RSC medicinal chemistry最新文献

{"title":"Syntheses and preclinical evaluations of ¹¹C-labeled radioligands for imaging brain orexin-1 and orexin-2 receptors with positron emission tomography.","authors":"Susovan Jana, Pooyeh Ahmadi, Xuefeng Yan, Ping Bai, Jeih-San Liow, Adrian E Jenson, Matilah T Pamie-George, Sami S Zoghbi, Shawn Wu, Changning Wang, Robert B Innis, Victor W Pike, Sanjay Telu","doi":"10.1039/d5md00382b","DOIUrl":"10.1039/d5md00382b","url":null,"abstract":"<p><p>Despite their importance in regulating several functions in the brain, there is no effective radioligand for <i>in vivo</i> imaging of brain orexin-1 (OX₁R) or orexin-2 receptors (OX₂R) with positron emission tomography (PET). In a search for radioligand candidates, we identified GSK1059865 (1) as a highly potent and selective inhibitor for OX₁R (<i>K</i> _i = 5.0 nM for OX₁R, ∼80-fold selective over OX₂R) and similarly ET1 (2) for OX₂R (IC₅₀ = 0.8 nM for OX₂R, ∼3000-fold selective over OX₁R) with each possessing many physicochemical properties conducive for good brain permeability. We labeled compound 1 and compound 2 with carbon-11 (<i>t</i> _1/2 = 20.4 min) in high isolated yields (∼10-20%), radiochemical purities (≥99.5%), and molar activities (100-340 GBq μmol^-1) and assessed their potential as PET radioligands for <i>in vivo</i> imaging of brain OX₁R and OX₂R in healthy rodents and non-human primates. [¹¹C]1 and [¹¹C]2 showed excellent <i>in vitro</i> stability and also lipophilicity in a desirable range with measured log<i>D</i> _7.4 values of 3.69 and 2.90, respectively. After intravenous administration to mouse or monkey, both [¹¹C]1 and [¹¹C]2 gave moderately high peak radioactivity in brain (∼1.0-1.6 SUV). Unexpectedly, both [¹¹C]1 and [¹¹C]2 showed slightly lower monkey brain uptakes and distribution volumes at baseline than under blocking with suvorexant (a dual OX₁R/OX₂R antagonist), indicating a lack of specific binding to the target receptors in healthy animals. We infer that both OXRs exist in healthy mouse and monkey brain at very low density. Animal models, where OX₁R and OX₂R levels might be elevated, are desirable for candidate PET radioligand development, as are candidates with higher affinity.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12180406/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476595","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}

{"title":"Glycosidase-activated prodrugs of a cytotoxic iron chelator for targeted cancer therapy.","authors":"Debashish Tomar, Axel Steinbrueck, Adam C Sedgwick, Matthew S Levine, Jonathan L Sessler, Nils Metzler-Nolte","doi":"10.1039/d5md00232j","DOIUrl":"10.1039/d5md00232j","url":null,"abstract":"<p><p>New glycoside-prodrugs based on the iron chelator deferasirox were designed. Selective enzymatic activation by glycosidases was observed within 24 hours, accompanied by cancer cell-selective cytotoxicity. Notably, derivative 3a, bearing a β-d-galactose moiety, showed promising selective activity against galactosidase overexpressing OvCar-3 cells (IC₅₀ 9.1 ± 1.6 μM) while maintaining low activity against fibroblast control GM5756 cells (IC₅₀ > 100 μM).</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12177571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476591","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}

{"title":"Current progress in targeting mitotic kinases in PDAC.","authors":"Thomas M A Barlow, Ilse Rooman, Steven Ballet","doi":"10.1039/d5md00162e","DOIUrl":"10.1039/d5md00162e","url":null,"abstract":"<p><p>For a number of reasons, and unlike most other cancers, the mortality rate of PDAC is set to increase and, as such, it is predicted to become the second most common cause of cancer related mortality in the western world by the end of the current decade. One of the main reasons for this is the dire lack of robust therapeutic options. The clinical landscape of PDAC therapeutics is changing at an encouraging pace, exemplified by the breakthroughs in targeting not only KRAS but developing mutant-specific drugs against it. Nevertheless, the clinical community is still faced with a dire lack of effective therapeutics. The targeting of mitotic kinases - here limited to CDKs, Wee1, Chk1, Plk1 and the Aurora kinases - offers one potential avenue for exploitation. Here, we discuss ongoing efforts to target the mitotic kinases and present the advances that have been made for each, whilst also presenting the clinical and therapeutic perspectives for each category.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497986","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}

{"title":"Outstanding Reviewers for RSC Medicinal Chemistry in 2024","authors":"","doi":"10.1039/D5MD90024G","DOIUrl":"10.1039/D5MD90024G","url":null,"abstract":"<p >We would like to take this opportunity to thank all of <em>RSC Medicinal Chemistry</em>'s reviewers for helping to preserve quality and integrity in chemical science literature. We would also particularly like to highlight the Outstanding Reviewers for <em>RSC Medicinal Chemistry</em> in 2024.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 7","pages":" 2880-2880"},"PeriodicalIF":4.1,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476592","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}

