RSC medicinal chemistry最新文献

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Grassystatin G, a new cathepsin D inhibitor from marine cyanobacteria: discovery, synthesis, and biological characterization. 海洋蓝藻中新的组织蛋白酶D抑制剂Grassystatin G的发现、合成及生物学表征
IF 4.1 4区 医学
RSC medicinal chemistry Pub Date : 2025-04-25 DOI: 10.1039/d5md00017c
Lobna A Elsadek, Gustavo Seabra, Valerie J Paul, Hendrik Luesch
{"title":"Grassystatin G, a new cathepsin D inhibitor from marine cyanobacteria: discovery, synthesis, and biological characterization.","authors":"Lobna A Elsadek, Gustavo Seabra, Valerie J Paul, Hendrik Luesch","doi":"10.1039/d5md00017c","DOIUrl":"https://doi.org/10.1039/d5md00017c","url":null,"abstract":"<p><p>Through ongoing investigations of marine cyanobacteria, a prolific source of structurally diverse secondary metabolites, we isolated grassystatin G (1), a new statine-containing linear peptide, closely related to the cathepsin E (CatE) inhibitors grassystatins A-F, some of which may function as CatE probes. The planar structure of 1 was determined by analysis of 1D, 2D NMR and MS/MS fragmentation data, and is structurally distinct from its analogs by being shorter and containing a hydrophobic residue (Val) adjacent to the statine unit instead of a polar residue (Asn, Gln). We employed chiral HPLC analysis and modified Marfey's method to assign the absolute configuration of constituent amino acids, suggesting the presence of <i>N</i>-Me-l-Phe instead of <i>N</i>-Me-d-Phe in other grassystatins. To prove the structure and overcome the lack of material for further biological studies and mechanistic characterization, we developed a 3 + 3 convergent synthesis and have accessed the peptide with an overall yield of 19% using standard peptide coupling. As the statine moiety is a known pharmacophore with an inhibitory effect against aspartic proteases, we screened grassystatin G against a panel of human and virus aspartic proteases. In contrast to grassystatins A-F, preferentially targeting CatE over CatD with 18-66-fold selectivity, grassystatin G displayed 2-fold selectivity for CatD over CatE, suggesting that the key structural differences may be exploited for CatD probe design. Docking and molecular dynamics provided insights into the structural features responsible for the selectivity towards CatD. CatD is well-documented to play a role in cancer proliferation and metastasis, particularly in the context of breast cancer. We tested grassystatin G against MDA-MB-231 triple-negative breast cancer cells and demonstrated its cooperative effects with TRAIL. RNA-seq highlighted the potential pathways and molecular mechanisms governed by grassystatin G alone and in combination with TRAIL.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12024474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051256","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}
引用次数: 0
Synthesis and anti-mycobacterial activity of novel medium-chain β-lactone derivatives: a multi-target strategy to combat Mycobacterium abscessus. 新型中链β-内酯衍生物的合成及其抗分枝杆菌活性:对抗脓肿分枝杆菌的多靶点策略。
IF 4.1 4区 医学
RSC medicinal chemistry Pub Date : 2025-04-25 DOI: 10.1039/d5md00102a
Thomas Francis, Christina Dedaki, Phoebe Ananida-Dasenaki, Dimitra Bolka, Kanellos Albanis, Filippos Foteinakis, Julie Mezquida, Marie Hance, Alexandros Athanasoulis, Anna-Krinio Papagiorgou, Ioanna-Foteini Karampoula, George Georgitsis, Celia Jardin, Stéphane Audebert, Luc Camoin, Céline Crauste, Stéphane Canaan, Victoria Magrioti, Jean-François Cavalier
{"title":"Synthesis and anti-mycobacterial activity of novel medium-chain β-lactone derivatives: a multi-target strategy to combat <i>Mycobacterium abscessus</i>.","authors":"Thomas Francis, Christina Dedaki, Phoebe Ananida-Dasenaki, Dimitra Bolka, Kanellos Albanis, Filippos Foteinakis, Julie Mezquida, Marie Hance, Alexandros Athanasoulis, Anna-Krinio Papagiorgou, Ioanna-Foteini Karampoula, George Georgitsis, Celia Jardin, Stéphane Audebert, Luc Camoin, Céline Crauste, Stéphane Canaan, Victoria Magrioti, Jean-François Cavalier","doi":"10.1039/d5md00102a","DOIUrl":"10.1039/d5md00102a","url":null,"abstract":"<p><p>The constant emergence of drug-resistant mycobacteria, together with the lack of new antibiotics entering the market, has become a global public health problem that threatens the effective treatment of infectious