RSC medicinal chemistry最新文献

{"title":"Correction: 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 and Mohammad Abrar Alam","doi":"10.1039/D5MD90014J","DOIUrl":"10.1039/D5MD90014J","url":null,"abstract":"<p >Correction for ‘Thiazole-fused androstenone and ethisterone derivatives: potent β- and γ-actin cytoskeleton inhibitors to treat melanoma tumors’ by Sanjay Adhikary <em>et al.</em>, <em>RSC Med. Chem.</em>, 2025, <strong>16</strong>, 1105–1130, https://doi.org/10.1039/d4md00719k.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 4","pages":" 1842-1842"},"PeriodicalIF":4.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796267","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":"Unravelling the potency of the 4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile scaffold with <i>S</i>-arylamide hybrids as PIM-1 kinase inhibitors: synthesis, biological activity and <i>in silico</i> studies.","authors":"Soha R Abd El Hadi, Manar A Eldinary, Amna Ghith, Hesham Haffez, Aya Salman, Ghadir A Sayed","doi":"10.1039/d5md00021a","DOIUrl":"10.1039/d5md00021a","url":null,"abstract":"<p><p>PIM-1 is a type of serine/threonine kinase that plays a crucial role in controlling several vital processes, including proliferation and apoptosis. New synthetic <i>S</i>-amide tetrahydropyrimidinone derivatives were designed and synthesized as PIM-1 inhibitors with potential anticancer activity. Several biochemical assays were performed for anticancer assessment, including PIM-1 inhibitory assays, MTT, apoptosis and cell cycle, gene expression analysis, <i>c-MYC</i> analysis, and ATPase inhibitory assays. Compounds (8c, 8d, 8g, 8h, 8k, and 8l) exhibited strong <i>in vitro</i> broad antiproliferative activity against MCF-7, DU-145, and PC-3, with a relatively higher SI index suggesting minimal cytotoxicity to normal cells. Furthermore, these compounds induced mixed late apoptosis and necrosis with cell cycle arrest at the G2/M phase. Moreover, compounds 8b, 8f, 8g, 8k, and 8l showed potent inhibitory action against PIM-1 kinase, with corresponding IC₅₀ values of 660, 909, 373, 518, and 501 nM. <i>In silico</i> prediction studies of physiochemical properties, molecular dynamics, and induced fit docking studies were performed for these compounds to explain their potent biological activity. In conclusion, new pyrimidinone compounds (8c, 8d, 8g, 8h, 8k, and 8l) exhibit potential PIM-1 inhibitory activity and can be used as promising scaffolds for further optimization of new leads with selective PIM-inhibitors and anticancer activity.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754376","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":"Antiproliferative effects, mechanism of action and tumor reduction studies in a lung cancer xenograft mouse model of an organometallic gold(i) alkynyl complex.","authors":"Uttara Basu, Anna Wilsmann, Sebastian Türck, Henrik Hoffmeister, Matthias Schiedel, Gilles Gasser, Ingo Ott","doi":"10.1039/d4md00964a","DOIUrl":"https://doi.org/10.1039/d4md00964a","url":null,"abstract":"<p><p>Organometallic complexes offer a wide range of properties like structural variety, reaction kinetics, tunable lipophilicity and alternate mechanisms of activation under physiological conditions compared to platinum chemotherapeutics and are thus being explored for their potential anticancer applications. In this regard, gold(i) organometallics hold a pivotal position for their ability to act on biological targets different from DNA (which is the primary target of platinum therapeutics), such as thioredoxin reductase. Here, we report on the stability, <i>in vitro</i> antiproliferative effects, protein binding, cellular uptake, mechanism of action, effects on mitochondrial respiration of cancer cells as well as <i>in vivo</i> tolerance, toxicity and tumor reduction in an A549 lung cancer xenograft mouse model of an organometallic gold(i) complex (1) bearing 4-ethynylanisole and triethylphosphane as ligands. The complex, which was stable in DMSO and reactive towards <i>N</i>-acetylcysteine, triggered strong antiproliferative effects in various cancer cell lines and had a protein binding of approximately 65% that reduced its generally efficient uptake into tumor cells. Antimetastatic properties were indicated for 1 in a scratch assay and strong inhibition of thioredoxin reductase (TrxR) was confirmed for the purified enzyme as well as in A549 lung cancer cells, which strongly overexpress TrxR. Real time monitoring of the oxygen consumption rate in multiple cancer cell lines, using the Seahorse Mito stress assay, demonstrated that mitochondrial respiration was severely disrupted, showing a significantly low oxygen consumption rate. Other respiratory parameters, such as proton efflux, spare respiratory capacity and maximal respiration, were also attenuated upon treatment with 1. The complex was well tolerated <i>in vivo</i> in mice at a dose of 10 mg kg^-1 and showed tumor reduction compared to the control group of animals in a lung cancer xenograft model of nude mice. In summary, complex 1 represents a novel organometallic anticancer drug candidate with a mechanism related to TrxR inhibition and mitochondrial respiration inhibition, showing efficient <i>in vivo</i> antitumor efficacy.