MedChemComm最新文献

{"title":"Introduction to the themed collection on ‘Induced-Proximity Pharmacology’","authors":"Ingo V. Hartung, Lindsey I. James and Lyn H. Jones","doi":"10.1039/D5MD90023A","DOIUrl":"10.1039/D5MD90023A","url":null,"abstract":"<p >A graphical abstract is available for this content</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2311-2313"},"PeriodicalIF":3.597,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel benzimidazole hybrids: design, synthesis, mechanistic studies, antifungal potential and molecular dynamics†","authors":"Ahmed A. Ibrahim, Eman G. Said, Asmaa M. AboulMagd, Noha H. Amin and Hamdy M. Abdel-Rahman","doi":"10.1039/D5MD00122F","DOIUrl":"10.1039/D5MD00122F","url":null,"abstract":"<p >In this study, two series of benzimidazole hybrids were developed and designed using different strategies. The target compounds were designed through straight chemistry pathways and were screened as possible antimicrobial agents. Twenty new compounds were synthesized, among which compounds <strong>11</strong> and <strong>12</strong> displayed excellent activity against <em>Candida albicans</em> and <em>Cryptococcus neoformans</em> with growth inhibition percentage ranging from 86.42% to 100%. For gaining better insights into the mechanistic ability of the active candidates <strong>11</strong> and <strong>12</strong>, their inhibitory activity against lanosterol 14α-demethylase was studied. Results showed IC<small>₅₀</small> values of 5.6 and 7.1 μM for <strong>11</strong> and <strong>12</strong>, respectively, which were comparable to the reference value of fluconazole (2.3 μM), indicating low drug interaction possibilities. Notably, compound <strong>11</strong> displayed excellent inhibition of biofilm metabolic activity. In addition, their synergistic activity against <em>C. neoformans</em> displayed a 2-fold increase compared with fluconazole. Furthermore, it exhibited sustained antifungal activity with time clearance of over 24 h, which was better than the time clearance of fluconazole (6 h). Moreover, compounds <strong>11</strong> and <strong>12</strong> displayed considerable safety profiles, with no cytotoxicity reported against human embryonic kidney cells or hemolysis of red blood cells. Molecular dynamics simulation (MDS) experiments over 100 ns of compound <strong>11</strong> showed its ability to interact with the HEM binding site as the co-crystallized ligand (fluconazole). Finally, <em>in silico</em> ADMET studies predicted its significant oral bioavailability as antifungal candidates.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 7","pages":" 3291-3311"},"PeriodicalIF":3.597,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Photoresponsive prodrug for regulated inhibition of indoleamine 2,3-dioxygenase 1 enzyme activity†","authors":"Niku Moni Das, Biswa Mohan Prusty, Adyasa Sahoo, Priyanka Mazumder, Suravi Chauhan, Gunanka Hazarika, Sachin Kumar, Debdas Dhabal and Debasis Manna","doi":"10.1039/D5MD00061K","DOIUrl":"10.1039/D5MD00061K","url":null,"abstract":"<p >Targeting indoleamine 2,3-dioxygenase 1 (IDO1) has emerged as a promising therapeutic strategy for both cancer and Alzheimer's disease due to its critical role in modulating immune response and neurodegenerative processes. This study provides comprehensive evidence that thiourea derivatives of 2-imidazole-substituted 1-methyltryptamines exhibit strong binding affinity for the active site of IDO1. This interaction significantly inhibits the activity of the enzyme, which is an essential factor in tumour immune evasion and neuroinflammation. Furthermore, we have successfully developed a novel prodrug formulation that can restore the action of this potent IDO1 inhibitor upon photoirradiation. This prodrug represents a strategic advancement, allowing for spatial and temporal control of the therapeutic effect, potentially minimizing side effects and enhancing efficacy. Our findings underscore the potential of these compounds as valuable tools in the fight against cancer and Alzheimer's disease, paving the way for future research and clinical applications.