RSC medicinal chemistry最新文献

{"title":"Self-responsive biomimetic short lipopeptide-based delivery systems for enhanced antibiotic efficacy against drug-resistant infections.","authors":"Shruti Sharma, Deepanshi Saxena, Aanand Kautu, Sidharth Chopra, Khashti Ballabh Joshi","doi":"10.1039/d4md00911h","DOIUrl":"https://doi.org/10.1039/d4md00911h","url":null,"abstract":"<p><p>Biocompatible short peptide amphiphile nanostructures were developed as an innovative platform for the efficient delivery of meropenem. These nanostructures exhibit self-responsive behavior, specifically targeting infection sites and releasing the antibiotic in a controlled manner. Testing against clinically relevant bacteria, including methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) and vancomycin-resistant <i>Staphylococcus aureus</i> (VRSA), demonstrated their ability to enhance antibiotic concentration at the site of infection, significantly improving therapeutic efficacy. By reducing the required dosages, this approach minimizes systemic cytotoxicity and mitigates the side effects associated with higher drug concentrations. The study highlights the potential of these nanostructures as a promising strategy to combat drug-resistant bacterial infections, addressing a critical global health challenge.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143650246","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":"Leveraging efficiency metrics for the optimization of CELMoDs™ as cereblon-based molecular glue degraders.","authors":"Lei Jia, Jennifer R Riggs, Dahlia R Weiss, Brian L Claus, Veerabahu Shanmugasundaram, Stephen R Johnson, Christoph W Zapf","doi":"10.1039/d4md00870g","DOIUrl":"10.1039/d4md00870g","url":null,"abstract":"<p><p>Efficiency metrics are useful in medicinal chemistry to track small molecule progress in lead optimization (LO). Molecular glue degraders are small molecules that mediate targeted protein degradation by chemically inducing proximity between an E3 ligase and a protein target. The potency and depth of protein degradation are important factors in identifying molecular glue drug candidates. We developed degradation efficiency metrics based on both potency and depth of degradation to track lead optimization objectives. We applied these efficiency metrics retrospectively to track optimization of a clinical molecular glue degrader series, resulting in the identification of Golcadomide (CC-99282). This work illustrates that efficiency metrics are beneficial for the identification of molecular glue drug candidates.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568089","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":"Development of p300-targeting degraders with enhanced selectivity and onset of degradation.","authors":"Graham P Marsh, Mark S Cooper, Sean Goggins, Stephen J Reynolds, Dean F Wheeler, Joel O Cresser-Brown, Robert E Arnold, Emily G Babcock, Gareth Hughes, Darko Bosnakovski, Michael Kyba, Samuel Ojeda, Drew A Harrison, Christopher J Ott, Hannah J Maple","doi":"10.1039/d4md00969j","DOIUrl":"https://doi.org/10.1039/d4md00969j","url":null,"abstract":"<p><p>p300 and CBP are paralogous epigenetic regulators that are considered promising therapeutic targets for cancer treatment. Small molecule p300/CBP inhibitors have so far been unable to differentiate between these closely related proteins, yet selectivity is desirable in order to probe their distinct cellular functions. Additionally, in multiple cancers, loss-of-function <i>CREBBP</i> mutations set up a paralog dependent synthetic lethality with p300, that could be exploited with a selective therapeutic agent. To address this, we developed p300-targeting heterobifunctional degraders that recruit p300 through its HAT domain using the potent spiro-hydantoin-based inhibitor, iP300w. Lead degrader, BT-O2C, demonstrates improved selectivity and a faster onset of action compared to a recently disclosed A 485-based degrader in HAP1 cells and is cytotoxic in CIC::DUX4 sarcoma (CDS) cell lines (IC₅₀ = 152-221 nM), significantly reducing expression of CDS target genes (ETV1, ETV4, ETV5). Taken together, our results demonstrate that BT-O2C represents a useful tool degrader for further exploration of p300 degradation as a therapeutic strategy.