RSC medicinal chemistry最新文献

{"title":"In vivo demonstration of enhanced mRNA delivery by cyclic disulfide-containing lipid nanoparticles for facilitating endosomal escape†","authors":"Seigo Kimura, Kana Okada, Noriaki Matsubara, Fangjie Lyu, Susumu Tsutsumi, Yasuaki Kimura, Fumitaka Hashiya, Masahito Inagaki, Naoko Abe and Hiroshi Abe","doi":"10.1039/D5MD00084J","DOIUrl":"10.1039/D5MD00084J","url":null,"abstract":"<p >Current LNP technology faces challenges that must be addressed to enhance the functionality of mRNA therapeutics. Recent studies show disulfide-conjugated molecules improve cell membrane permeability. Here, we investigated incorporating cyclic disulfide (CDL) units into lipid components of LNPs to enhance LNP-mRNA performance. A lipid library with branched and unbranched alkyl chains (C16–C20) and tertiary amine groups modified with CDLs was designed. While cellular uptake was unchanged, some mRNA-loaded LNPs with CDLs achieved more than 2-fold higher transfection efficiency than LNPs with MC3 or SM102 alone. Intracellular analysis revealed that the addition of CDL lipids significantly promoted endosomal escape. The CDL-incorporated LNPs administered subcutaneously in mice showed significantly higher luciferase gene expression compared to LNPs without CDL. Additionally, LNPs encapsulating OVA antigen-encoding mRNA induced a potent antitumor response against the EG7-OVA lymphoma model. These results suggest CDL modifications enhance LNP-based mRNA delivery, offering potential for broader therapeutic applications and improved clinical outcomes.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 4122-4137"},"PeriodicalIF":3.6,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144643321","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":"Bioassay-guided isolation of hepatoprotective lignans from Vernonia cinerea: DeepSAT-driven structural elucidation and predictive mechanistic insights against drug-induced liver injury†","authors":"Mu Li, Meng-Ke Zhang, Xin Song, Yu-Ting Zhong, Ming-An Gui, Jie Ping, You-Sheng Cai and Rui-Ying Yuan","doi":"10.1039/D5MD00331H","DOIUrl":"10.1039/D5MD00331H","url":null,"abstract":"<p >Three new dibenzylbutane lignans, vernolignans A–C (<strong>1–3</strong>), along with three known compounds (<strong>4–6</strong>), were isolated from <em>Vernonia cinerea</em> through a bioactivity-guided isolation process. The planar structures of the new compounds (<strong>1–3</strong>) were elucidated through comprehensive analysis of HR-ESI-MS and 1D/2D NMR data, with the assistance of AI-based structure annotation tool DeepSAT. The absolute configurations of <strong>1–3</strong> were determined by comparing the experimental and calculated ECD spectra. Compounds <strong>2</strong> and <strong>3</strong> exhibited significant improvements in cell viability and attenuated acetaminophen-induced alanine aminotransferase levels in murine hepatocytes at 20 μM. Bioinformatics analysis and molecular docking suggested that BRAF might be a potential target for these lignans.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 4270-4277"},"PeriodicalIF":3.6,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576191","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":"ATP-competitive inhibitors for cancer treatment – kinases and the world beyond","authors":"Ana Jug and Janez Ilaš","doi":"10.1039/D5MD00235D","DOIUrl":"10.1039/D5MD00235D","url":null,"abstract":"<p >Adenosine 5′-(tetrahydrogen triphosphate) (ATP), an essential molecule for cellular energy transfer, plays a crucial role in various biochemical processes, including protein folding, DNA repair and intracellular signalling. A promising strategy for the development of anticancer therapies is to target ATP-binding sites of proteins involved in these processes with ATP-competitive inhibitors. They either mimic ATP to block its binding or bind allosterically to induce conformational changes that prevent ATP interaction. While protein kinases are the main focus of ATP-competitive inhibitors used in cancer therapy, other non-kinase targets such as Hsp90, Topo II, p97, RNA helicases and ABC transporters are also recognized as important molecular targets. Their inhibition can overcome resistance to kinase inhibitors, which develops due to mutations in kinase domains, and at the same time alter essential