsp;Yunfei Du","doi":"10.1002/cmdc.202500259","DOIUrl":"10.1002/cmdc.202500259","url":null,"abstract":"<p>Tetrahydrofuran (THF), a five-membered cyclic ether with a carbon-oxygen ring structure, is a common solvent and an important functional group in the field of organic synthesis methodology. In addition, THF also plays an important role in drug discovery. The US food and drug administration (FDA) has approved a total of 13 THF-containing drugs for a range of clinical diseases, such as Terazosin and Darunavir. These drugs exhibit superior pharmacological effects in multiple therapeutic fields. This review offers an extensive overview of FDA-approved drugs containing the THF nucleus, emphasizing their pharmacological activities and structure–activity relationships.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 16","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223832","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
Novel 4,5-Dihydrothiazole-Phenylpiperazine Derivatives: Synthesis, Docking Studies and Pharmacological Evaluation as Serotonergic Agents 新型4,5-二氢噻唑-苯哌嗪衍生物:合成、对接研究及作为血清素能剂的药理评价。
IF 3.4 4区 医学
ChemMedChem Pub Date : 2025-06-03 DOI: 10.1002/cmdc.202500288
Giorgia Andreozzi, Natalia Karkoszka, Rosa Sparaco, Angela Corvino, Beatrice Severino, Vincenzo Santagada, Elisa Magli, Ewa Gibuła-Tarłowska, Jolanta H. Kotlińska, Kinga Gawel, Raffaele Capasso, Anna Lesniak, Nataliia Semenko, Agnieszka A. Kaczor, Anna Bielenica, Grażyna Biała, Giuseppe Caliendo, Ewa Kędzierska, Ferdinando Fiorino
{"title":"Novel 4,5-Dihydrothiazole-Phenylpiperazine Derivatives: Synthesis, Docking Studies and Pharmacological Evaluation as Serotonergic Agents","authors":"Giorgia Andreozzi,&nbsp;Natalia Karkoszka,&nbsp;Rosa Sparaco,&nbsp;Angela Corvino,&nbsp;Beatrice Severino,&nbsp;Vincenzo Santagada,&nbsp;Elisa Magli,&nbsp;Ewa Gibuła-Tarłowska,&nbsp;Jolanta H. Kotlińska,&nbsp;Kinga Gawel,&nbsp;Raffaele Capasso,&nbsp;Anna Lesniak,&nbsp;Nataliia Semenko,&nbsp;Agnieszka A. Kaczor,&nbsp;Anna Bielenica,&nbsp;Grażyna Biała,&nbsp;Giuseppe Caliendo,&nbsp;Ewa Kędzierska,&nbsp;Ferdinando Fiorino","doi":"10.1002/cmdc.202500288","DOIUrl":"10.1002/cmdc.202500288","url":null,"abstract":"<p>The synthesis of a new series of long-chain arylpiperazine as serotoninergic ligands (<b>FG 1-18</b>) is described. The combination of structural elements including heterocyclic nucleus, propyl chain, and 4,5-dihydrothiazol-2-ylphenylpiperazines leads to the preparation of different derivatives tested for their affinity toward 5-HT<sub>1A</sub>, 5-HT<sub>2A</sub>, and 5-HT<sub>2C</sub> receptors. The compounds with better affinity and selectivity binding profiles toward 5-HT<sub>1A</sub> and 5-HT<sub>2C</sub> (<b>FG-1</b>, <b>FG-4</b>, <b>FG-5</b>, <b>FG-6</b>, <b>FG-7</b>, <b>FG-8</b>, and <b>FG-18</b>) are selected for further <i>in vivo</i> assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies are performed. The results of pharmacological studies show that compounds <b>FG-1</b>, <b>FG-5</b>, <b>FG-8</b>, and <b>FG-6</b> exert antidepressant-like effects, and <b>FG-1</b>, <b>FG-18</b>, <b>FG-6</b>, and <b>FG-7</b> reveal also significant anxiolytic properties. Among the developed derivatives, the most promising compounds seem to be <b>FG-1</b>, which exhibit antidepressant, anxiolytic, and anticonvulsant properties, <b>FG-7</b> and <b>FG-18</b> that show features as anxiolytic combine to a pro-cognitive property and notable affinity and selectivity for 5-HT<sub>2C</sub> receptor, respectively.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 15","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202500288","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207262","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