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143650271","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":"Betaine-salicylic acid cocrystal for enhanced skincare and acne treatment.","authors":"Zhenyuan Wang, Mi Wang, Qingsheng Tao, Yufei Li, Hao Wang, Mei Zhang, Xueli Liu, Jiaheng Zhang","doi":"10.1039/d5md00001g","DOIUrl":"https://doi.org/10.1039/d5md00001g","url":null,"abstract":"<p><p>Salicylic acid (SA) is a natural lipophilic active ingredient commonly used in cosmetics and skin disease treatments, offering benefits such as exfoliation, anti-inflammation effects, antibacterial properties, oil control, and acne alleviation. However, its poor water solubility, low bioavailability, and potential side effects, such as allergies, irritation, and dryness, hinder its widespread application. In this study, we prepared a betaine-salicylic acid (BeSA) cocrystal and systematically characterized its crystal structure, biological activity, and clinical efficacy. The results showed that BeSA has significantly lower irritancy and cytotoxicity than SA, but exhibits excellent anti-inflammatory and antioxidant properties as well as high moisturizing and anti-acne efficacy, making it a potential alternative to SA. Further, quantum chemical calculations and molecular docking simulations were conducted to investigate the intrinsic mechanisms underlying the excellent bioactivity of BeSA cocrystals. This study introduces an innovative solution for safer and more effective skincare formulations based on SA and offers theoretical guidance regarding material engineering and further material optimization, which has crucial implications for both industry and academia.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543024","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":"Application of a bivalent \"click\" approach to target tyrosyl-DNA phosphodiesterase 1 (TDP1).","authors":"Xue Zhi Zhao, Wenjie Wang, Md Rasel Al Mahmud, Keli Agama, Yves Pommier, Terrence R Burke","doi":"10.1039/d4md00824c","DOIUrl":"10.1039/d4md00824c","url":null,"abstract":"<p><p>Although inhibiting the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) synergizes with topoisomerase type I (TOP1) inhibitors in anticancer therapy, development of TDP1 inhibitors has been highly challenging. This may be due to the open and shallow nature of the TDP1 catalytic site and the necessity of competing with a large and highly extended substrate. The toolbox available to chemical biologists for studying TDP1 could be significantly enhanced by introducing the ability to selectively eliminate TDP1 using protein degraders. Our current work starts from phenyl imidazopyridine-based TDP1 inhibitors previously developed from small molecule microarrays (SMMs). Using crystal structures of lead inhibitors bound to TDP1, we designed and synthesized a series of bivalent proteolysis-targeting chimeras (PROTACs). The focus of our current work is to explore synthetic approaches that permit installation of E3 ligase-targeting functionality, while retaining the TDP1 binding. We employed copper-catalyzed azide-alkyne cycloaddition (CuAAC) \"click\" reactions to assemble PROTAC constituents with 1,2,3-triazole-containing linkers. With the addition of the relatively large parts of the linkers and E3-targeting moieties, we retained the ability to inhibit TDP1. The successful development of TDP1-directed PROTACS would yield a new therapeutic class that could potentially enhance the efficacy and selectivity of TOP1 inhibitors including those used as payloads in antibody drug conjugates (ADCs).</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483535","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":"Design, synthesis and biological evaluation of 2<i>H</i>-[1,4]oxazino-[2,3-<i>f</i>]quinazolin derivatives as potential EGFR inhibitors for non-small cell lung cancer.","authors":"Linchang Huang, Ying Zhang, Peng Liu, Lihong Lan, Lifang Yang, Bo Wang, Tingting Cao, Liming Hu, Xuemei Qin","doi":"10.1039/d4md01016g","DOIUrl":"https://doi.org/10.1039/d4md01016g","url":null,"abstract":"<p><p>Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have emerged as the first-line treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC). A series of 2<i>H</i>-[1,4]oxazino[2,3-<i>f</i>]quinazolin derivatives were synthesized and evaluated as irreversible EGFR-TKIs for the treatment of NSCLC. Most of the synthesized compounds demonstrated strong inhibitory activity against the EGFR kinase and the tested cancer cells. Notably, compound 4a exhibited considerable inhibitory effects against the EGFR kinase and the EGFR^L858R/T790M mutant NCI-H1975 cancer cells. Compound 4a was found to suppress cell proliferation, colony formation, cell invasion, and migration, while also inducing G0/G1 phase arrest of the cell cycle in NCI-H1975 cells. Compound 4a was docked into the active pocket of the EGFR mutant to ascertain the probable binding conformation. Overall, compound 4a was identified as a promising irreversible EGFR-TKI for the treatment of NSCLC.