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 7","pages":" 3240-3250"},"PeriodicalIF":3.597,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and biological evaluation of novel β-caryophyllene derivatives as potential anti-cancer agents through the ROS-mediated apoptosis pathway†","authors":"Zhiwei Wang, Yang Chen, Anjie Huang, Hui Wen, Yetian Wu, Xingjun Xu, Zhongjing Qiao, Liangyu Chen, Yaopeng Zhao and Xinmiao Liang","doi":"10.1039/D4MD00951G","DOIUrl":"10.1039/D4MD00951G","url":null,"abstract":"<p >As a top-three cancer in global incidence and mortality, colorectal cancer (CRC) urgently demands novel treatments. β-Caryophyllene (β-CP) and its derivatives, a class of sesquiterpenoids with broad anticancer potential, were structurally optimized in this study to enhance efficacy against CRC. Among the synthesized derivatives, <strong>AC-7</strong> exhibited potent cytotoxicity and selectivity in HT-29 cells (IC<small>₅₀</small> = 3.09 μM, SI = 6.1), comparable to 5-fluorouracil (5-FU, IC<small>₅₀</small> = 3.63 μM, SI = 0.4). Network pharmacology and gene enrichment analyses indicated that apoptosis, autophagy, ROS, and NF-κB were key downstream pathways of <strong>AC-7</strong>, which were later validated experimentally. <strong>AC-7</strong> arrested the cell cycle in the G0/G1 phase, promoted autophagy and apoptosis. ROS were identified as having a central role in regulating these related pathways. <em>In vivo</em> studies revealed the significant antitumor and DNA damage activity of <strong>AC-7</strong> in a nude mouse model. These findings suggest that <strong>AC-7</strong> is a promising candidate for anti-CRC therapy, acting through the ROS-mediated apoptosis pathway.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 7","pages":" 3174-3189"},"PeriodicalIF":3.597,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of novel antimyeloma agents targeting TRIP13 by molecular modeling and bioassay†","authors":"Samuel Jacob Bunu, Haiyan Cai, Zhaoyin Zhou, Yanlei Zhang, Yue Lai, Guanli Wang, Dongliang Song, Chengkun Wu, Hang Zheng, Zhijian Xu, Jumei Shi and Weiliang Zhu","doi":"10.1039/D4MD01008F","DOIUrl":"10.1039/D4MD01008F","url":null,"abstract":"<p >Thyroid hormone receptor-interacting protein-13 (TRIP13) is an AAA<small>⁺</small> ATPase that regulates protein complex assembly and disassembly and is known to be a chromosomal instability gene with the ability to repair DNA double-strand breaks. TRIP13 overexpression has been linked to the proliferation and development of many human malignancies, including multiple myeloma (MM). Accordingly, TRIP13 is recognized as a potential drug target for anticancer drug development. Although some TRIP13 inhibitors have been reported, none are under clinical trial or approved for clinical use. This study aimed to identify novel small molecules as potential TRIP13 inhibitors structurally different from previously reported compounds through molecular modeling and bioassays. As a result, five compounds were successfully identified as novel TRIP13 inhibitors. F368-0183 showed the best antiproliferative activity with IC<small>₅₀</small> = 5.25 μM (NCI-H929 cell line), comparable with the positive control DCZ0415 (IC<small>₅₀</small> = 9.64 μM). Also, the cellular thermal shift assay confirmed that this compound could interact with the TRIP13 protein in MM cells. In addition, the AAA<small>⁺</small> ATPase inhibitory bioassay demonstrated that the five compounds had better inhibitory activity than DCZ0415, having strong correlations with the calculated free energy perturbation (FEP). Further molecular dynamics simulation studies revealed that the novel compounds could significantly interact with 12 residues of TRIP13, especially R386, L139, R389, L135, S138, Y141, and G385. We also assessed the F368-0183 inhibition on a kinase panel, no other targets were found, but the potential binding to other target proteins of these compounds cannot be totally excluded. Therefore, the new molecular scaffolds of these compounds, their efficacy in suppressing MM cell line proliferation, and the displayed TRIP13 AAA<small>⁺</small> ATPase inhibitory properties provide important clues for developing novel TRIP13-based multi-target anti-MM drugs.