RSC medicinal chemistry最新文献

{"title":"Towards catalytic fluoroquinolones: from metal-catalyzed to metal-free DNA cleavage.","authors":"Moshe N Goldmeier, Alina Khononov, Tomasz Pieńko, Valery Belakhov, Feng-Chun Yen, Limor Baruch, Marcelle Machluf, Timor Baasov","doi":"10.1039/d4md00984c","DOIUrl":"10.1039/d4md00984c","url":null,"abstract":"<p><p>A library of eight new fluoroquinolone-nuclease conjugates containing a guanidinoethyl or aminoethyl auxiliary pendant on the 1,4,7-triazacyclononane (TACN) moiety was designed and synthesized to investigate their potential as catalytic antibiotics. The Cu(ii) complexes of the designer structures showed significant <i>in vitro</i> hydrolytic and oxidative DNA cleavage activity and good antibacterial activity against both Gram-negative and Gram-positive bacteria. The observed activity of all the Cu(ii)-TACN-ciprofloxacin complexes was strongly inhibited in the presence of Cu(ii)-chelating agents, thereby demonstrating \"vulnerability\" under physiological conditions. However, selected TACN-ciprofloxacin conjugates in their metal-free form efficiently cleaved plasmid DNA under physiological conditions. The lead compound 1 showed good DNase activity which was retained in the presence of strong metal chelators and exhibited excellent antibacterial activity against both Gram-negative and Gram-positive bacteria. Density functional theory calculations combined with quantum mechanics/molecular mechanics simulations suggest a general base-general acid mechanism for the hydrolytic DNA cleavage mechanism by compound 1.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754375","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":"Membrane lipid composition directs the cellular selectivity of antimicrobial metallohelices.","authors":"Nicola J Rogers, Miles L Postings, Ann M Dixon, John Moat, Georgia Shreeve, Louise Stuart, Nicholas R Waterfield, Peter Scott","doi":"10.1039/d4md00973h","DOIUrl":"10.1039/d4md00973h","url":null,"abstract":"<p><p>Two enantiomeric pairs of iron(ii) metallohelices, available as water-soluble, stable, and optically pure bimetallic complexes, differ principally in the length of the central hydrophobic region between two cationic domains, and have distinct activity and cell selectivity profiles against Gram-positive and Gram-negative microbes. The effects of dose concentration and temperature on levels of intracellular accumulation in <i>E. coli</i> and <i>S. aureus</i>, studied <i>via</i> isotopic labelling, indicate that the metallohelices enter the microbial cells <i>via</i> passive diffusion, whereupon (as previously determined) they act on intracellular targets. Whilst the metallohelices with the shorter central hydrophobic regions accumulate less readily than those with the longer hydrophobic bridge in both <i>E. coli</i> and <i>S. aureus</i> cells when incubated at the same concentration, an order of magnitude <i>less</i> is actually required per cell to inhibit growth in <i>E. coli</i>, hence they are more active. Furthermore, these more Gram-negative active compounds (with the shorter central hydrophobic region) are less toxic towards human APRE-19 mammalian cells and equine red blood cells. We hypothesise that these cell selectivities originate from the membrane composition. Dynamic light scattering and zeta potential measurements demonstrate that the more lipophilic metallohelices interact more strongly with the membrane-mimetic vesicles, notably in the charge-neutral mammalian model; thus the selectivity is not simply a result of electrostatic effects. For the less lipophilic metallohelices we observe that the binding affinity with the <i>E. coli</i> model vesicles is greater than with <i>S. aureus</i> vesicles, despite the lower negative surface charge, and this corresponds with the cellular accumulation data and the measured MICs. Specifically, the presence of membrane phosphatidylethanolamine (POPE) significantly increases the binding affinity of these metallohelices, and we postulate that a high proportion of such conical, non-lamellar phospholipids is important for metallohelix transport across the membrane. The metallohelices with the shorter hydrophobic bridge studied have a balance of charge and lipophilicity which allows selective cell entry in <i>E. coli</i> over mammalian cells, while the more lipophilic metallohelices are membrane promiscuous and unselective.