{"title":"Structure-guided design of a methyltransferase-like 3 (METTL3) proteolysis targeting chimera (PROTAC) incorporating an indole-nicotinamide chemotype.","authors":"Annabelle C Weldert, Ariane F Frey, Mackenzie W Krone, Franziska Krähe, Hannah Kuhn, Christian Kersten, Fabian Barthels","doi":"10.1039/d5md00359h","DOIUrl":"10.1039/d5md00359h","url":null,"abstract":"<p><p>Methyltransferase-like 3 (METTL3) is the main catalytic subunit of the m⁶A methyltransferase complex (MTC) and plays an essential role in various disease indications, including acute myeloid leukemia (AML). Here, we describe the structure-guided design and evaluation of METTL3 proteolysis-targeting chimeras (PROTACs), starting from the potent small-molecule inhibitor STM2457. Across four design generations, we highlight key considerations, particularly regarding the exit vector, linker mechanics, and METTL3-binding chemotype composition. Our most effective PROTAC, AF151, forms a stable complex between the E3 ligase von Hippel-Lindau (VHL) and the target-of-interest METTL3, demonstrating efficient METTL3 degradation (DC₅₀ = 430 nM) in the AML cell line MOLM-13. This molecule candidate exhibits more pronounced effects on viability inhibition (IC₅₀ = 0.45 μM) and more significant m⁶A level reduction in cancer cells than its non-PRTOAC parent compounds. By incorporating the indole-nicotinamide chemotype as the METTL3-binding recruiter, this PROTAC is structurally distinct from recently published METTL3 PROTACs, expanding the design options for future METTL3 degrader development.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12207533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144542104","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}

{"title":"Rational design of gold(i)-NHC complexes as anticancer agents: induction of necroptosis and paraptosis in lung adenocarcinoma.","authors":"Sayari Dewan, Himanshu Sonker, Kajal Chaudhary, Ritika Gautam Singh","doi":"10.1039/d5md00290g","DOIUrl":"10.1039/d5md00290g","url":null,"abstract":"<p><p>Gold(i)-NHC complexes bearing sterically demanding ligands remain largely underexplored as anticancer agents. In this study, we rationally designed and synthesized a series of gold(i)-NHC complexes derived from cytotoxic 1,10-phenanthroline-based NHC ligands. Comprehensive structural characterization was performed using ¹H and ¹³C NMR spectroscopy, ESI-MS, IR spectroscopy, and single-crystal X-ray diffraction. Among the synthesized complexes AuL1-AuL7, AuL4 emerged as the most active compound, exhibited potent anticancer activity, triggering mitochondrial membrane depolarization and inducing necroptosis and paraptosis in human lung adenocarcinoma (A549) cells-a mechanism distinct from conventional apoptosis-inducing gold complexes. Notably, AuL4 effectively suppressed both metastasis and clonal expansion of malignant cells, reinforcing the therapeutic potential of gold-based chemotherapeutics. These findings establish AuL4 and its analogues as promising candidates for the development of next-generation gold(i)-NHC anticancer agents, particularly for treating apoptosis-resistant lung cancers.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554377","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}

{"title":"Novel furo[2,3-<i>d</i>]pyrimidine derivatives as PI3K/AKT dual inhibitors: design, synthesis, biological evaluation, and molecular dynamics simulation.","authors":"M A M Abdel Reheim, Walid E Elgammal, Mahmoud S Bashandy, Mohammed I A Hamed, Asmaa M AboulMagd, Mona G Khalil, Amr M Abdou, Rasha A Hassan","doi":"10.1039/d5md00139k","DOIUrl":"10.1039/d5md00139k","url":null,"abstract":"<p><p>The current study aimed to synthesize a series of innovative improved anticancer chemical entities by combining the unique advantages of 1,3,4-thiadiazole as an established anticancer pharmacophore with the furopyrimidine scaffold which is a key component of many reported cytotoxic agents. Sixteen furopyrimidine derivatives were designed and evaluated by several biological tests including antiproliferative activity against 60 human cancer cell lines, measurement of GI₅₀, TGI, and LC₅₀ values, MTT and selectivity index (SI) calculation, <i>in vitro</i> enzymatic PI3Kα/β and AKT inhibitory assay, cell cycle analysis and apoptosis evaluation. The results indicated that the designed compound 10b revealed potent anticancer activity with a mean GI of 108.32%, remarkable anticancer activity with GI₅₀ values ranging from 0.91 to 16.7 μM and strong cytostatic action (TGI range: 2.32-15.0 μM) against 38 cancer cell lines. It also exhibited a potent and selective antiproliferative activity against the breast cancer HS 578T cell line (GI₅₀ = 1.51 μM and TGI = 4.96 μM). Furthermore, compound 10b demonstrated the highest inhibitory activity against PI3Kα/β and AKT enzymes with IC₅₀ = 0.175 ± 0.007, 0.071 ± 0.003 and 0.411 ± 0.02 μM, respectively. Additionally, it could strongly induce cell cycle arrest in breast cancer HS 578T cells at the G0-G1 phase and trigger apoptosis. Molecular docking and dynamics were also performed in this study which revealed that compound 10b provided an improved binding pattern with the key amino acids in the PI3K and AKT-1 binding sites. According to the findings, the designed compound 10b has potent antiproliferative and apoptotic activities with a wide therapeutic index particularly against breast cancer.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171737/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326806","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}