Front Cover: Carborane-Based Analogs of Celecoxib and Flurbiprofen, their COX Inhibition Potential, and COX Selectivity Index (ChemMedChem 11/2025) 封面:塞来昔布和氟比洛芬的碳硼烷类类似物,它们的COX抑制潜能和COX选择性指数(ChemMedChem 11/2025)
IF 3.4 4区 医学
ChemMedChem Pub Date : 2025-06-03 DOI: 10.1002/cmdc.202581101
Lea Ueberham, Jonas Schädlich, Kim Schramke, Sebastian Braun, Christoph Selg, Markus Laube, Peter Lönnecke, Jens Pietzsch, Evamarie Hey-Hawkins
{"title":"Front Cover: Carborane-Based Analogs of Celecoxib and Flurbiprofen, their COX Inhibition Potential, and COX Selectivity Index (ChemMedChem 11/2025)","authors":"Lea Ueberham,&nbsp;Jonas Schädlich,&nbsp;Kim Schramke,&nbsp;Sebastian Braun,&nbsp;Christoph Selg,&nbsp;Markus Laube,&nbsp;Peter Lönnecke,&nbsp;Jens Pietzsch,&nbsp;Evamarie Hey-Hawkins","doi":"10.1002/cmdc.202581101","DOIUrl":"10.1002/cmdc.202581101","url":null,"abstract":"<p>An illustrative Eurasian jay, representing the COX-2 enzyme, selectively picks up two superior <i>nido</i>-carborane acorns (shown without caps), while ignoring inferior <i>closo</i>-carborane analogues (acorns with caps). The removal of one boron vertex (<i>nido</i> form) significantly enhances COX-2 inhibitory potency, highlighting their potential as novel anti-inflammatory drug candidates. More details can be found in article 10.1002/cmdc.202500166 by Evamarie Hey-Hawkins. Art by Christoph Selg.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 11","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202581101","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144206817","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
Cover Feature: Advances in Diclofenac Derivatives: Exploring Carborane-Substituted N-Methyl and Nitrile Analogs for Anticancer Therapy (ChemMedChem 11/2025) 封面专题:双氯芬酸衍生物的进展:探索碳硼烷取代的n -甲基和腈类似物用于抗癌治疗(ChemMedChem 11/2025)
IF 3.4 4区 医学
ChemMedChem Pub Date : 2025-06-03 DOI: 10.1002/cmdc.202581102
Christoph Selg, Robert Schuster, Aleksandr Kazimir, Peter Lönnecke, Mara Wolniewicz, Jonas Schädlich, Markus Laube, Jens Pietzsch, Vuk Gordić, Tamara Krajnović, Sanja Mijatović, Danijela Maksimović-Ivanić, Evamarie Hey-Hawkins
{"title":"Cover Feature: Advances in Diclofenac Derivatives: Exploring Carborane-Substituted N-Methyl and Nitrile Analogs for Anticancer Therapy (ChemMedChem 11/2025)","authors":"Christoph Selg,&nbsp;Robert Schuster,&nbsp;Aleksandr Kazimir,&nbsp;Peter Lönnecke,&nbsp;Mara Wolniewicz,&nbsp;Jonas Schädlich,&nbsp;Markus Laube,&nbsp;Jens Pietzsch,&nbsp;Vuk Gordić,&nbsp;Tamara Krajnović,&nbsp;Sanja Mijatović,&nbsp;Danijela Maksimović-Ivanić,&nbsp;Evamarie Hey-Hawkins","doi":"10.1002/cmdc.202581102","DOIUrl":"10.1002/cmdc.202581102","url":null,"abstract":"<p>Just as spikes help to deter birds from landing on building facades, strategic <i>N</i>-methylation in carborane-substituted diclofenac prevents the carboxylic acid from unwanted lactam formation, thus maintaining the open-chain structure for exploration of its anti-cancer potential. More details can be found in article 10.1002/cmdc.202500084 by Evamarie Hey-Hawkins and co-workers. Art by Christoph Selg.