RSC medicinal chemistry最新文献

{"title":"2-(4-Bromobenzyl) tethered 4-amino aryl/alkyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-<i>d</i>]pyrimidines: design, synthesis, anticancer assessment <i>via</i> dual topoisomerase-I/II inhibition, and <i>in silico</i> studies.","authors":"Sahil Arora, Bhagyshree Patra, Isha Dhamija, Santosh Kumar Guru, Raj Kumar","doi":"10.1039/d4md00817k","DOIUrl":"https://doi.org/10.1039/d4md00817k","url":null,"abstract":"<p><p>A series of 2-(4-bromobenzyl) tethered 4-amino aryl/alkyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-<i>d</i>]pyrimidines (7a-7u) were designed, synthesized, characterized and screened against a panel of cancer cell lines. Compound 7a, in particular, emerged as a potent antiproliferative agent against FaDu cells (HTB-43) with an IC₅₀ value of 1.73 μM. 7a induced morphological alterations in FaDu cells were observed <i>via</i> brightfield microscopy and DAPI staining, confirming cytotoxicity. Autophagy and apoptotic effects of 7a were confirmed by acridine orange staining, Rhodamine 123 staining, and western blot analysis, which revealed dose-dependent increases in LC3A/B and cleaved caspase-3 levels, respectively. Further, 7a impaired cell migration and colony formation, as demonstrated by scratch and clonogenic assays. Additionally, 7a reduced oxidative stress and induced G2/M phase cell cycle arrest in MCF-7 cells. 7a emerged as a dual topoisomerase I and II inhibitor, and results were supported by molecular docking and simulation studies. In anti-inflammatory studies, 7a exhibited selective inhibition of COX-2 over COX-1, supporting its dual anticancer and anti-inflammatory properties.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855228","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":"Distinctive roles of aquaporins and novel therapeutic opportunities against cancer.","authors":"Dharmendra Kumar Yadav, Desh Deepak Singh, Dongyun Shin","doi":"10.1039/d4md00786g","DOIUrl":"https://doi.org/10.1039/d4md00786g","url":null,"abstract":"<p><p>Aquaporins (AQPs) are integral membrane proteins responsible for facilitating the transmembrane transport of water and small solutes. Their involvement in diverse physiological functions extends to pathological conditions, including cancer, positioning them as promising targets for anticancer therapy. Tumor cells, particularly those with high metastatic potential, exhibit elevated AQP expression, reinforcing their critical role in tumor biology. Emerging evidence highlights AQPs' involvement in key oncogenic processes such as cell migration, proliferation, and tumor-associated edema, suggesting their potential as novel therapeutic targets. Despite this, the development of selective and potent AQP inhibitors has proven challenging. Efforts to produce small-molecule AQP inhibitors have largely been unsuccessful. However, recent advancements include monoclonal human IgG antibodies targeting extracellular domains of aquaporin-4, offering new therapeutic strategies, particularly in glioblastoma, where AQP-4 is overexpressed. However, recent advancements include monoclonal human IgG antibodies targeting extracellular domains of aquaporin-4, offering new therapeutic strategies, particularly in glioblastoma, where AQP-4 is over expressed. These antibodies hold promise for selectively targeting and eradicating AQP-4-expressing cells in malignant brain tumors. This review discusses the critical role AQPs play in cancer, including their contributions to tumor cell proliferation, migration, angiogenesis, and edema formation. Additionally, we explore innovative therapeutic approaches, such as antibody-based interventions, and outline potential future research directions in AQP-targeted cancer therapies.