properties of cancer cells. Although they target different protein families, selectivity remains a challenge due to the conserved nature of ATP binding sites. However, the structural differences between the target proteins allow the development of specific inhibitors. In addition, dual inhibitors targeting multiple ATP-dependent proteins can increase therapeutic efficacy, reduce drug resistance and minimize side effects. Several ATP-competitive kinase inhibitors are already approved for clinical use and many more are in clinical trials, demonstrating their potential in cancer therapy. In this review, we focus on ATP-competitive inhibition in cancer therapy beyond kinases, highlighting recent advances and challenges in the field while applying lessons learned from the development of kinase inhibitors.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 4044-4067"},"PeriodicalIF":3.6,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12219944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560955","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":"5-(Thiophen-2-yl)isoxazoles as novel anti-breast cancer agents targeting ERα: synthesis, in vitro biological evaluation, in silico studies, and molecular dynamics simulation†","authors":"Paramita Pattanayak, Sripathi Nikhitha, Debojyoti Halder, Balaram Ghosh and Tanmay Chatterjee","doi":"10.1039/D5MD00339C","DOIUrl":"10.1039/D5MD00339C","url":null,"abstract":"<p >Herein, we report the design and synthesis of novel 5-(thiophen-2-yl)-4-(trifluoromethyl)isoxazoles (<strong>TTI</strong>), and <em>in vitro</em> evaluation of their anti-cancer activities. Based on the molecular structure of our previously developed isoxazole-based anti-breast cancer lead molecule, 3-(3,4-dimethoxyphenyl)-5-(thiophen-2-yl)-4-(trifluoromethyl)isoxazole (<strong>TTI-4</strong>), we designed a set of 14 new analogues of <strong>TTI-4</strong>. The <strong>TTIs</strong> are a synthetically challenging class of molecules, and we synthesized them with high purity by utilizing our in-house developed novel synthetic strategy, <em>i.e.</em>, metal-free, cascade regio- and stereoselective trifluoromethyloximation, cyclization, and elimination strategy, with readily available α,β-unsaturated ketones by using commercially available and cheap reagents such as CF<small>₃</small>SO<small>₂</small>Na and <small>^<em>t</em></small>BuONO (cost-effective and sustainable synthesis). Subsequently, the anti-cancer activities of the newly synthesized molecules were evaluated against various cancer cell lines such as MCF-7, 4T1, and PC-3, and the molecules showed potential and more selective cytotoxicity against the human breast cancer cell line, MCF-7, among others. The <em>in vitro</em> screening revealed a new molecule, <em>i.e.</em>, 5-(thiophen-2-yl)-4-(trifluoromethyl)-3-(3,4,5-trimethoxyphenyl)isoxazole (<strong>TTI-6</strong>), possessing an IC<small>₅₀</small> value of 1.91 μM against MCF-7, is superior to the previous lead molecule (<strong>TTI-4</strong>) and also the best anti-cancer agent among all. The structure–activity relationship (SAR) studies revealed the importance of an unsubstituted thiophene ring in the 5th position, a –CF<small>₃</small> functional group in the 4th position, and a highly electron-rich benzene ring bearing three –OCH<small>₃</small> functional groups in the 3rd position of the isoxazole core to have superior activity. Further studies with <strong>TTI-6</strong>, such as apoptosis induction, cell cycle analysis, and nuclear staining, revealed an apoptotic cell death mechanism. The <em>in silico</em> molecular docking, induced fit analysis, and ADMET studies further supported the effects of various functional groups of <strong>TTIs</strong> on their anti-breast cancer activity by inhibiting the estrogen receptor alpha (ERα), a crucial nuclear hormone receptor involved in gene regulation that plays an important role in several human cancers.