diseases. The development of single molecules targeting different proteins should significantly reduce the emergence of resistant strains, and therefore represent a promising strategy to overcome such an issue. In this challenging context, a new series of 30 lipophilic compounds based on the β-lactone-core has been synthesized by varying the nature of the substituents on the lactone ring. The evaluation of their antibacterial activity against <i>M. tuberculosis</i> and <i>M. abscessus</i>, two major pathogenic mycobacteria, highlighted potential candidates. The VM038, VM040 and VM045 were active only against <i>M. tuberculosis</i>, while VM025, VM026 and VM043 inhibited the growth of both <i>M. tuberculosis</i> and the S and R variants of <i>M. abscessus</i>. Competitive click chemistry activity-based protein profiling revealed several potential <i>M. abscessus</i> target enzymes of VM043, the best extracellular growth inhibitor. Finally, when tested against intracellular bacteria, although VM043 was found inactive, VM025 & VM026 proved to be potent and promising inhibitors of intramacrophagic <i>M. abscessus</i> growth with minimal inhibitory concentrations (MIC<sub>50Raw</sub>) comparable to the standard antibiotic imipenem. Overall, these results strengthen the added value of our VM β-lactone derivatives not only in the fight against pathogenic mycobacteria, leading to the arrest of <i>M. abscessus</i> and/or <i>M. tuberculosis</i> growth through multitarget enzyme inhibition, but also as efficient probes to identify novel potential therapeutic targets using chemoproteomics approaches.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12101465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143484","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}
引用次数: 0
New Trypanosoma brucei acting derivatives incorporating 1-(4-phenyl)adamantane and 1-(4-phenoxyphenyl)adamantane. 含有1-(4-苯基)金刚烷和1-(4-苯氧苯基)金刚烷的新型布氏锥虫衍生物。
IF 4.1 4区 医学
RSC medicinal chemistry Pub Date : 2025-04-25 DOI: 10.1039/d5md00135h
Konstantina Stavropoulou, Angeliki Kaimaki, Maria Nikolaou, Ana K Brown, Andrew Tsotinis, Martin C Taylor, John M Kelly, Ioannis P Papanastasiou
{"title":"New <i>Trypanosoma brucei</i> acting derivatives incorporating 1-(4-phenyl)adamantane and 1-(4-phenoxyphenyl)adamantane.","authors":"Konstantina Stavropoulou, Angeliki Kaimaki, Maria Nikolaou, Ana K Brown, Andrew Tsotinis, Martin C Taylor, John M Kelly, Ioannis P Papanastasiou","doi":"10.1039/d5md00135h","DOIUrl":"https://doi.org/10.1039/d5md00135h","url":null,"abstract":"<p><p>In this work, we describe the design, synthesis and evaluation of novel functionalised 1-(4-phenyl)adamantane and 1-(4-phenoxyphenyl)adamantane derivatives. Based on previous findings, we incorporated a phenyl ring between the adamantane core and the pharmacophoric side chain to enhance the activity and selectivity index (SI). The aromatic imidazolines 1a-d and the linear amidines 2a,b and 3a,b exhibited notable activity against <i>T. brucei</i>. The 1-(4-phenyl)adamantane 1-(4-phenoxyphenyl)adamantane core was further functionalized with the aminoguanylhydrazone and thiosemicarbazone moieties. 2-[(<i>E</i>)-4-(1-adamantyl)benzylidene]hydrazine-1-carbothioamide 4c emerged as a promising trypanocidal agent with an EC<sub>50</sub> of 0.16 μM and an SI of 17. Future studies will focus on optimizing the length and the distance of the side chain between the aromatic ring and the chromophores to further enhance the activity and selectivity of these molecules.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12053444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982027","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}
引用次数: 0
Human chitinases and chitinase-like proteins as emerging drug targets - a medicinal chemistry perspective. 人几丁质酶和几丁质酶样蛋白作为新兴的药物靶点-药物化学的观点。
IF 4.1 4区 医学
RSC medicinal chemistry Pub Date : 2025-04-24 DOI: 10.1039/d4md01050g
Önder Kurç, Nick Rähse, Holger Gohlke, Jonathan Cramer
