RSC medicinal chemistry最新文献

{"title":"Structure–activity relationship expansion and microsomal stability assessment of the 2-morpholinobenzoic acid scaffold as antiproliferative phosphatidylcholine-specific phospholipase C inhibitors†","authors":"Shaun W. P. Rees, Tayla A. Rees, Emily K. Paulin, Olivia R. Arnerich, Euphemia Leung, Christopher S. Walker, David Barker and Lisa I. Pilkington","doi":"10.1039/D4MD00831F","DOIUrl":"10.1039/D4MD00831F","url":null,"abstract":"<p >Dysregulation of choline phospholipid metabolism and overexpression of phosphatidylcholine-specific phospholipase C (PC-PLC) is implicated in various cancers. Current known enzyme inhibitors include compounds based on a 2-morpholino-5-<em>N</em>-benzylamino benzoic acid, or hydroxamic acid, scaffold. In this work, 81 compounds were made by modifying this core structure to explore the pharmacophore. Specifically, these novel compounds result from changes to the central ring substitution pattern, alkyl heterocycle and methylation of the <em>N</em>-benzyl bridge. The anti-proliferative activity of the synthesised compounds was assessed against cancer cell lines MDA-MB-231 and HCT116. PC-PLC<small>_BC</small> enzyme inhibition was also assessed, and the development of a pharmacokinetic profile was initiated using a microsomal stability assay. The findings confirmed the optimal pharmacophore as a 2-morpholino-5-<em>N</em>-benzylamino benzoic acid, or acid derivative, scaffold, and that this family of molecules demonstrate a high degree of stability following treatment with rat microsomes. Additionally, benzylic <em>N</em>-methylated compounds were the most biologically active compounds, encouraging further investigation into this region of the pharmacophore.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 3","pages":" 1250-1267"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010728","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":"Exploration of degrons and their ability to mediate targeted protein degradation","authors":"Timothy J. Harris Jr. and Darci J. Trader","doi":"10.1039/D4MD00787E","DOIUrl":"10.1039/D4MD00787E","url":null,"abstract":"<p >Degrons are short amino acid sequences that can facilitate the degradation of protein substrates. They can be classified as either ubiquitin-dependent or -independent based on their interactions with the ubiquitin proteasome system (UPS). These amino acid sequences are often found in exposed regions of proteins serving as either a tethering point for an interaction with an E3 ligase or initiating signaling for the direct degradation of the protein. Recent advancements in the protein degradation field have shown the therapeutic potential of both classes of degrons through leveraging their degradative effects to engage specific protein targets. This review explores what targeted protein degradation applications degrons can be used in and how they have inspired new degrader technology to target a wide variety of protein substrates.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 3","pages":" 1067-1082"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047841","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":"Development of PROTACs targeting estrogen receptor: an emerging technique for combating endocrine resistance","authors":"Rouming Peng, Xin Liu, Chun-Chi Chen, Rey-Ting Guo and Jian Min","doi":"10.1039/D4MD00961D","DOIUrl":"10.1039/D4MD00961D","url":null,"abstract":"<p >Despite the success of endocrine therapies in treating ER-positive breast cancer, the development of resistance remains a significant challenge. Estrogen receptor targeting proteolysis-targeting chimeras (ER PROTACs) offer a unique approach by harnessing the ubiquitin–proteasome system to degrade ER, potentially bypassing resistance mechanisms. In this review, we present the drug design, efficacy and early clinical trials of these ER PROTACs. This review underscores the academic and industrial opportunities presented by this emerging technology, as well as the challenges that must be addressed to translate these findings into effective clinical therapies.