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 4355-4376"},"PeriodicalIF":3.6,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144660089","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":"Structure-based design and evaluation of tyrosinase inhibitors targeting both human and mushroom isozymes†","authors":"Salvatore Mirabile, Giovanna Pitasi, Sonia Floris, Kristina Schira, Lyna Khettabi, Montserrat Soler-Lopez, Jörg Scheuermann, Rosaria Gitto, Maria Paola Germanò, Antonella Fais and Laura De Luca","doi":"10.1039/D5MD00357A","DOIUrl":"10.1039/D5MD00357A","url":null,"abstract":"<p >Tyrosinase inhibition represents an attractive challenge to fight skin hyperpigmentation for medicinal and cosmeceutical application. We have previously provided insights for the development of novel compounds with a specific shape and functional groups interacting with tyrosinases from distinct sources. We chose to employ the <em>Agaricus bisporus</em> tyrosinase (AbTYR) isoform as a cost-effective and rapid screening method prior to carrying out the assay toward human tyrosinase (hTYR). Through this approach, the inhibitor [4-(4-hydroxyphenyl)piperazin-1-yl](2-methoxyphenyl)methanone (MehT-3) has been identified as an effective inhibitor against both TYRs with potency comparable to that of the marketed inhibitor Thiamidol. Continuing our efforts, in this work we designed a focused small series of MehT-3 derivatives that were <em>in silico</em> predicted for their ability to occupy the cavity of AbTYR and hTYR; subsequently, we proceeded with the execution of a very simple and efficient synthetic procedure to obtain the designed compounds. As a result, we obtained potent AbTYR and hTYR inhibitors with affinity values ranging from 5.3 to 40.7 μM. Notably, compounds <strong>2</strong> and <strong>3</strong> emerged as the most promising candidates; they exhibited superior activity against hTYR and demonstrated low toxicity as effective antioxidant agents and sunscreen products. Overall, these achievements further strengthened our computational protocol, which could be effectively applied to develop newer tyrosinase inhibitors.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 8","pages":" 3814-3825"},"PeriodicalIF":3.6,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485765","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":"Glycosidase-activated prodrugs of a cytotoxic iron chelator for targeted cancer therapy†","authors":"Debashish Tomar, Axel Steinbrueck, Adam C. Sedgwick, Matthew S. Levine, Jonathan L. Sessler and Nils Metzler-Nolte","doi":"10.1039/D5MD00232J","DOIUrl":"10.1039/D5MD00232J","url":null,"abstract":"<p >New glycoside-prodrugs based on the iron chelator deferasirox were designed. Selective enzymatic activation by glycosidases was observed within 24 hours, accompanied by cancer cell-selective cytotoxicity. Notably, derivative <strong>3a</strong>, bearing a β-<small>D</small>-galactose moiety, showed promising selective activity against galactosidase overexpressing OvCar-3 cells (IC<small>₅₀</small> 9.1 ± 1.6 μM) while maintaining low activity against fibroblast control GM5756 cells (IC<small>₅₀</small> &gt; 100 μM).</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 8","pages":" 3507-3511"},"PeriodicalIF":3.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12177571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476591","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":"Outstanding Reviewers for <i>RSC Medicinal Chemistry</i> in 2024.","authors":"","doi":"10.1039/d5md90024g","DOIUrl":"https://doi.org/10.1039/d5md90024g","url":null,"abstract":"<p><p>We would like to take this opportunity to thank all of <i>RSC Medicinal Chemistry</i>'s reviewers for helping to preserve quality and integrity in chemical science literature. We would also particularly like to highlight the Outstanding Reviewers for <i>RSC Medicinal Chemistry</i> in 2024.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":"16 7","pages":"2880"},"PeriodicalIF":3.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12179654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144966943","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":"Outstanding Reviewers for RSC Medicinal Chemistry in 2024","authors":"","doi":"10.1039/D5MD90024G","DOIUrl":"10.1039/D5MD90024G","url":null,"abstract":"<p >We would like to take this opportunity to thank all of <em>RSC Medicinal Chemistry</em>'s reviewers for helping to preserve quality and integrity in chemical science literature. We would also particularly like to highlight the Outstanding Reviewers for <em>RSC Medicinal Chemistry</em> in 2024.