RSC medicinal chemistry最新文献

{"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":"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":"Recent advancements in the therapeutic approaches for Alzheimer's disease treatment: current and future perspective.","authors":"Amit Sharma, Santosh Rudrawar, Sandip B Bharate, Hemant R Jadhav","doi":"10.1039/d4md00630e","DOIUrl":"10.1039/d4md00630e","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a complex, incurable neurological condition characterized by cognitive decline, cholinergic neuron reduction, and neuronal loss. Its exact pathology remains uncertain, but multiple treatment hypotheses have emerged. The current treatments, single or combined, alleviate only symptoms and struggle to manage AD due to its multifaceted pathology. The developmental drugs target pivotal disease factors involved in the envisaged hypotheses and include targets such as amyloid aggregation, hyperphosphorylated tau proteins, and receptors like cholinergic, adrenergic, <i>etc.</i> Present-day research focuses on multi-target directed ligands (MTDLs), which inhibit multiple factors simultaneously, helping slow the disease's progression. This review attempts to collate the recent information related to proposed hypotheses for AD etiology. It systematically organizes the advances in various therapeutic options for AD, with a particular emphasis on clinical candidates. Also, it is expected to help medicinal chemists design novel AD treatments based on available information, which could be helpful to AD patients.</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/PMC11707861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142954199","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":"Design, synthesis and antiviral evaluation of triazole-linked 7-hydroxycoumarin-monoterpene conjugates as inhibitors of RSV replication.","authors":"Dmitry O Tsypyshev, Artem M Klabukov, Daria N Razgulaeva, Anastasia V Galochkina, Anna A Shtro, Sophia S Borisevich, Tatyana M Khomenko, Konstantin P Volcho, Nina I Komarova, Nariman F Salakhutdinov","doi":"10.1039/d4md00728j","DOIUrl":"https://doi.org/10.1039/d4md00728j","url":null,"abstract":"<p><p>Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections in babies across the world. Irrespective of progress in the development of RSV vaccines, effective small molecule drugs are still not available on the market. Based on our previous data we designed and synthesized triazole-linked coumarin-monoterpene hybrids and showed that they are indeed effective in inhibiting the RSV replication. The most effective compounds are active against both RSV serotypes, A and B, with IC₅₀ in the low micromolar or submicromolar range of concentrations. These are the most active coumarin derivatives found so far. Compound 45 combining 3,7-dimethyloctane and cyclopentane-annealed coumarin fragments has a selectivity index of 160 for serotype A and 1147 for serotype B. According to the results of the time-of-addition experiments, the conjugates are active at the early stages of the virus cycle. Based on biological evaluation and molecular modeling data, RSV F protein is a possible target.</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/PMC11696315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932562","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":"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":"Novel sigma 1-antagonists with <i>cis</i>-(+)-normetazocine scaffold: synthesis, molecular modeling, and antinociceptive effect.","authors":"Giuliana Costanzo, Giuseppe Cosentino, Margherita Grasso, Vincenzo Patamia, Sara Zuccalà, Alessandro Coco, Elisabetta Novello, Mahmoud Al-Khrasani, Raffaele Morrone, Giovanni Mario Pitari, Emanuele Amata, Agostino Marrazzo, Antonio Rescifina, Lorella Pasquinucci, Carmela Parenti","doi":"10.1039/d4md00397g","DOIUrl":"https://doi.org/10.1039/d4md00397g","url":null,"abstract":"<p><p>Inflammatory pain represents one of the unmet clinical needs for patients, as conventional therapies cause several side effects. Recently, new targets involved in inflammatory pain modulation have been identified, including the sigma-1 receptor (σ1R). Selective σ1R antagonists have demonstrated analgesic efficacy in acute and chronic inflammatory pain models. Considering these findings, a series of novel <i>N</i>-normetazocine derivatives has been designed and synthesized to investigate the pivotal role of <i>N</i>-normetazocine stereochemistry in their pharmacological fingerprint. The affinity profile of new ligands <i>versus</i> sigma receptors and opioid receptors was evaluated <i>in vitro</i>, and compound 7 showed a relevant σ1R affinity, with <i>K</i> _iσ1 = 27.5 ± 8.1 nM, and selectivity over sigma-2 receptor (σ2R) and opioid receptors. Furthermore, <i>in vivo</i>, compound 7 significantly reduced inflammatory pain in the second phase of the formalin test. Molecular modeling studies were also performed to analyze the binding mode and the key interactions between the new ligands and σ1R.</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/PMC11702864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142954194","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}