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143812233","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 allosteric inhibitor targeting the STAT3 coiled-coil domain selectively suppresses proliferation of breast cancer.","authors":"Min Huang, Wei Wang, Liyue Cao, Jiaxin Liu, Can Du, Jian Zhang","doi":"10.1039/d4md00926f","DOIUrl":"10.1039/d4md00926f","url":null,"abstract":"<p><p>Signal transducer and activator of transcription 3 (STAT3) remains a challenging and attractive therapeutic target in cancer research. The coiled-coil domain (CCD) of STAT3 represents a novel site for targeted intervention, distinct from the Src-homology 2 domain, and plays a crucial role in regulating the earlier activation and biological function of STAT3 in cell proliferation, survival and invasion of breast cancer cells. We previously reported K116, <i>N</i>'-(1-(2,4-dihydroxyphenyl)ethylidene)thiophene-2-carbohydrazide, as a potent allosteric inhibitor specifically targeting the STAT3 CCD. This study aimed to investigate the antiproliferation effect of K116 on breast cancer cells <i>in vitro</i> and <i>in vivo</i>. The results showed that K116 inhibited the proliferation of breast cancer cell lines in a dose-dependent manner by reducing the phosphorylation of STAT3 Lyr705 and did not inhibit the proliferation of HGC-27 and A549 cells nor their STAT3 Lyr705 phosphorylation. Compared with Stattic (STAT3 SH2 inhibitor), K116 selectively inhibited the proliferation of breast cancer cells. Furthermore, K116 (20 μM) directly monitored STAT3 stabilization and engagement within MDA-MB-468 cells, without affecting STAT1, STAT5, and Akt1. K116 induced apoptosis and inhibited migration as well as pY705STAT3 nuclear translocation and transcriptional activity of STAT3. In addition, K116 (30 mg kg^-1) markedly suppressed tumor growth and inhibited STAT3 activity in a 4T1 cell-derived murine breast cancer model. Overall, our results provided pharmacological evidence supporting future clinical investigation of K116 as a promising STAT3 CCD allosteric inhibitor for breast cancer treatment.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796259","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":"Thiochromenes and thiochromanes: a comprehensive review of their diverse biological activities and structure-activity relationship (SAR) insights.","authors":"Jatin, Solai Murugappan, Shivani Kirad, Chandu Ala, Pranali Vijaykumar Kuthe, Chandra Sekhar Venkata Gowri Kondapalli, Murugesan Sankaranarayanan","doi":"10.1039/d4md00995a","DOIUrl":"10.1039/d4md00995a","url":null,"abstract":"<p><p>Thiochromene and thiochromane scaffolds, sulfur containing heterocycles, have gained significant attention in medicinal chemistry due to their diverse pharmacological activities. This review provides a comprehensive analysis of their antibacterial, antifungal, antiviral, anti-parasitic, and anticancer properties, emphasizing their therapeutic potential. SAR studies highlight key molecular modifications such as electron withdrawing substituents, sulfur oxidation, and tailored ring substitutions that enhance bioactivity, potency, and target specificity. Mechanistic insights reveal their ability to inhibit microbial enzymes, disrupt cellular pathways, and modulate key biological targets. By summarizing recent advancements, this review underscores the potential of thiochromene and thiochromane based therapeutics and encourages further research to address existing limitations and enhance their drug development prospects.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711140","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":"Contributors to our Emerging Investigators collection","authors":"","doi":"10.1039/D5MD90009C","DOIUrl":"10.1039/D5MD90009C","url":null,"abstract":"<p >A graphical abstract is available for this content</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 4","pages":" 1472-1475"},"PeriodicalIF":4.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711005","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":"Near-infrared photochemical internalization: design of a distorted zinc phthalocyanine for efficient intracellular delivery of immunotoxins.","authors":"Mikako Hamabe, Wakako Dewa, Mizue Yuki, Eriko Yamada, Tamako Aiba, Keisuke Horikoshi, Takao Hamakubo, Riuko Ohashi, Akimitsu Okamoto","doi":"10.1039/d4md00931b","DOIUrl":"10.1039/d4md00931b","url":null,"abstract":"<p><p>In the treatment of cancer, the physical and mental stress on patients and the potential for strong side effects are serious problems; therefore, reliable delivery of drugs into cancer tissue cells is required. We have developed a near-infrared (NIR) photosensitizing dye, Zn6PTPc, for NIR-photochemical internalization (PCI) to achieve gentle and efficient endosomal escape and delivery of antibody drugs, which are known to have high targeting ability but low intracellular activity, into target cancer cells. Zn6PTPc allowed longer wavelengths to be used to achieve higher singlet oxygen generation efficiency by the molecular design based on a distorted π-electron system. The system effectively introduced immunotoxins into cells to significantly inhibit tumor tissue growth. The developed potent NIR photosensitizers facilitated NIR-PCI with high tumor-targeting ability.