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 3","pages":" 1023-1036"},"PeriodicalIF":4.1,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010528","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":"Discovery and biological evaluation of nitrofuranyl–pyrazolopyrimidine hybrid conjugates as potent antimicrobial agents targeting Staphylococcus aureus and methicillin-resistant S. aureus†","authors":"Sapna Saini, G. Lakshma Reddy, Anjali Gangwar, Harpreet Kour, Gajanan G. Nadre, Ramajayan Pandian, Sunny Pal, Utpal Nandi, Rashmi Sharma and Sanghapal D. Sawant","doi":"10.1039/D4MD00826J","DOIUrl":"10.1039/D4MD00826J","url":null,"abstract":"<p >Nitrofuran and pyrazolopyrimidine-based compounds possess a broad antimicrobial spectrum including Gram-positive and Gram-negative bacteria. In the present work, a series of conjugates of these scaffolds was synthesized and evaluated for antimicrobial activity against <em>Staphylococcus aureus</em> and methicillin-resistant <em>S. aureus</em> (MRSA). Many compounds showed MIC values of ≤2 μg ml<small>⁻¹</small>, with compound <strong>35</strong> demonstrating excellent activity (MICs: 0.7 and 0.15 μg ml<small>⁻¹</small> against <em>S. aureus</em> and MRSA, respectively) and safety up to 50 μg ml<small>⁻¹</small> in HepG2 cells. Compound <strong>35</strong> also exhibited no hemolytic activity, biofilm eradication, and effectiveness against efflux-pump-overexpressing strains (NorA, TetK, MsrA) without resistance development. It showed synergistic effects with vancomycin (<em>S. aureus</em>) and rifampicin (MRSA). Mechanistic studies revealed that compound <strong>35</strong> exhibits good membrane-targeting abilities, as evidenced by DAPI/PI staining and scanning electron microscopy (SEM). In an intracellular model, it reduced bacterial load efficiently in both <em>S. aureus</em> and MRSA strains. With a strong <em>in vitro</em> profile, compound <strong>35</strong> demonstrated favorable oral pharmacokinetics at 30 mg kg<small>⁻¹</small> and potent <em>in vivo</em> anti-MRSA activity, highlighting its potential against antibiotic-resistant infections.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 3","pages":" 1304-1328"},"PeriodicalIF":4.1,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010448","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":"Targeting host integrated stress response: lead discovery of flavonoid compounds active against coronaviruses PEDV and PDCoV†","authors":"Liang Yi, Yishuai Wang, Jiehuang Wang, Yihan Chen, Weixue Huang, Ying Liao and Qingwen Zhang","doi":"10.1039/D4MD00846D","DOIUrl":"10.1039/D4MD00846D","url":null,"abstract":"<p >Viral infections trigger the integrated stress response (ISR) in eukaryotic cells that leads to the activation of eIF2α kinases, the elevation of eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, and thereby the shutdown of global protein synthesis that viruses rely on to replicate. Coronaviruses and other viruses have evolved various subversion mechanisms to counteract the antiviral ISR. These intricate host–virus interactions may be exploited by pharmacologically activating the host ISR for the development of host-directed antivirals (HDAs), an increasingly relevant area of research. In this study, we have discovered a new class of flavonoid-based ISR activators that exhibit potent antiviral activity against porcine epidemic diarrhea virus (PEDV) and porcine deltacoronavirus (PDCoV). PEDV and PDCoV are animal coronaviruses of great veterinary and economic importance, for which there are currently no effective therapeutics. The mechanistic study indicated that lead compounds <strong>1-B</strong> and <strong>1-C</strong> inhibit PEDV and PDCoV replication <em>via</em> upregulating eIF2α phosphorylation and thereby downregulating global protein synthesis in host cells, suggesting they are HDA antivirals.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 3","pages":" 1131-1140"},"PeriodicalIF":4.1,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142897155","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":"Design and synthesis of cyclic lipidated peptides derived from the C-terminus of Cx43 for hemichannel inhibition and cardiac endothelium targeting†","authors":"Debora Iaculli, Jade Montgomery, Arthur Lamouroux, Anne Caufriez, Rafael Gozalbes, Mathieu Vinken, Filippo Molica, Brenda R. Kwak and Steven Ballet","doi":"10.1039/D4MD00850B","DOIUrl":"10.1039/D4MD00850B","url":null,"abstract":"<p >A peptide segment that is 10 residues long at the C-terminal (CT) region of Cx43 is known to be involved in interactions, both with the Cx43 protein itself and with other proteins, that result in hemichannel (HC) activity regulation. Previously reported mimetic peptides based on this region (<em>e.g.