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855236","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":"Exploiting the DCAF16-SPIN4 interaction to identify DCAF16 ligands for PROTAC development.","authors":"Isabella A Riha, Miguel A Campos, Xiaokang Jin, Fiona Y Wang, Chenlu Zhang, Sara F Dunne, Benjamin F Cravatt, Xiaoyu Zhang","doi":"10.1039/d4md00681j","DOIUrl":"https://doi.org/10.1039/d4md00681j","url":null,"abstract":"<p><p>Traditional small molecule drugs often target protein activity directly, but challenges arise when proteins lack suitable functional sites. An alternative approach is targeted protein degradation (TPD), which directs proteins to cellular machinery for proteolytic degradation. Recent studies have identified additional E3 ligases suitable for TPD, expanding the potential of this approach. Among these, DCAF16 has shown promise in facilitating protein degradation through both PROTAC and molecular glue mechanisms. In this study, we developed a homogeneous time resolved fluorescence (HTRF) assay to discover new DCAF16 binders. Using an in-house electrophile library, we identified two diastereomeric compounds, with one engaging DCAF16 at cysteines C177-179 and another reducing its expression. We demonstrated that the compound covalently engaging DCAF16 can be transformed into a PROTAC capable of degrading FKBP12.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847590","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":"Thiazole-fused androstenone and ethisterone derivatives: potent β- and γ-actin cytoskeleton inhibitors to treat melanoma tumors.","authors":"Sanjay Adhikary, Subrata Roy, Shailesh Budhathoki, Siam Chowdhury, Abbey Stillwell, Alexei G Basnakian, Alan Tackett, Nathan Avaritt, Mohamed Milad, Mohammad Abrar Alam","doi":"10.1039/d4md00719k","DOIUrl":"https://doi.org/10.1039/d4md00719k","url":null,"abstract":"<p><p>Melanoma, the most fatal form of skin cancer, often becomes resistant to the current therapeutic approaches in most patients. To explore new treatment options, fused thiazole derivatives were synthesized, and several of these compounds demonstrated potent anti-melanoma activity both <i>in vitro</i> and <i>in vivo</i>. These compounds exhibited significant cytotoxicity against melanoma cell lines at low concentrations. The lead molecules induced apoptosis and caused G2/M phase cell cycle arrest to a lesser extent. These compounds also displayed remarkable antimetastatic activities in several cell-based and molecular assays, significantly inhibiting key processes of metastasis, such as cell migration and adhesion. mRNA sequencing revealed significant downregulation of β-actin (<i>ACTB</i>) and γ-actin (<i>ACTG1</i>) at the transcriptional level, and a similar effect was observed at the protein level by western immunoblotting and proteomics assays. Actin-rich membrane protrusions formation is crucial for facilitating metastasis by promoting cell migration. Fluorescence microscopy demonstrated that compounds E28 and E47 inhibited the formation of these membrane protrusions and impaired actin cytoskeleton dynamics. Docking studies suggested the lead compounds may suppress tumor proliferation and metastasis by targeting the mechanistic target of Rapamycin complex 2 (mTORC2). All these findings unanimously indicated the translational perspective of ethisterone and androstenone fused thiazole derivatives as potent antimetastatic and antimelanoma agents. In a preclinical mouse melanoma model, compounds E2 and E47 significantly reduced tumor growth and greatly improved overall mice survival, while showing a favorable safety profile based on a comprehensive blood plasma metabolite profile. These lead molecules also displayed promising physicochemical properties, making them strong candidates for further drug development studies.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11653411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865166","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":"Design and synthesis of novel cathepsin C inhibitors with anti-inflammatory activity.","authors":"Xiaobao Shen, Nan Li, Miao Liu, Xuanzheng Han, Yazhi Wang, Jingwen Jia, Fufang Wu, Hongwei Chen, Xinhua Liu","doi":"10.1039/d4md00730a","DOIUrl":"10.1039/d4md00730a","url":null,"abstract":"<p><p>Cathepsin C (Cat C) is a potential candidate for addressing inflammatory conditions associated with neutrophil serine proteases (NSPs). The high reactivity of electrophilic warheads and the metabolic instability of peptide structures are among the primary challenges in developing potent cathepsin C inhibitors. Compound 36, a lead compound derived from compound 1 through structure-based drug design and structure-activity relationship (SAR), exhibited strong Cat C inhibitory activity with an IC₅₀ value of 437 nM. It also showed a substantial enhancement in overall anti-inflammatory activity, achieving an inhibitory effect on NO release at 4.1 μM. Furthermore, molecular docking was conducted to analyze the mode of action with Cat C. And cell thermal shift analysis (CETSA) revealed that this compound increases the temperature tolerance of Cat C in a concentration-dependent manner, suggesting strong binding to the target Cat C. Prolonged pharmacological inhibition activity may result in the depletion of active NSPs.