RSC medicinal chemistry最新文献_第6页

Structural insights into the nirmatrelvir-resistant SARS-CoV-2 Mpro L50F/E166A/L167F triple mutant-inhibitor-complex reveal strategies for next generation coronaviral inhibitor design nmatrelvir耐药SARS-CoV-2 Mpro L50F/E166A/L167F三重突变抑制剂复合物的结构洞察揭示了下一代冠状病毒抑制剂设计策略。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2025-08-15 DOI: 10.1039/D5MD00356C

Conrad Fischer, Jimmy Lu, Marco J. van Belkum, Sydney Demmon, Pu Chen, Chaoxiang Wang, Tayla J. Van Oers, Tess Lamer, M. Joanne Lemieux and John C. Vederas

{"title":"Structural insights into the nirmatrelvir-resistant SARS-CoV-2 Mpro L50F/E166A/L167F triple mutant-inhibitor-complex reveal strategies for next generation coronaviral inhibitor design","authors":"Conrad Fischer, Jimmy Lu, Marco J. van Belkum, Sydney Demmon, Pu Chen, Chaoxiang Wang, Tayla J. Van Oers, Tess Lamer, M. Joanne Lemieux and John C. Vederas","doi":"10.1039/D5MD00356C","DOIUrl":"10.1039/D5MD00356C","url":null,"abstract":"Drug-resistance is an eminent threat in antiviral therapy, and is currently a concern in nirmatrelvir-based therapy of SARS-CoV-2. Nirmatrelvir (antiviral component in Paxlovid) binds covalently to the active site cysteine of the main protease of SARS-CoV-2 (Mpro), thereby blocking enzyme activity and halting viral replication. In vitro passage experiments mimicking a multi-dosage nirmatrelvir treatment regime, identified Mpro variants with mutations in the active site and near the C-terminal dimerization interface with variable levels of nirmatrelvir resistance. One such variant harbors a triple mutation in Mpro, L50F/E166A/L167F, that displays decreased potency for nirmatrelvir (IC50 ∼ 850–1600 nM) and ibuzatrelvir while viral replication remained similar to that of the wildtype (WT) virus. We here confirm a previously developed short peptide aldehyde bisulfite compound 4 as potent inhibitor for SARS-CoV-2 Mpro L50F/E166A/L167F and related variants. A co-crystal structure reveals tight inhibitor binding that is stabilized by a network of hydrogen bonds formed by the mutated residues A166 and F167. This study provides the groundwork for optimized Mpro inhibitors against potential emerging variants of SARS-CoV-2, as well as strategies for broad-spectrum inhibitor design against variants of Mpro.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 10","pages":" 5032-5040"},"PeriodicalIF":3.6,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144875029","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}

引用次数: 0

Benzo-ring modification on Malaria Box hit MMV008138: effects on antimalarial potency and microsomal stability 二苯环修饰对疟盒中MMV008138抗疟效力和微粒体稳定性的影响。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2025-08-15 DOI: 10.1039/D5MD00439J

Maryam Ghavami, Haibo Li, Lixuan Liu, Joshua H. Butler, Sha Ding, Grant J. Butschek, Reagan S. Haney, R. McAlister Council-Troche, R. Justin Grams, Emilio F. Merino, Jennifer M. Davis, Maxim Totrov, Maria B. Cassera and Paul R. Carlier

{"title":"Benzo-ring modification on Malaria Box hit MMV008138: effects on antimalarial potency and microsomal stability","authors":"Maryam Ghavami, Haibo Li, Lixuan Liu, Joshua H. Butler, Sha Ding, Grant J. Butschek, Reagan S. Haney, R. McAlister Council-Troche, R. Justin Grams, Emilio F. Merino, Jennifer M. Davis, Maxim Totrov, Maria B. Cassera and Paul R. Carlier","doi":"10.1039/D5MD00439J","DOIUrl":"10.1039/D5MD00439J","url":null,"abstract":"Tetrahydro-β-carboline 1 (MMV008138) controls growth of asexual blood-stage Plasmodium falciparum by inhibiting IspD, an enzyme in the MEP pathway for synthesis of a critical metabolite, isopentenyl pyrophosphate (IPP). We have previously investigated the structure activity relationship (SAR) of three of its four rings (B, C, and D). In this report we investigate the SAR of the benzo- (i.e. A-ring) of 1, with the goal of increasing its in vitro antimalarial potency and metabolic stability. As in our previous studies of the B- and C-ring substitution, extreme sensitivity to substitution was also seen in the benzo-ring. In total, 19 benzo-ring substitution variants of 1 were prepared. When tested against multidrug-resistant (Dd2 strain) P. falciparum, only three derivatives (20a, c, d) possessed asexual blood stage (ABS) activity with EC50 values within 3-fold of the parent. As hoped, one analog (20c) showed a marked improvement in microsomal stability. However, this improvement unfortunately did not improve plasma exposure relative to 1, and did not lead to oral efficacy in a mouse model of malaria.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 10","pages":" 5052-5058"},"PeriodicalIF":3.6,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12378621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144967082","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}

引用次数: 0

Design, synthesis, and biological evaluation of 5-chlorine-2-amino-pyrimidine derivatives as potent PLK4 inhibitors† 5-氯-2-氨基嘧啶衍生物作为PLK4抑制剂的设计、合成和生物学评价。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2025-08-14 DOI: 10.1039/D5MD00435G

Shuyi Mu, Wenqiang Sun, Zehui Qi, Minghui Tong, Xuan Shi, Han Wang, Nian Liu, Pengkun Sun, Cunzheng Fan, Ningyuan Hu, Yixiang Sun, Haoyu Zhang, Zixuan Gao, Dongmei Zhao and Maosheng Cheng