</em>, <strong>αCT1</strong>, <strong>CT10</strong>) have been revealed to be promising therapeutic agents in the context of cardiovascular diseases. In this work, novel approaches, such as C- and N-terminal modification and cyclization, to improve the proteolytic stability and bioavailability of the <strong>CT10</strong> peptide are presented. These efforts resulted in a set of unprecedented potent cyclic inhibitors of HC-mediated ATP release with a half-life largely exceeding 24 hours. Additionally, the introduction of a lipophilic moiety with different solubilizing linkers led to the generation of a novel series of water-soluble and lipidated peptides that exhibited high inhibitory capacity in <em>in vitro</em> assays at submicromolar concentrations. A cardiac endothelium targeting strategy was also adopted, exploiting the ability of the CRPPR peptide to selectively deliver the peptides to endothelial cells.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 3","pages":" 1289-1303"},"PeriodicalIF":4.1,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010524","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 and Dongyun Shin","doi":"10.1039/D4MD00786G","DOIUrl":"10.1039/D4MD00786G","url":null,"abstract":"<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":" 2","pages":" 640-651"},"PeriodicalIF":4.1,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of coumarin-inspired bifunctional hybrids as a new class of anti-Alzheimer's agents with potent <i>in vivo</i> efficacy.","authors":"Atamjit Singh, Aman Sharma, Karanvir Singh, Kirandeep Kaur, Pallvi Mohana, Jignesh Prajapati, Uttam Kaur, Dweipayan Goswami, Saroj Arora, Renu Chadha, Preet Mohinder Singh Bedi","doi":"10.1039/d4md00782d","DOIUrl":"10.1039/d4md00782d","url":null,"abstract":"<p><p>Considering the multifactorial and complex nature of Alzheimer's disease and the requirement of an optimum multifunctional anti-Alzheimer's agent, a series of triazole tethered coumarin-eugenol hybrid molecules was designed as potential multifunctional anti-Alzheimer's agents using donepezil and a template. The designed hybrid molecules were synthesized <i>via</i> a click chemistry approach and preliminarily screened for cholinesterase and Aβ_1-42 aggregation inhibition. Among them, AS15 emerged as a selective inhibitor of AChE (IC₅₀ = 0.047 μM) over butyrylcholinesterase (BuChE: IC₅₀ ≥ 10 μM) with desired Aβ_1-42 aggregation inhibition (72.21% at 50 μM) properties. In addition, AS15 showed protective effects against DNA damage caused by hydroxyl radicals originating from H₂O₂. Molecular docking and simulation studies confirmed the favorable interactions of AChE and the Aβ_1-42 monomer desired for their inhibition. AS15 exhibited an LD₅₀ value of 300 mg kg^-1 and showed significant improvements in memory and learning behavior in scopolamine-induced cognition impairment mouse-based animal models (Y-maze test and Morris water maze test) for behavioral analysis. Overall outcomes suggest AS15 as a potential preclinical multifunctional candidate for the management of Alzheimer's disease, and it serves as a promising lead for further development of potent and safer multifunctional anti-Alzheimer's agents.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142954188","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":"An estrogen receptor β-targeted near-infrared probe for theranostic imaging of prostate cancer†","authors":"Junhong Dai, Yihe Wu, Xiaofei Deng, Hai-Bing Zhou and Chune Dong","doi":"10.1039/D4MD00767K","DOIUrl":"10.1039/D4MD00767K","url":null,"abstract":"<p >Estrogen receptor β (ERβ) is aberrantly expressed in castration-resistant prostate cancer (CRPC). Therefore, a diagnostic and therapeutic ERβ probe not only helps to reveal the complex role of ERβ in prostate cancer (PCa), but also promotes ERβ-targeted PCa therapy. Herein, we reported a novel ERβ-targeted near-infrared fluorescent probe <strong>D3</strong> with both imaging and therapeutic functions, which had the advantages of high ERβ selectivity, good optical performance, and strong anti-interference ability. In addition, it displayed excellent antiproliferative activity in CRPC cells. Finally, <strong>D3</strong> was also successfully applied to the <em>in vivo</em> imaging of ERβ in the prostate cancer mouse model. Thus, this ERβ-targeted near-infrared fluorescent probe can be used as a potential tool for the study of ERβ-targeted diagnostic and therapeutic PCa.