{"title":"Small-molecule probes for imaging and impairing the Golgi apparatus in cancer.","authors":"Phanindra Kumar, Poulomi Sengupta, Sudipta Basu","doi":"10.1039/d5md00320b","DOIUrl":"10.1039/d5md00320b","url":null,"abstract":"<p><p>The Golgi apparatus (GA) is one of the most important subcellular organelles controlling protein processing, post-translational modification and secretion. Dysregulation of the GA structure and function leads to multiple pathological states, including cancer development and metastasis. Consequently, visualizing GA dynamic structures and their impairment in cancer has emerged as a novel strategy for next-generation unorthodox cancer therapeutics. However, the major challenge in GA-mediated theranostic probe development is the specific targeting of the GA within the subcellular milieu due to the lack of GA-recognizing chemical entities. In this review, we delineated various chemical functionalities that are extensively used as GA-homing moieties. Moreover, we outlined GA imaging probes consisting of classical fluorophores as well as novel aggregation-induced emissive (AIE) probes tagged with GA-homing moieties. Furthermore, we described GA-impairing molecules that can damage GA morphology through chemotherapeutic and photodynamic therapy (PDT) in cancer. Finally, we addressed the current challenges in this emerging and underexplored field of GA-targeted theranostics and proposed potential solutions to guide future cancer therapeutics.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12212356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554378","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}

{"title":"Yohimbine as a multifunctional therapeutic agent: inhibition of lysozyme aggregation, glycation and antioxidant properties.","authors":"Vibeizonuo Rupreo, Jhimli Bhattacharyya","doi":"10.1039/d5md00155b","DOIUrl":"10.1039/d5md00155b","url":null,"abstract":"<p><p>Protein misfolding and glycation are central to the pathogenesis of several chronic diseases, including neurodegenerative disorders and diabetes. Lysozyme (Lyz), a model protein, serves as an excellent system to study these pathological processes due to its propensity to form amyloid fibrils and undergo glycation. This study investigates the multifunctional therapeutic potential of yohimbine (Yoh) as an inhibitor of Lyz aggregation and glycation and its role as an antioxidant. The ability of Yoh to suppress amyloid fibrillation was evaluated using thioflavin T fluorescence, Congo red absorbance, and Nile red assays, which confirmed its efficacy in reducing fibrillar and surface hydrophobic changes in Lyz. Glycation inhibition was assessed through fluorescence spectroscopy, showing a significant reduction in the formation of advanced glycation end products (AGEs) in the presence of Yoh. Antioxidant assays demonstrated Yoh's capability to scavenge free radicals, contributing to its protective role against oxidative stress. Molecular modelling revealed stable binding of Yoh to lysozyme, driven by hydrogen bonds, hydrophobic contacts, and van der Waals interactions. These findings position Yoh as a promising therapeutic agent with dual activity in mitigating protein misfolding and glycation-associated diseases.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302814","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}

{"title":"Structure-activity relationships of 1,5-dihydro-2<i>H</i>-benzo[<i>b</i>][1,4]diazepine-2,4(3<i>H</i>)-diones as inhibitors of <i>Trypanosoma cruzi</i>.","authors":"Michael G Thomas, Joanne Dunne, Peter G Dodd, Emiliana D'Oria, Laura Frame, Adolfo Garcia-Perez, Kate McGonagle, Pilar Manzano, Lorna MacLean, Christy Paterson, Jennifer Riley, John Thomas, Leah S Torrie, Karolina Wrobel, Kevin D Read, Maria Marco, Manu De Rycker","doi":"10.1039/d5md00185d","DOIUrl":"10.1039/d5md00185d","url":null,"abstract":"<p><p>Chagas disease, caused by infection with the protozoan parasite <i>Trypanosoma cruzi</i> (<i>T. cruzi</i>), is responsible for a large health burden with around 6-8 million people infected globally. The current drug development pipeline is sparsely populated and there is an urgent need for new treatments. In this paper we describe the identification of a series of benzodiazepinediones with antiparasitic activity, and the platform we utilised to demonstrate that they act <i>via</i> a novel mechanism of action. Two distinct sub-series were identified, and the medicinal chemistry program identified compounds from both with pIC₅₀'s >6.4 which were progressed to a <i>T. cruzi</i> washout assay. This assay showed that neither sub-series was suitable for further development. This work demonstrated the value of a robust Chagas disease discovery platform for focusing the limited resources available for neglected disease drug discovery onto the most promising series.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144542103","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}