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 7","pages":" 2880-2880"},"PeriodicalIF":4.1,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476592","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":"Novel furo[2,3-d]pyrimidine derivatives as PI3K/AKT dual inhibitors: design, synthesis, biological evaluation, and molecular dynamics simulation†","authors":"M. A. M. Abdel Reheim, Walid E. Elgammal, Mahmoud S. Bashandy, Mohammed I. A. Hamed, Asmaa M. AboulMagd, Mona G. Khalil, Amr M. Abdou and Rasha A. Hassan","doi":"10.1039/D5MD00139K","DOIUrl":"10.1039/D5MD00139K","url":null,"abstract":"<p >The current study aimed to synthesize a series of innovative improved anticancer chemical entities by combining the unique advantages of 1,3,4-thiadiazole as an established anticancer pharmacophore with the furopyrimidine scaffold which is a key component of many reported cytotoxic agents. Sixteen furopyrimidine derivatives were designed and evaluated by several biological tests including antiproliferative activity against 60 human cancer cell lines, measurement of GI<small>₅₀</small>, TGI, and LC<small>₅₀</small> values, MTT and selectivity index (SI) calculation, <em>in vitro</em> enzymatic PI3Kα/β and AKT inhibitory assay, cell cycle analysis and apoptosis evaluation. The results indicated that the designed compound <strong>10b</strong> revealed potent anticancer activity with a mean GI of 108.32%, remarkable anticancer activity with GI<small>₅₀</small> values ranging from 0.91 to 16.7 μM and strong cytostatic action (TGI range: 2.32–15.0 μM) against 38 cancer cell lines. It also exhibited a potent and selective antiproliferative activity against the breast cancer HS 578T cell line (GI<small>₅₀</small> = 1.51 μM and TGI = 4.96 μM). Furthermore, compound <strong>10b</strong> demonstrated the highest inhibitory activity against PI3Kα/β and AKT enzymes with IC<small>₅₀</small> = 0.175 ± 0.007, 0.071 ± 0.003 and 0.411 ± 0.02 μM, respectively. Additionally, it could strongly induce cell cycle arrest in breast cancer HS 578T cells at the G0–G1 phase and trigger apoptosis. Molecular docking and dynamics were also performed in this study which revealed that compound <strong>10b</strong> provided an improved binding pattern with the key amino acids in the PI3K and AKT-1 binding sites. According to the findings, the designed compound <strong>10b</strong> has potent antiproliferative and apoptotic activities with a wide therapeutic index particularly against breast cancer.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 8","pages":" 3714-3735"},"PeriodicalIF":3.6,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326806","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":"Small-molecule probes for imaging and impairing the Golgi apparatus in cancer","authors":"Phanindra Kumar, Poulomi Sengupta and Sudipta Basu","doi":"10.1039/D5MD00320B","DOIUrl":"10.1039/D5MD00320B","url":null,"abstract":"<p >The Golgi apparatus (GA) is one of the most important subcellular organelles controlling protein processing, post-translational modification and secretion. Dysregulation of the GA structure and function leads to multiple pathological states, including cancer development and metastasis. Consequently, visualizing GA dynamic structures and their impairment in cancer has emerged as a novel strategy for next-generation unorthodox cancer therapeutics. However, the major challenge in GA-mediated theranostic probe development is the specific targeting of the GA within the subcellular milieu due to the lack of GA-recognizing chemical entities. In this review, we delineated various chemical functionalities that are extensively used as GA-homing moieties. Moreover, we outlined GA imaging probes consisting of classical fluorophores as well as novel aggregation-induced emissive (AIE) probes tagged with GA-homing moieties. Furthermore, we described GA-impairing molecules that can damage GA morphology through chemotherapeutic and photodynamic therapy (PDT) in cancer. Finally, we addressed the current challenges in this emerging and underexplored field of GA-targeted theranostics and proposed potential solutions to guide future cancer therapeutics.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 3884-3892"},"PeriodicalIF":3.6,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12212356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554378","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}