{"title":"Human chitinases and chitinase-like proteins as emerging drug targets - a medicinal chemistry perspective.","authors":"Önder Kurç, Nick Rähse, Holger Gohlke, Jonathan Cramer","doi":"10.1039/d4md01050g","DOIUrl":"https://doi.org/10.1039/d4md01050g","url":null,"abstract":"<p><p>Human chitinases and chitinase-like proteins (CLPs) provide the immune system with the ability to recognize or process chitin originating from chitinous pathogens. In addition to their role in host defense, most members of this protein family have evolved pleiotropic cellular effector functions broadly related to immune homeostasis, cell proliferation, and tissue remodeling. This wide-ranging ability to modulate crucial cellular processes proceeds <i>via</i> the activation of cellular signal transduction cascades and appears to be fully independent of chitin recognition. Dysregulation of chitinase/CLP functions has been linked to a plethora of inflammatory diseases, such as allergic airway diseases and asthma, fibrosis, as well as cancer. This fact predetermines certain members of this protein family as prime targets for pharmacological intervention. Here, we provide an extensive review of medicinal chemistry efforts targeting the most widely studied members of the human chitinase/CLP family, namely acidic mammalian chitinase (AMCase), chitotriosidase (CHIT1), and chitinase-3-like protein 1 (CHI3L1/YKL-40).</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044147","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}
引用次数: 0
From genetic code to global health: the impact of nucleic acid vaccines on disease prevention and treatment. 从遗传密码到全球健康:核酸疫苗对疾病预防和治疗的影响。
IF 4.1 4区 医学
RSC medicinal chemistry Pub Date : 2025-04-24 DOI: 10.1039/d5md00032g
Alessandra Del Bene, Antonia D'Aniello, Salvatore Mottola, Vincenzo Mazzarella, Roberto Cutolo, Erica Campagna, Rosaria Benedetti, Lucia Altucci, Sandro Cosconati, Salvatore Di Maro, Anna Messere
{"title":"From genetic code to global health: the impact of nucleic acid vaccines on disease prevention and treatment.","authors":"Alessandra Del Bene, Antonia D'Aniello, Salvatore Mottola, Vincenzo Mazzarella, Roberto Cutolo, Erica Campagna, Rosaria Benedetti, Lucia Altucci, Sandro Cosconati, Salvatore Di Maro, Anna Messere","doi":"10.1039/d5md00032g","DOIUrl":"https://doi.org/10.1039/d5md00032g","url":null,"abstract":"<p><p>Vaccinology has revolutionized modern medicine, delivering groundbreaking solutions to prevent and control infectious diseases while pioneering innovative strategies to tackle non-infectious challenges, including cancer. Traditional vaccines faced inherent limitations, driving the evolution of next-generation vaccines such as subunit vaccines, peptide-based vaccines, and nucleic acid-based platforms. Among these, nucleic acid-based vaccines, including DNA and mRNA technologies, represent a major innovation. Pioneering studies in the 1990s demonstrated their ability to elicit immune responses by encoding specific antigens. Recent advancements in delivery systems and molecular engineering have overcome initial challenges, enabling their rapid development and clinical success. This review explores nucleic acid-based vaccines, including chemically modified variants, by examining their mechanisms, structural features, and therapeutic potential, while underscoring their pivotal role in modern immunization strategies and expanding applications across contemporary medicine.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12053015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024132","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}
引用次数: 0
A data-driven journey using results from target-based drug discovery for target deconvolution in phenotypic screening. 数据驱动的旅程,利用基于靶标的药物发现结果,在表型筛选中进行靶标反褶积。
IF 4.1 4区 医学
RSC medicinal chemistry Pub Date : 2025-04-22 DOI: 10.1039/d4md01051e
Gergely Takács, György T Balogh, Róbert Kiss
{"title":"A data-driven journey using results from target-based drug discovery for target deconvolution in phenotypic screening.","authors":"Gergely Takács, György T Balogh, Róbert Kiss","doi":"10.1039/d4md01051e","DOIUrl":"https://doi.org/10.1039/d4md01051e","url":null,"abstract":"<p><p>In drug discovery, various approaches exist to find compounds that alter the different states in living organisms. There are two fundamental discovery strategies regarding the mechanism of action: target-based and phenotypic methods. Both have strengths and weaknesses in assay development, target selection, target validation and structure optimization. While phenotypic screening can identify chemical starting points with the desired phenotype, it is typically difficult to carry out efficient, structure-based