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11612923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781013","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":"Correction: A comprehensive apoptotic assessment of niloticin in cervical cancer cells: a tirucallane-type triterpenoid from Aphanamixis polystachya (Wall.) Parker","authors":"Anuja Gracy Joseph, Mohanan Biji, Vishnu Priya Murali, Daisy R. Sherin, Alisha Valsan, Vimalkumar P. Sukumaran, Kokkuvayil Vasu Radhakrishnan and Kaustabh Kumar Maiti","doi":"10.1039/D4MD90049A","DOIUrl":"10.1039/D4MD90049A","url":null,"abstract":"<p >Correction for ‘A comprehensive apoptotic assessment of niloticin in cervical cancer cells: a tirucallane-type triterpenoid from <em>Aphanamixis polystachya</em> (Wall.) Parker’ by Anuja Gracy Joseph <em>et al.</em>, <em>RSC Med. Chem.</em>, 2024, <strong>15</strong>, 3444–3459, https://doi.org/10.1039/D4MD00318G.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 12","pages":" 4223-4223"},"PeriodicalIF":4.1,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11610388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142771774","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":"Hepatocyte targeting <i>via</i> the asialoglycoprotein receptor.","authors":"Fabricio Ramírez-Cortés, Petra Ménová","doi":"10.1039/d4md00652f","DOIUrl":"10.1039/d4md00652f","url":null,"abstract":"<p><p>This review highlights the potential of asialoglycoprotein receptor (ASGPR)-mediated targeting in advancing liver-specific treatments and underscores the ongoing progress in the field. First, we provide a comprehensive examination of the nature of ASGPR ligands, both natural and synthetic. Next, we explore various drug delivery strategies leveraging ASGPR, with a particular emphasis on the delivery of therapeutic nucleic acids such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs). An in-depth analysis of the current status of RNA interference (RNAi) and ASO-based therapeutics is included, detailing approved therapies and those in various stages of clinical development (phases 1 to 3). Afterwards, we give an overview of other ASGPR-targeted conjugates, such as those with peptide nucleic acids or aptamers. Finally, targeted protein degradation of extracellular proteins through ASGPR is briefly discussed.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11609720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142771698","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":"Advances in the development of Wnt/β-catenin signaling inhibitors.","authors":"Minami Fujita, Yosuke Demizu","doi":"10.1039/d4md00749b","DOIUrl":"https://doi.org/10.1039/d4md00749b","url":null,"abstract":"<p><p>The Wnt/β-catenin signaling pathway plays a critical role in various biological processes, including cell proliferation, differentiation, and tissue homeostasis. Aberrant activation of this pathway is strongly associated with the development of various cancers, including colorectal, pancreatic, and gastric cancers, making it a promising therapeutic target. In recent years, inhibitors targeting different components of the Wnt/β-catenin pathway, including small molecules, peptides, and nucleic acid-based therapies, have been developed to suppress cancer cell growth. These inhibitors work by disrupting key interactions within the pathway, thereby preventing tumor progression. Antibody-based therapies have also emerged as potential strategies to block ligand-receptor interactions within this pathway. Despite these advancements, challenges such as the complexity of the pathway and toxicity concerns remain. Innovative approaches, including allosteric inhibitors, proteolysis-targeting chimeras (PROTACs), and peptide-based inhibitors, offer new opportunities to address these challenges. This review provides an overview of the latest progress in the development of Wnt/β-catenin pathway inhibitors and explores future directions in cancer therapy.