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 11","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202581102","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144206653","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
Inhibition of the Clathrin Terminal Domain—Amphiphysin Protein–Protein Interaction. Probing the Pitstop 2 Aromatic Moiety 网格蛋白末端结构域-两性蛋白-蛋白相互作用的抑制。探测Pitstop®2芳香部分。
IF 3.4 4区 医学
ChemMedChem Pub Date : 2025-06-02 DOI: 10.1002/cmdc.202500321
Kate Prichard, Mark J. Robertson, Ngoc Chau, Jing Xue, Martin Neuenschwander, Uwe Fink, Andre Horatscheck, Marc Nazare, Phillip J. Robinson, Volker Haucke, Adam McCluskey
{"title":"Inhibition of the Clathrin Terminal Domain—Amphiphysin Protein–Protein Interaction. Probing the Pitstop 2 Aromatic Moiety","authors":"Kate Prichard,&nbsp;Mark J. Robertson,&nbsp;Ngoc Chau,&nbsp;Jing Xue,&nbsp;Martin Neuenschwander,&nbsp;Uwe Fink,&nbsp;Andre Horatscheck,&nbsp;Marc Nazare,&nbsp;Phillip J. Robinson,&nbsp;Volker Haucke,&nbsp;Adam McCluskey","doi":"10.1002/cmdc.202500321","DOIUrl":"10.1002/cmdc.202500321","url":null,"abstract":"<p>Pitstop 2, (<i>Z</i>)-<i>N</i>-(5-(4-bromenzylidene)-4-oxo-4,5-dihydrothiazol-2-yl)naphthalene-1-sulfonamide (<b>1</b>) inhibits the clathrin terminal domain–amphiphysin interaction (NTD-PPI) and has been widely used to investigate endocytosis. Herein, the synthesis of 56 novel Pitstop 2 analogues via four discrete focused libraries is reported. Specific modification to the 4-bromonenzylidene moiety is explored, and their ability to inhibit the NTD-PPI interaction is examined by ELISA. In cell endocytosis, effects are measured for selective analogues as is the inhibition of dynamin, another protein involved in the endocytosis process. The most NTD-PPI active analogues retain 2- and 4-disposed substituents on the aromatic head, with 2,3,4-trihydroxy (<b>28</b>) the most active (IC<sub>50</sub> 0.94 μ<span>m</span>). Catechol-free 2,3-dihydroxybenzo[<i>b</i>][1,4]dioxone (<b>54</b>) is a more promising lead with an NTD-PPI IC<sub>50</sub> = 1.16 μ<span>m</span>. The corresponding benzo[<i>d</i>][1,3]dioxole (<b>53</b>) is threefold less active suggesting ring size preference at this position. Nine analogues show improved or comparable NTD-PPI activity to Pitstop 2 with IC<sub>50</sub> values from 0.94 to 2.1 μM. Heterocyclic analogues are well tolerated and potent inhibitors of CME in U2OS cells, in particular, benzofuran <b>67</b> (NTD-PPI IC<sub>50</sub> 1.5 μ<span>m</span> and CME IC<sub>50</sub> 6.8 ± 2.7 μ<span>m</span>). This positions <b>67</b> as one of the most cell active inhibitors of clathrin-mediated endocytosis yet reported.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 16","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202500321","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207261","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
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