optimization without confirming the mechanism of action of such hits. It is therefore critical to uncover the targets behind the phenotype. Target deconvolution is typically carried out by a set of highly selective compounds, where each ligand is associated with a particular target. Hits of such a high-selectivity set can provide valuable information on the phenotype's underlying targets and may also enable novel target-based therapeutic strategies. Consequently, there is a continuously high demand for novel highly-selective tool compounds for target deconvolution. In this work, the ChEMBL database, comprising over 20 million bioactivity data, was mined to identify the most selective novel ligands for a diverse set of targets. A novel method for the automated selection of such high-selectivity ligands is presented. Using these high-selectivity compounds in phenotypic screening campaigns can provide a valuable preliminary direction during target deconvolution. 87 representative compounds were purchased and screened against 60 cancer cell lines. Several compounds were found to possess selective inhibition of cell growth of a few distinct cell lines. The phenotypic assay results, along with the nanomolar activities of individual proteins obtained from the ChEMBL database suggest some novel mechanisms of action for anti-cancer drug discovery.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019373","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}
引用次数: 0
Recent advances in targeting COX-2 for cancer therapy: a review. 以COX-2为靶点治疗癌症的研究进展
IF 4.1 4区 医学
RSC medicinal chemistry Pub Date : 2025-04-21 DOI: 10.1039/d5md00196j
Asmaa E Kassab
{"title":"Recent advances in targeting COX-2 for cancer therapy: a review.","authors":"Asmaa E Kassab","doi":"10.1039/d5md00196j","DOIUrl":"10.1039/d5md00196j","url":null,"abstract":"<p><p>Cyclooxygenase-2 (COX-2) is involved in the production of prostaglandins and thromboxanes, which control biological processes like inflammation, angiogenesis, and cell division. Numerous premalignant tissues and many human malignant tumors overexpress COX-2. Metabolites from COX-2 may support tumor growth, transformation, invasion, metastatic dissemination, premalignant hyperproliferation, downregulation of apoptosis, and tumor survival. COX-2 also triggers activity like cancer stem cells (CSCs). Populations of CSCs isolated from many cancer types are linked to overexpression of COX-2. Using nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of solid tumors, including colon, stomach, and esophageal malignancies. The anticancer potential of NSAIDs is mediated <i>via</i> COX-2 dependent or COX-2 independent pathways. For cancer patients, COX-2 may be a crucial target for therapeutic and chemoprotective measures. This review introduces the involvement of COX-2 in cancer <i>via</i> different pathways and provides a comprehensive review of the most recent updates on COX-2 inhibitors as potential anticancer candidates. This review aims to spark fresh thinking in the pursuit of more logical COX-2 inhibitor designs that may effectively treat cancer.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12082340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094692","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}
引用次数: 0
Chromenochalcones: a comprehensive review on developments towards a medicinal perspective. 铬查尔酮:从医学角度全面回顾其发展。
IF 4.1 4区 医学
RSC medicinal chemistry Pub Date : 2025-04-21 DOI: 10.1039/d5md00062a
Rohit Singh, Archita Katrolia, Ved Pal
{"title":"Chromenochalcones: a comprehensive review on developments towards a medicinal perspective.","authors":"Rohit Singh, Archita Katrolia, Ved Pal","doi":"10.1039/d5md00062a","DOIUrl":"https://doi.org/10.1039/d5md00062a","url":null,"abstract":"<p><p>Chalcones are indeed a versatile scaffold in medicinal chemistry. Their structure, featuring an α,β-unsaturated carbonyl group, makes them highly reactive and capable of interacting with various biological targets. This reactivity is a key reason why chalcones and their derivatives are of such interest in drug discovery. The continued exploration of chalcone derivatives in medicinal chemistry will likely yield new insights and therapeutic candidates, given their broad spectrum of biological activities and the flexibility in modifying their structures. As chalcone