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 7","pages":" 3132-3145"},"PeriodicalIF":3.597,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144034657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Niclosamide: CRL4AMBRA1 mediated degradation of cyclin D1 following mitochondrial membrane depolarization†","authors":"Seemon Coomar, Jessica A. Gasser, Mikołaj Słabicki, Katherine A. Donovan, Eric S. Fischer, Benjamin L. Ebert, Dennis Gillingham and Nicolas H. Thomä","doi":"10.1039/D5MD00054H","DOIUrl":"10.1039/D5MD00054H","url":null,"abstract":"<p >Targeted protein degradation has emerged as a promising approach in drug discovery, utilizing small molecules like molecular glue degraders to harness the ubiquitin-proteasome pathway for selective degradation of disease-driving proteins. Based on results from proteomics screens we investigated the potential of niclosamide, an FDA-approved anthelmintic drug with a 50 year history in treating tapeworm infections, as a molecular glue degrader targeting the proto-oncogene cyclin D1. Proteomics screens in HCT116 colon carcinoma and KELLY neuroblastoma cells, found that niclosamide induces rapid cyclin D1 degradation through a mechanism involving the ubiquitin-proteasome pathway. A genetic CRISPR screen identified the E3 ligase CRL4<small>^AMBRA1</small> as a key player in this process. Structure–activity relationship studies highlighted critical features of niclosamide necessary for cyclin D1 degradation, demonstrating a correlation between mitochondrial membrane potential (MMP) disruption and cyclin D1 downregulation. Notably, various mitochondrial uncouplers and other compounds with similar drug sensitivity profiles share this correlation suggesting that MMP disruption can trigger cyclin D1 degradation, and that the cellular signal driving the degradation differs from previously described mechanism involving CRL4<small>^AMBRA1</small>. Our findings underscore the complexities of proteostatic mechanisms and the multitude of mechanisms that contribute to degrader drug action.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 7","pages":" 3049-3057"},"PeriodicalIF":3.597,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrocyclic RGD-peptides with high selectivity for αvβ3 integrin in cancer imaging and therapy†","authors":"Xiaozhong Cheng, Chen Li, Haofei Hong, Zhifang Zhou and Zhimeng Wu","doi":"10.1039/D5MD00280J","DOIUrl":"10.1039/D5MD00280J","url":null,"abstract":"<p >Integrins, particularly the α<small>_v</small>β<small>₃</small> subtype, are critical receptors involved in cell adhesion, migration, and signaling, playing a significant role in tumor progression and metastasis. Despite extensive research into integrin-targeted therapies, challenges remain in developing ligands that exhibit high selectivity for α<small>_v</small>β<small>₃</small> over other integrin subtypes, such as α<small>_v</small>β<small>₅</small>. This study employs a one-pot sortase A-mediated on-resin peptide cleavage and <em>in situ</em> cyclization method to synthesize two generations of macrocyclic RGD-peptide libraries. Systematic screening through surface plasmon resonance and cell-based competition assays identified the lead compound, c-(G5RGDKcLPET), which demonstrated high affinity and selectivity for α<small>_v</small>β<small>₃</small>. Additionally, the optimized cyclic peptide was functionalized with a fluorescent dye (Cy5) and the cytotoxic drug monomethyl auristatin E (MMAE), enhancing its potential for cancer imaging and targeted therapy. This work contributes a novel platform for developing integrin-targeted diagnostics and therapeutics, highlighting the importance of macrocyclic peptides in cancer treatment strategies.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 7","pages":" 3077-3083"},"PeriodicalIF":3.597,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144080063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proximity-induced membrane protein degradation for cancer therapies","authors":"Dingpeng Zhang, Zhen Wang, Hiroyuki Inuzuka and Wenyi Wei","doi":"10.1039/D5MD00141B","DOIUrl":"10.1039/D5MD00141B","url":null,"abstract":"<p >The selective modulation of membrane proteins presents a significant challenge in drug development, particularly in cancer therapies. However, conventional small molecules and biologics often face significant hurdles in effectively targeting membrane-bound proteins, largely due to the structural complexity of these proteins and their involvement in intricate cellular processes. In light of these limitations, proximity-induced protein modulation has recently emerged as a transformative approach. It leverages molecule-induced proximity strategies to commandeer endogenous cellular machinery for precise