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847589","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":"Toward target 2035: EUbOPEN - a public-private partnership to enable & unlock biology in the open.","authors":"Claudia Tredup, Suzanne Ackloo, Hartmut Beck, Peter J Brown, Alex N Bullock, Alessio Ciulli, Ivan Dikic, Kristina Edfeldt, Aled M Edwards, Jonathan M Elkins, Henner F Farin, Edward A Fon, Matthias Gstaiger, Judith Günther, Anna-Lena Gustavsson, Sandra Häberle, Laura Isigkeit, Kilian V M Huber, Andras Kotschy, Oliver Krämer, Andrew R Leach, Brian D Marsden, Hisanori Matsui, Daniel Merk, Florian Montel, Monique P C Mulder, Susanne Müller, Dafydd R Owen, Ewgenij Proschak, Sandra Röhm, Alexandra Stolz, Michael Sundström, Frank von Delft, Timothy M Willson, Cheryl H Arrowsmith, Stefan Knapp","doi":"10.1039/d4md00735b","DOIUrl":"10.1039/d4md00735b","url":null,"abstract":"<p><p>Target 2035 is a global initiative that seeks to identify a pharmacological modulator of most human proteins by the year 2035. As part of an ongoing series of annual updates of this initiative, we summarise here the efforts of the EUbOPEN project whose objectives and results are making a strong contribution to the goals of Target 2035. EUbOPEN is a public-private partnership with four pillars of activity: (1) chemogenomic library collections, (2) chemical probe discovery and technology development for hit-to-lead chemistry, (3) profiling of bioactive compounds in patient-derived disease assays, and (4) collection, storage and dissemination of project-wide data and reagents. The substantial outputs of this programme include a chemogenomic compound library covering one third of the druggable proteome, as well as 100 chemical probes, both profiled in patient derived assays, as well as hundreds of data sets deposited in existing public data repositories and a project-specific data resource for exploring EUbOPEN outputs.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11605244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142771816","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":"Enhancing the radionuclide theranostic concept through the radiohybrid approach.","authors":"Tobias Krönke, Klaus Kopka, Constantin Mamat","doi":"10.1039/d4md00591k","DOIUrl":"https://doi.org/10.1039/d4md00591k","url":null,"abstract":"<p><p>Radionuclide theranostics - a fast-growing emerging field in radiopharmaceutical sciences and nuclear medicine - offers a personalised and precised treatment approach by combining diagnosis with specific and selective targeted endoradiotherapy. This concept is based on the application of the same molecule, labelled with radionuclides possessing complementary imaging and therapeutic properties, respectively. In radionuclide theranostics, radionuclide pairs consisting of the same element, such as ^61/64Cu/⁶⁷Cu, ²⁰³Pb/²¹²Pb or ^123/124I/¹³¹I are of significant interest due to their identical chemical and pharmacological characteristics. However, such \"true matched pairs\" are seldom, necessitating the use of complementary radionuclides from different elements for diagnostics and endoradiotherapy with similar chemical characteristics, such as ^99mTc/^186/188Re, ⁶⁸Ga/¹⁷⁷Lu or ⁶⁸Ga/²²⁵Ac. Corresponding combinations of such two radionuclides in one and the same radioconjugate is referred to as a \"matched pair\". Notably, the pharmacological behavior remains consistent across both diagnostic and therapeutic applications with \"true matched pairs\", which may differ for \"matched pairs\". As \"true matched pairs\" of theranostic radioisotopes are rare and that some relevant radionuclides do not fit with the diagnostic or therapeutic counterpart, the radionuclide theranostic concept can be expanded and improved by the introduction of the radiohybrid approach. Radiohybrid (rh) ligands represent a new class of radiopharmaceutical bearing two different positions for the introduction of a (radio)metal and (radio)halogen in one molecule, which can be then used for both therapeutic and diagnostic purposes. The following review will give an insight into recent developments of this approach.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11606402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142771697","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}