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143650268","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":"<i>In vitro</i> and <i>in vivo</i> ADME of heterobifunctional degraders: a tailored approach to optimize DMPK properties of PROTACs©.","authors":"Christine Katharina Maurer, Zhizhou Fang, Christina Schindler, Gianna Pohl, Fouzia Machrouhi-Porcher, Marc Lecomte, Carl Petersson, Heide Marika Duevel","doi":"10.1039/d4md00854e","DOIUrl":"10.1039/d4md00854e","url":null,"abstract":"<p><p>Proteolysis-targeting chimeras (PROTACs©) have recently emerged as a promising new drug modality. Residing beyond the rule-of-five space, they pose challenges in terms of physicochemical properties. With this study, we contribute to enhancing the understanding of their early ADME characterization. For permeability assessment, transwell assays such as Caco-2 remain challenging. Although the addition of serum may reduce unspecific binding and improve recovery, the assay was not found predictive for absorption. As a surrogate, we propose to focus optimization on molecular descriptors and support a preferred space for oral PROTACs© with ≤3 H-bond donors (HBDs), molecular weight (MW) ≤950 Da and number of rotatable bonds ≤12. We have developed a predictive score serving as initial guidance for design and prioritization according to this property space. In addition, the reduction of exposed polar surface area, <i>e.g.</i> through shielding of HBDs, is a powerful approach to optimize permeability. Using standard small molecule-based methods for <i>in vitro</i>-<i>in vivo</i> extrapolation (IVIVE) of intrinsic clearance (CL_int) with experimentally determined hepatocyte CL_int and fraction unbound in plasma, and predicted fraction unbound in the incubation (<i>f</i> _u,inc), a systematic under-prediction from mouse hepatocytes was observed for PROTACs©. In line with our observation that the Kilford equation was not suitable for PROTAC© <i>f</i> _u,inc prediction, this bias could be overcome by using experimentally determined <i>f</i> _u,inc. Taken together, this study suggests a tailored <i>in vitro</i> DMPK discovery assay cascade and frontloading <i>in vivo</i> studies. It also underlines the need for inclusion of surrogate permeability descriptors and experimentally determined values for IVIVE of CL_int.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483530","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":"Pyrazolo[3,4-<i>d</i>]pyrimidine-based neplanocin analogues identified as potential <i>de novo</i> pharmacophores for dual-target HBV inhibition.","authors":"Mohan Kasula, Masaaki Toyama, Ramakrishnamraju Samunuri, Ashok Kumar Jha, Mika Okamoto, Masanori Baba, Ashoke Sharon","doi":"10.1039/d4md00932k","DOIUrl":"10.1039/d4md00932k","url":null,"abstract":"<p><p>The discovery of selective and potent inhibitors through <i>de novo</i> pathways is essential to combat drug resistance in chronic hepatitis B (CHB) infections. Recent studies have highlighted that neplanocin A (NepA) derivatives are biologically selective inhibitors of the hepatitis B virus (HBV). In this study, we designed, synthesized, and evaluated various pyrazolo[3,4-<i>d</i>]pyrimidine-based NepA analogues (4a-h) for their anti-HBV activity. Notably, analogue 4g demonstrated significant activity against HBV replication, with EC₅₀ (HBV DNA) = 0.96 μM, CC₅₀ > 100 μM and EC₅₀ (HBsAg) = 0.82 μM, showing selective inhibition of HBsAg secretion. The SAR analysis concluded that replacing the polar 4-NH₂ group with -CH₃ also acted as a weak H-bonding donor, and the presence of 3-iodo was found to be desirable for the activity/toxicity profile. The nucleoside analogues exhibited a distinct mechanism of action compared to existing nucleoside analogues for the selective inhibition of HBsAg secretion. Based on these findings, compound 4g represents a promising lead molecule for the development of new anti-HBV agents with unique mechanisms of action.