protein manipulation. One of these modulatory strategies is protein degradation, wherein membrane-targeting degraders derived from proximity-induction approaches offer a unique therapeutic avenue by inducing the irreversible removal of key oncogenic and immune-regulatory proteins to combat cancer. This review explores the fundamental principles underlying proximity-driven membrane protein degradation, highlighting key strategies such as LYTACs, PROTABs, TransTACs, and IFLD that are reshaping targeted cancer therapy. We discuss recent technological advancements in the application of proximity-induced degraders across breast cancer, lung cancer, immunotherapy, and other malignancies, underscoring how these innovative approaches have demonstrated significant therapeutic potential. Lastly, while these emerging technologies offer significant promise, they still face substantial limitations, including drug delivery, selectivity, and resistance mechanisms that need to be addressed to achieve successful clinical translation.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 7","pages":" 2881-2901"},"PeriodicalIF":3.597,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144049888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research prospects and AI-driven strategies for metal–organic framework-hydrogel composite materials in cancer treatment","authors":"Zijun Zhang, Yuelin Zhang, Taiwei Liang, Jiajia Zhang, Weidong Liu, Ying Pan, Jianqiang Liu and Xiaoxiu Li","doi":"10.1039/D5MD00207A","DOIUrl":"10.1039/D5MD00207A","url":null,"abstract":"<p >Metal–organic frameworks (MOFs) as emerging materials with highly tunable structures, large specific surface areas, and abundant pores show unique advantages in gas storage, catalysis, and drug delivery. Hydrogels are a class of materials consisting of polymers or small molecules that can trap a large amount of water and are thus widely used in biomedical applications owing to their high water content, good biocompatibility, biotissue-like softness and elasticity, and low immunogenicity. Consequently, composite materials formed by combining MOFs with hydrogels have been rapidly developed for cancer therapy. We have carried out considerable work on this type of composite material, exploring various combinations and investigating different treatment modalities, such as chemotherapy, immunotherapy, targeted therapy and combination therapy. Particularly, artificial intelligence (AI) technology was employed to characterize and enhance the therapeutic efficacy of the materials. This review first introduces the basic properties of MOFs and hydrogels and the role played by AI technology in their development. Subsequently, we describe the types, characteristics, applications, and challenges of MOF-hydrogel combinations, focusing on the research progress of various types of cancer treatments based on MOF hydrogels and the application of AI technology in this field. With the deepening of research, the development of smarter and more efficient MOF-hydrogel materials and the in-depth exploration of the application of AI technology in cancer therapy are expected to realize the precise treatment and effective control of cancer and bring new hope to cancer patients.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 7","pages":" 3003-3029"},"PeriodicalIF":3.597,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Trypanosoma brucei 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 and Ioannis P. Papanastasiou","doi":"10.1039/D5MD00135H","DOIUrl":"10.1039/D5MD00135H","url":null,"abstract":"<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 <strong>1a–d</strong> and the linear amidines <strong>2a</strong>,<strong>b</strong> and <strong>3a</strong>,<strong>b</strong> exhibited notable activity against <em>T. brucei</em>. The 1-(4-phenyl)adamantane 1-(4-phenoxyphenyl)adamantane core was further functionalized with the aminoguanylhydrazone and thiosemicarbazone moieties. 2-[(<em>E</em>)-4-(1-adamantyl)benzylidene]hydrazine-1-carbothioamide <strong>4c</strong> emerged as a promising trypanocidal agent with an EC<small>₅₀</small> 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":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2441-2451"},"PeriodicalIF":3.597,"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":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}