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 3","pages":" 1385-1396"},"PeriodicalIF":4.1,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047838","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":"Sulphonyl thiourea compounds containing pyrimidine as dual inhibitors of I, II, IX, and XII carbonic anhydrases and cancer cell lines: synthesis, characterization and in silico studies†","authors":"Nguyen Dinh Thanh, Vu Ngoc Toan and Vu Minh Trang","doi":"10.1039/D4MD00816B","DOIUrl":"10.1039/D4MD00816B","url":null,"abstract":"<p >Some novel sulphonyl thiourea derivatives (<strong>7a–m</strong>) containing 4,6-diarylpyrimidine rings were designed and synthesized using a one-pot procedure. These compounds exhibited remarkable dual inhibitory activity against human carbonic anhydrase <em>h</em>CA I, <em>h</em>CA II, <em>h</em>CA IX, and XII isoenzymes and some cancer cell lines. Among them, some thioureas had significantly more potent inhibitory activities in the order of <strong>7l</strong> &gt; <strong>7c</strong> &gt; <strong>7f</strong> (against the <em>h</em>CA I isoform), <strong>7f</strong> &gt; <strong>7b</strong> &gt; <strong>7c</strong> (against the <em>h</em>CA II isoform), <strong>7c</strong> &gt; <strong>7g</strong> &gt; <strong>7a</strong> &gt; <strong>7b</strong> (against the <em>h</em>CA IX isoform), and <strong>7d</strong> &gt; <strong>7c</strong> &gt; <strong>7g</strong> &gt; <strong>7f</strong> (against the <em>h</em>CA XII isoform). The obtained inhibitory activity data against the <em>h</em>CA IX and XII isoforms showed that compound <strong>7c</strong> was the most potent inhibitor in this sulphonyl thiourea series against enzyme <em>h</em>CA IX, with <em>K</em><small>_I</small> = 125.1 ± 12.4 nM, while compound <strong>7d</strong> was the most potent inhibitor against enzyme <em>h</em>CA XII, with <em>K</em><small>_I</small> = 111.0 ± 12.3 nM. Compound <strong>7c</strong> exhibited strong inhibitory activity among all four tested <em>h</em>CA enzymes, while thiourea <strong>7f</strong> was a potent inhibitor for enzymes <em>h</em>CA I, II and XII. All these compounds demonstrated non-competitive inhibition of both enzymes. Some selected potential inhibitory compounds, including <strong>7c</strong>, <strong>7d</strong>, and <strong>7g</strong>, exhibited remarkable cytotoxic activity against human cancer cell lines, including human breast adenocarcinoma (MCF-7), human liver adenocarcinoma (HepG2), human cervical epithelial carcinoma (HeLa), and human lung adenocarcinoma cells (A549). These compounds exhibited low cytotoxicity in the WI-38 cell line. The compounds <strong>7c</strong> and <strong>7d</strong> were the most potent inhibitors against tumour-associated <em>h</em>CA IX and <em>h</em>CA XII isoenzymes. Furthermore, these compounds exhibited remarkable inhibition against some cancer cell lines, such as MCF-7, HepG2, HeLa, and A549. They were subjected to <em>in silico</em> screening for molecular docking and molecular dynamics simulations. The results of <em>in vitro</em> and <em>in silico</em> studies revealed that compounds <strong>7c</strong> and <strong>7d</strong> were the most promising derivatives in this series owing to their significant effects on the studied <em>h</em>CA IX and <em>h</em>CA XII isoenzymes, respectively. The results showed that the sulphonyl thiourea moiety was deeply accommodated in the active site and interacted with zinc ions in the receptors.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 3","pages":" 1268-1288"},"PeriodicalIF":4.1,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010450","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}