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796307","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":"Methods for kinetic evaluation of reversible covalent inhibitors from time-dependent IC₅₀ data.","authors":"Lavleen K Mader, Jeffrey W Keillor","doi":"10.1039/d5md00050e","DOIUrl":"10.1039/d5md00050e","url":null,"abstract":"<p><p>Potent reversible covalent inhibitors are often slow in establishing their covalent modification equilibrium, resulting in time-dependent inhibition. While these inhibitors are commonly assessed using IC₅₀ values, there are no methods available to analyze their time-dependent IC₅₀ data to provide their inhibition (<i>K</i> _i and ) and covalent modification rate (<i>k</i> ₅ and <i>k</i> ₆) constants, leading to difficulty in accurately ranking drug candidates. Herein, we present an implicit equation that can estimate these constants from incubation time-dependent IC₅₀ values and a numerical modelling method, EPIC-CoRe, that can fit these kinetic parameters from pre-incubation time-dependent IC₅₀ data. The application of these new methods is demonstrated by the evaluation of a known inhibitor, saxagliptin, providing results consistent with those obtained by other known methods. This work introduces two new practical methods of evaluation for time-dependent reversible covalent inhibitors, allowing for rigorous characterization to enable the fine-tuning of their binding and reactivity.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754357","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":"Investigation of the <i>in vitro</i> anticancer potential of bis(imino)acenaphthene-N-heterocyclic carbene transition metal complexes revealed TrxR inhibition and triggering of immunogenic cell death (ICD) for allyl palladates.","authors":"Chiara Donati, Ishfaq Ibni Hashim, Nestor Bracho Pozsoni, Laurens Bourda, Kristof Van Hecke, Catherine S J Cazin, Fabiano Visentin, Steven P Nolan, Valentina Gandin, Thomas Scattolin","doi":"10.1039/d5md00039d","DOIUrl":"10.1039/d5md00039d","url":null,"abstract":"<p><p>Immunogenic cell death (ICD) is a regulated form of cell death that activates an immune response through the release of danger-associated molecular patterns (DAMPs), including calreticulin, ATP, and HMGB1. Gold complexes are known to induce ICD, but the ICD-inducing potential of palladium complexes remains largely unexplored. We report the first examples of palladium compounds capable of inducing ICD, specifically allyl palladates bearing bis(imino)acenaphthene-NHC (BIAN-NHC) ligands. Cytotoxicity tests on human cancer cell lines revealed that allyl palladates outperform their cinnamyl analogues and gold(i)/copper(i) BIAN-NHC complexes. Notably, [BIAN-IMes·H][PdCl₂(allyl)] 2a showed excellent TrxR inhibition, reducing activity by 67% and surpassing auranofin. This inhibition strongly correlates with ICD induction, as evidenced by enhanced DAMP marker expression, including superior ATP and HMGB1 release compared to doxorubicin. These findings establish allyl palladates as a novel class of ICD inducers with dual anticancer activity and immune activation potential.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11956031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764959","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":"Synthesis, <i>in silico</i> and <i>in vitro</i> antimicrobial efficacy of some amidoxime-based benzimidazole and benzimidamide derivatives.","authors":"Gbolahan O Oduselu, Olayinka O Ajani, Temitope A Ogunnupebi, Oluwadunni F Elebiju, Damilola S Bodun, Oluwabukayo Toluwunmiju Opebiyi, Ezekiel Adebiyi","doi":"10.1039/d5md00114e","DOIUrl":"10.1039/d5md00114e","url":null,"abstract":"<p><p>Amidoximes are employed as building blocks to synthesise heterocyclic motifs with biological significance. They are very reactive and are used as prodrugs of amidine. This present study unveils the synthesis of amidoxime-based benzimidazole and benzimidamide motifs and evaluates their <i>in silico</i> and <i>in vitro</i> antimicrobial potential as future drug candidates. The compounds (2a, 2b, 4a-c) were synthesized using multi-step synthetic pathways. The synthesised compounds were characterised using physico-chemical examination, ¹H- and ¹³C-NMR, DEPT-135, and FT-IR spectroscopic analyses. The <i>in silico</i> antimicrobial potentials of the synthesized compounds were carried out against glucosamine-6-phosphate synthase of <i>E. coli</i> (PDB ID: 2VF5), and <i>N</i>-myristoyltransferase (NMT) of <i>C. albicans</i> (PDB ID: 1IYL), while the <i>in vitro</i> antimicrobial screening was investigated against selected bacteria and fungi. The <i>in silico</i> studies were carried out using predicted ADMET screening, molecular docking, MM-GBSA, induced-fit docking (IFD), and molecular dynamics (MD) simulation studies. Furthermore, the <i>in vitro</i> experimental validations were performed using the agar diffusion method and the standard antibacterial and antifungal drugs used were gentamicin and ketoconazole respectively. The predicted toxicity test of the compounds showed no significant risk, except for 4c, which showed high tumorigenic risk. Compounds 2b and 2a gave better binding energies; -8.0 kcal mol^-1 for 2VF5 and -11.7 kcal mol^-1 for 1IYL, respectively. The antimicrobial zone of inhibition and minimum inhibitory concentration values were 40 mm and 3.90 mg mL^-1 against <i>S. mutans</i>, then 42 mm and 1.90 mg mL^-1 against <i>C. albicans</i>. Potential antimicrobial drug candidates have been identified in this report and should be explored for future preclinical research.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754362","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}