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483611","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":"Oxazole and isoxazole-containing pharmaceuticals: targets, pharmacological activities, and their SAR studies.","authors":"Shanshan Li, Yiou Mei, Luchen Jiang, Xueyan Yang, Wei Zeng, Yunfei Du","doi":"10.1039/d4md00777h","DOIUrl":"10.1039/d4md00777h","url":null,"abstract":"<p><p>Oxazole, a five-membered aromatic heterocycle featuring a nitrogen and an oxygen atom separated by a carbon atom, and its isomer isoxazole, with directly attached oxygen and nitrogen atoms, have been pivotal in medicinal chemistry. Over the past few decades, the U.S. Food and Drug Administration (FDA) has approved more than 20 drugs containing these nuclei for various clinical conditions, including Tafamidis and Oxaprozin. Due to their unique physicochemical properties, these drugs often exhibit superior pharmacokinetic profiles and pharmacological effects compared to those with similar heterocycles. This review provides a comprehensive overview of all FDA-approved drugs containing oxazole and isoxazole nuclei, focusing on their pharmacological activities and structure-activity relationships.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11848632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503738","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":"Towards more efficient synthetic immunomodulators: biological characterization and mechanism of action of monosaccharide-derived TLR4 agonists.","authors":"Ana Rita Franco, Zaineh Aladailleh, Alessio Romerio, Alice Italia, Federico Lami, Mohammed Monsoor Shaik, Natalia Skupinska, Valentina Artusa, Grisha Pirianov, Francesco Peri","doi":"10.1039/d4md00950a","DOIUrl":"10.1039/d4md00950a","url":null,"abstract":"<p><p>Toll-like receptors (TLRs), including TLR4, play a crucial role in innate immunity activation, and small molecular TLR4 activators (agonists) are in the preclinical and clinical phases of development as vaccine adjuvants or tumor immunotherapeutics. Recently, we generated novel glucosamine-derived compounds, FP molecules, that are active as TLR4 agonists. Despite their chemical structure differing from LPS, some of these compounds, including compound FP18, mimicked the biological activity of LPS and its capacity to activate TLR4 and its downstream pathways. In contrast to FP18, compound FP20 showed immunostimulant activity that was only partially due to TLR4 agonism. This activity was mainly associated with NLRP3 inflammasome activation. We generated a panel of glycosylated FP20 derivatives (glyco-FP20) bearing different monosaccharides linked to C6 of the glucosamine. The biological activity of glyco-FP20 was related to TLR4 activation, as assessed from preliminary experiments in HEK-Blue cells. We presented a comprehensive study of the mechanism of action of glyco-FP20 derivatives and their effect on TLR4 signalling, leading to macrophage M1 polarisation and pyroptosis in THP-1 derived macrophages. Results revealed that, similarly to LPS and differently from FP20, glyco-FP20 derivatives were potent TLR4 agonists inducing TLR4/MyD88 signalling pathways that led to M1 macrophage polarisation, associated with NF-kB activation/translocation and release of a number of proinflammatory mediators in THP-1-derived macrophages. In particular, compound FP20 Rha activated TLR4/TRIF signalling, associated with phosphorylation of STAT1/IRF3, leading to the production of IFN-β in THP-1-derived macrophages. Furthermore, using a specific GSD inhibitor (U73), we demonstrated the ability of FP20 and glyco-FP20 to induce GSD-dependent pyroptosis, which was associated with IL-1β/IL-18 and LDH release in THP-1-derived macrophages. These results show that the optimization of FP20 glycosylation can increase the biological potency of the parent molecule and can be used in preclinical development as vaccine adjuvants or macrophage-based cancer immunotherapy.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143693001","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}