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11917443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664498","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":"Structural insights, regulation, and recent advances of RAS inhibitors in the MAPK signaling cascade: a medicinal chemistry perspective.","authors":"Vineet Prajapati, Ankit Kumar Singh, Adarsh Kumar, Harshwardhan Singh, Prateek Pathak, Maria Grishina, Vikas Kumar, Habibullah Khalilullah, Amita Verma, Pradeep Kumar","doi":"10.1039/d4md00923a","DOIUrl":"10.1039/d4md00923a","url":null,"abstract":"<p><p>The MAPK pathway has four main components: RAS, RAF, MEK, and ERK. Among these, RAS is the most frequently mutated protein and the leading cause of cancer. The three isoforms of the RAS gene are HRAS, NRAS, and KRAS. The KRAS gene is characterized by two splice variants, K-Ras4A and K-Ras4B. The occurrence of cancer often involves a mutation in both KRAS4A and KRAS4B. In this study, we have elucidated the mechanism of the RAS protein complex and the movement of switches I and II. Only two RAS inhibitors, sotorasib and adagrasib, have been approved by the FDA, and several are in clinical trials. This review comprises recent developments in synthetic RAS inhibitors, their unique properties, their importance in inhibiting RAS mutations, and the current challenges in developing new RAS inhibitors. This review will undoubtedly help researchers design novel RAS inhibitors.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11880839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573939","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":"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":"Synthesis and <i>in vitro</i> antiprotozoal evaluation of novel Knoevenagel hydroxychloroquine derivatives.","authors":"Priscila P Dario, Luis H D Yamashita, Kahlil S Salome, Gabriel L Kosinski, Guilherme A Justen, Daniel da S Rampon, Danielle Lazarin-Bidoia, Celso V Nakamura, Fernanda A Rosa, Marcelo G Montes D'Oca","doi":"10.1039/d4md00884g","DOIUrl":"10.1039/d4md00884g","url":null,"abstract":"<p><p>Leishmaniasis and Chagas diseases affect millions of people, particularly in developing countries, with conventional treatments proving unsatisfactory due to increasing drug resistance and high toxicity. Therefore, there is an urgent need for new drugs to combat neglected tropical diseases (NTDs). In this study, we synthesized 15 new Knoevenagel adducts derived from hydroxychloroquine and evaluated their antiprotozoal activity against <i>Leishmania infantum</i>, <i>L. amazonensis</i>, and <i>Trypanosoma cruzi</i>. The new adducts exhibited low toxicity in epithelial LLC-MK2 cells and J774A.1 macrophages. The Knoevenagel adducts derived from <i>meta</i>- and <i>para</i>-chloro benzaldehyde demonstrated antiprotozoal activity against <i>T. cruzi</i> epimastigotes, though with a lower selective index (SI) compared to the standard drug benznidazole. However, the adducts derived from isovaleraldehyde and <i>ortho</i>-, <i>meta</i>-, and <i>para</i>-chloro benzaldehyde showed SI values ranging from 10.97 to 8.11 against <i>L. amazonensis</i>, similar to amphotericin B (AmpB, SI = 9.37), with no statistically significant difference (<i>p</i> > 0.05). These same compounds inhibited <i>L. infantum</i> promastigotes, but with less activity compared to AmpB. These results suggest that Knoevenagel adducts derived from hydroxychloroquine may serve as selective antileishmanial agents.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754358","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":"Design and synthesis of 2-phenyl-1<i>H</i>-benzo[<i>d</i>]imidazole derivatives as 17β-HSD10 inhibitors for the treatment of Alzheimer's disease.","authors":"Xiaohan Liu, Bin Zhou, Yan Chen, Jinyuan Lin, Chenwen Shao, Liuzeng Chen, Banfeng Ruan, Xingxing Zhang, Yong Qian","doi":"10.1039/d4md00861h","DOIUrl":"10.1039/d4md00861h","url":null,"abstract":"<p><p>It has been reported that 17β-HSD10 plays a key role in Alzheimer's disease. Here, a total of 44 2-phenyl-1<i>H</i>-benzo[<i>d</i>]imidazole derivatives were designed and synthesized as novel 17β-HSD10 inhibitors based on rational design and SAR studies. Among them, compound 33 (<i>N</i>-(4-(1,4,6-trimethyl-1<i>H</i>-benzo[<i>d</i>] imidazol-2-yl)phenyl)cyclohexanecarboxamide) showed high inhibitory efficacy (17β-HSD10 IC₅₀ = 1.65 ± 0.55 μM) and low toxicity (HepaRG IC₅₀ >100 μM). The Morris water maze experiment revealed that compound 33 could alleviate cognitive impairment induced by scopolamine in mice. This study facilitates the further development of more potent 17β-HSD10 inhibitors for the treatment of Alzheimer's disease.</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/PMC11947984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754350","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}