derivatives, pyranochalcones and chromanchalcones are members of a subclass of flavonoids that are widely distributed. Several scientific databases were investigated to compile articles that illustrated the biological functions of chromenochalcones and their derivatives. Preclinical research on chromenochalcones and their derivatives is well covered in this review, highlighting the compounds with enormous significance as antimalarial, anti-inflammatory, antileishmanial, cytotoxic, antibacterial, antifungal, and antioxidant agents. In addition, the article briefly discusses the synthetic pathways employed for the total synthesis of selected pyranochalcones, including mallaophilippens C and E, citrunobin, and lesperol. Consequently, this overview may help research and design novel, potent therapeutic medications based on previously developed methodologies. This review is intended to provide a thorough, authoritative, and critical assessment of the chromenochalcone template for the chemistry community.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032257","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}
引用次数: 0
New acridone derivatives to target telomerase and oncogenes - an anticancer approach. 新的吖啶酮衍生物靶向端粒酶和癌基因-一种抗癌方法。
IF 4.1 4区 医学
RSC medicinal chemistry Pub Date : 2025-04-17 DOI: 10.1039/d4md00959b
Tiago J S Marques, Diana Salvador, Helena Oliveira, Vanda V Serra, Nicholas Paradis, Chun Wu, Vera L M Silva, Catarina I V Ramos
{"title":"New acridone derivatives to target telomerase and oncogenes - an anticancer approach.","authors":"Tiago J S Marques, Diana Salvador, Helena Oliveira, Vanda V Serra, Nicholas Paradis, Chun Wu, Vera L M Silva, Catarina I V Ramos","doi":"10.1039/d4md00959b","DOIUrl":"https://doi.org/10.1039/d4md00959b","url":null,"abstract":"<p><p>In this work, two new acridone derivatives, <b>AcridPy</b> and <b>AcridPyMe</b>, were synthesized, for the first time, aiming to evaluate their potential as quadruplex stabilizers and anticancer agents. <b>AcridPy</b> was synthesized through a very straightforward one-pot sequential chemical reaction involving the Heck cross-coupling reaction of (<i>E</i>)-3-iodo-2-(4-methoxystyryl)-1-methylquinolin-4(1<i>H</i>)-one with a vinyl pyridine followed by <i>in situ</i> electrocyclization and oxidation, while the synthesis of <b>AcridPyMe</b> involved an additional <i>N</i>-methylation of the pyridine ring. Their ability to stabilize G-quadruplex DNA structures, which are associated with the regulation of oncogenes, was assessed using biophysical methods. Both compounds demonstrated significant quadruplex stabilization properties, showing selectivity to G-quadruplexes over duplex DNA. Molecular dynamics simulation experiments supported the preferential binding of <b>AcridPyMe</b> to MYC. The cytotoxicity of these derivatives was further evaluated <i>in vitro</i> in two distinct pancreatic tumor cell lines, PanC-1 and MIA PaCa-2, the lung tumor A549 cell line, the melanoma A375 cell line, and the immortalized human keratinocyte HaCaT cell line, through the evaluation of cell viability. For PanC-1 and MIA PaCa-2, the cell cycle dynamics and apoptotic cell death along with colocalization were also evaluated. The results revealed that <b>AcridPyMe</b> exhibited anticancer activity, correlated with its quadruplex stabilization ability and, although not exclusive, nuclear co-localization was observed. These findings suggest that the newly synthesized cationic acridone is a promising candidate for the development of novel anticancer therapies targeting G-quadruplex structures.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12004264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978043","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}
引用次数: 0
Design and development of sulfenylated 5-aminopyrazoles as inhibitors of acetylcholinesterase and butyrylcholinesterase: exploring the implication for Aβ1-42 aggregation inhibition in Alzheimer's disease. 磺化5-氨基吡唑作为乙酰胆碱酯酶和丁基胆碱酯酶抑制剂的设计和开发:探索a - β1-42聚集抑制在阿尔茨海默病中的意义
IF 4.1 4区 医学
RSC medicinal chemistry Pub Date : 2025-04-17 DOI: 10.1039/d5md00069f
Payal Rani, Sandhya Chahal, Anju Ranolia, Kiran, Devendra Kumar, Ramesh Kataria, Parvin Kumar, Devender Singh, Anil Duhan, Vibhu Jha, Muhammad Wahajuddin, Gaurav Joshi, Jayant Sindhu
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