RSC medicinal chemistry最新文献

{"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 and Xiaoyu Zhang","doi":"10.1039/D4MD00681J","DOIUrl":"10.1039/D4MD00681J","url":null,"abstract":"<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":" 2","pages":" 892-906"},"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":"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 and Xinhua Liu","doi":"10.1039/D4MD00730A","DOIUrl":"10.1039/D4MD00730A","url":null,"abstract":"<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 <strong>36</strong>, a lead compound derived from compound <strong>1</strong> through structure-based drug design and structure–activity relationship (SAR), exhibited strong Cat C inhibitory activity with an IC<small>₅₀</small> 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":" 2","pages":" 876-891"},"PeriodicalIF":4.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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 via the asialoglycoprotein receptor","authors":"Fabricio Ramírez-Cortés and Petra Ménová","doi":"10.1039/D4MD00652F","DOIUrl":"10.1039/D4MD00652F","url":null,"abstract":"<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":" 2","pages":" 525-544"},"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 and Nariman F. Salakhutdinov","doi":"10.1039/D4MD00728J","DOIUrl":"10.1039/D4MD00728J","url":null,"abstract":"<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 IC<small>₅₀</small> in the low micromolar or submicromolar range of concentrations. These are the most active coumarin derivatives found so far. Compound <strong>45</strong> 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":" 3","pages":" 1151-1171"},"PeriodicalIF":4.1,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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 and Stefan Knapp","doi":"10.1039/D4MD00735B","DOIUrl":"10.1039/D4MD00735B","url":null,"abstract":"<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":" 2","pages":" 457-464"},"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}

{"title":"Natural peptides and their synthetic congeners acting against Acinetobacter baumannii through the membrane and cell wall: latest progress","authors":"Gautam Kumar","doi":"10.1039/D4MD00745J","DOIUrl":"10.1039/D4MD00745J","url":null,"abstract":"<p > <em>Acinetobacter baumannii</em> is one of the deadliest Gram-negative bacteria (GNB), responsible for 2–10% of hospital-acquired infections. Several antibiotics are used to control the growth of <em>A. baumannii</em>. However, in recent decades, the abuse and misuse of antibiotics to treat non-microbial diseases have led to the emergence of multidrug-resistant <em>A. baumannii</em> strains. <em>A. baumannii</em> possesses a complex cell wall structure. Cell wall-targeting agents remain the center of antibiotic drug discovery. Notably, the antibacterial drug discovery intends to target the membrane of the bacteria, offering several advantages over antibiotics targeting intracellular systems, as membrane-targeting agents do not have to travel through the plasma membrane to reach the cytoplasmic targets. Microorganisms, insects, and mammals produce antimicrobial peptides as their first line of defense to protect themselves from pathogens and predators. Importantly, antimicrobial peptides are considered potential alternatives to antibiotics. This communication summarises the recently identified peptides of natural origin and their synthetic congeners acting against the <em>A. baumannii</em> membrane by cell wall disruption.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 2","pages":" 561-604"},"PeriodicalIF":4.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11629675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814170","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":"Anticancer potential of copper(i) complexes based on isopropyl ester derivatives of bis(pyrazol-1-yl)acetate ligands†","authors":"Maura Pellei, Carlo Santini, Miriam Caviglia, Jo' Del Gobbo, Chiara Battocchio, Carlo Meneghini, Simone Amatori, Chiara Donati, Eleonora Zampieri, Valentina Gandin and Cristina Marzano","doi":"10.1039/D4MD00610K","DOIUrl":"10.1039/D4MD00610K","url":null,"abstract":"<p >In this paper, the isopropyl ester derivatives L<small>^OiPr</small> and L<small>^2OiPr</small> of bis(pyrazol-1-yl)acetic acid and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid were used as chelators for the preparation of new Cu(<small>I</small>) phosphane complexes <strong>1–4</strong>. They were synthesized by the reaction of [Cu(CH<small>₃</small>CN)<small>₄</small>]PF<small>₆</small> and triphenylphosphine or 1,3,5-triaza-7-phosphaadamantane with L<small>^OiPr</small> and L<small>^2OiPr</small> ligands, in acetonitrile or acetonitrile/methanol solution. The authenticity of the compounds was confirmed by CHN analysis, <small>¹</small>H-, <small>¹³</small>C- and <small>³¹</small>P-NMR, FT-IR spectroscopy, and electrospray ionization mass spectrometry (ESI-MS). Furthermore, the electronic and molecular structures of the selected Cu(<small>I</small>) coordination compound <strong>3</strong> were investigated by synchrotron radiation-induced X-ray photoelectron spectroscopy (SR-XPS), and the local structure around the copper ion site was studied combining X-ray absorption fine structure (XAFS) spectroscopy techniques and DFT modelling. Triphenylphosphine as a coligand confers to [Cu(L<small>^OiPr</small>)(PPh<small>₃</small>)]PF<small>₆</small> (<strong>1</strong>) and [Cu(L<small>^2OiPr</small>)(PPh<small>₃</small>)]PF<small>₆</small> (<strong>3</strong>) a significant antitumor activity in 3D spheroidal models of human colon cancer cells. Investigations focused on the mechanism of action evidenced protein disulfide-isomerase (PDI) as an innovative molecular target for this class of phosphane copper(<small>I</small>) complexes. By hampering PDI activity, copper(<small>I</small>) complexes were able to cause an imbalance in cancer cell redox homeostasis thus leading to cancer cell death – a non-apoptotic programmed cell death.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 2","pages":" 849-861"},"PeriodicalIF":4.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11605304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142771769","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":"Antibacterial activity of the structurally novel C-2 amine-substituted analogues based on quinoxaline†","authors":"Yuting Liu, Pengju Yang, Yunyun Zhou and Zhiwen Zhou","doi":"10.1039/D4MD00670D","DOIUrl":"10.1039/D4MD00670D","url":null,"abstract":"<p >In the current study, we have designed and prepared a series of quinoxaline-based compounds, which were derived from <em>o</em>-phenylenediamine. Among them, compounds <strong>5m–5p</strong> displayed good to moderate antibacterial activity with MICs of 4–16 μg mL<small>⁻¹</small> against <em>S. aureus</em>, 8–32 μg mL<small>⁻¹</small> against <em>B. subtilis</em>, 8–32 μg mL<small>⁻¹</small> against MRSA and 4–32 μg mL<small>⁻¹</small> against <em>E. coli</em>, respectively. Compound <strong>5p</strong>, identified as a potent broad-spectrum antibacterial agent, demonstrated the strongest inhibitory effects against a range of bacterial strains and low cytotoxicity, thereby warranting further investigation. Compound <strong>5p</strong> not only demonstrated the ability to disperse established bacterial biofilms but also induced a slower development of bacterial resistance compared to norfloxacin. Moreover, bactericidal time-kill kinetic studies revealed that at a high concentration of 3MIC, compound <strong>5p</strong> was capable of directly killing MRSA cells. The subsequent postcontact effect (PCE) results showed that the growth rate of viable bacteria (MRSA) was greatly impacted and did not recover in less than 24 hours, even after antibacterial agent <strong>5p</strong> was removed. The drug-like properties and ADME prediction exhibited that <strong>5m–5p</strong> obeyed Lipinski's rule of five and therefore presumably maintained moderate to good bioavailability and human intestinal absorption rate when administered orally. Mechanistic investigations have elucidated that compound <strong>5p</strong> exerted its antibacterial effect by compromising the structural integrity of bacterial cell membranes, resulting in the leakage of intracellular constituents and ultimately causing bacterial demise. Further studies <em>in vivo</em> have demonstrated that <strong>5p</strong> exhibited potent antibacterial efficacy against MRSA in murine corneal infection models, particularly at elevated concentrations. The current dataset has also been meticulously analyzed to delineate the structure–activity relationships (SARs) of the synthesized compounds.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 2","pages":" 812-825"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142688706","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}