{"title":"Design, synthesis, and biological evaluation of 5-chlorine-2-amino-pyrimidine derivatives as potent PLK4 inhibitors†","authors":"Shuyi Mu, Wenqiang Sun, Zehui Qi, Minghui Tong, Xuan Shi, Han Wang, Nian Liu, Pengkun Sun, Cunzheng Fan, Ningyuan Hu, Yixiang Sun, Haoyu Zhang, Zixuan Gao, Dongmei Zhao and Maosheng Cheng","doi":"10.1039/D5MD00435G","DOIUrl":"10.1039/D5MD00435G","url":null,"abstract":"Serine/threonine kinase PLK4, a critical regulator of centrosome duplication, is closely associated with tumorigenesis due to its role in centrosome amplification. PLK4 is overexpressed in multiple cancers and has recently emerged as a promising therapeutic target for TRIM37-amplified breast cancer. Developing safe and effective PLK4 inhibitors holds significant therapeutic potential. However, currently reported PLK4 inhibitors face challenges such as limited structural diversity and potential safety concerns. Here, we designed a series of amino-pyrimidine-based PLK4 inhibitors using a structure–activity relationship (SAR)-guided strategy. Half of these compounds exhibited potent PLK4 inhibition (IC50 < 10 nM), with three compounds showed significant anti-proliferative activity against TRIM37-amplified MCF-7 cells (IC50 < 1 μM). Compound 5f demonstrated more exceptional potency (PLK4 IC50 = 0.8 nM; MCF-7 IC50 = 0.48 μM), along with favorable plasma binding and liver microsomal stability. Further evaluation in MCF-7 cells revealed its ability to suppress clonogenic survival, induce mitotic arrest, and trigger apoptosis. These findings highlight 5f as a promising PLK4 inhibitor warranting further investigation.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 10","pages":" 4997-5011"},"PeriodicalIF":3.6,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874975","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}

引用次数: 0

Discovery of an orally bioavailable, CNS active pan-mutant RET kinase heterobifunctional degrader† 发现一种口服生物可利用的、中枢神经系统活性的泛突变RET激酶异双功能降解物。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2025-08-13 DOI: 10.1039/D5MD00337G

Douglas L. Orsi, Kiel E. Lazarski, Reina Improgo, R. V. Agafonov, Jae Young Ahn, Joelle Baddour, Katelyn Cassidy, Prasoon Chaturvedi, Kyle S. Cole, Richard W. Deibler, W. Austin Elam, Mark E. Fitzgerald, Victoria J. Garza, Andrew Good, Christopher H. Hulton, Marta Isasa, Katrina L. Jackson, Ping Li, Yanke Liang, Ryan E. Michael, Morgan Welzel O'Shea, Moses Moustakim, Samantha Perino, Fazlur Rahman, Matthew J. Schnaderbeck, Nicholas P. Stone, Bonnie Tillotson, Gesine K. Veits, Abigail Vogelaar, Jeremy L. Yap, Robert T. Yu, Hongwei Huang and James A. Henderson

{"title":"Discovery of an orally bioavailable, CNS active pan-mutant RET kinase heterobifunctional degrader†","authors":"Douglas L. Orsi, Kiel E. Lazarski, Reina Improgo, R. V. Agafonov, Jae Young Ahn, Joelle Baddour, Katelyn Cassidy, Prasoon Chaturvedi, Kyle S. Cole, Richard W. Deibler, W. Austin Elam, Mark E. Fitzgerald, Victoria J. Garza, Andrew Good, Christopher H. Hulton, Marta Isasa, Katrina L. Jackson, Ping Li, Yanke Liang, Ryan E. Michael, Morgan Welzel O'Shea, Moses Moustakim, Samantha Perino, Fazlur Rahman, Matthew J. Schnaderbeck, Nicholas P. Stone, Bonnie Tillotson, Gesine K. Veits, Abigail Vogelaar, Jeremy L. Yap, Robert T. Yu, Hongwei Huang and James A. Henderson","doi":"10.1039/D5MD00337G","DOIUrl":"10.1039/D5MD00337G","url":null,"abstract":"Point mutations and chromosomal fusions of the Rearranged During Transfection (RET) transmembrane receptor tyrosine kinase cause constitutive substrate-free activation, driving numerous human cancers. RET-selective kinase inhibitors (selpercatinib, pralsetinib) are in current clinical use for RET-driven tumors. However, the emergence of resistance mutations, such as those at the solvent-front G810 residue, results in reduced efficacy. We sought to exploit the event-driven pharmacology of targeted protein degradation to achieve pan-mutant activity against RET-driven cancers with a single selective RET degrader, while utilizing non-phthalimide cereblon (CRBN) ligands to discover orally bioavailable heterobifunctional degraders. Here we describe the medicinal chemistry efforts that led to compound 20, an orally bioavailable, brain-penetrant, pan-mutant and pan-fusion RET heterobifunctional degrader.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 10","pages":" 4781-4795"},"PeriodicalIF":3.6,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874976","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}

引用次数: 0

Bicyclic temporin L peptide inhibitors targeting the SARS-CoV-2 main protease: design, synthesis, in vitro inhibition efficiency and molecular dynamics insights. 针对SARS-CoV-2主要蛋白酶的双环颞叶L肽抑制剂：设计、合成、体外抑制效果及分子动力学观察

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2025-08-12 DOI: 10.1039/d5md00528k

Md Taimuzzaman Sharif, Md Omor Farque, Md Habibur Rahaman, Md Arafat Hossen, Mohammed Akhter Hossain, Mohammad A Halim

{"title":"Bicyclic temporin L peptide inhibitors targeting the SARS-CoV-2 main protease: design, synthesis, in vitro inhibition efficiency and molecular dynamics insights.","authors":"Md Taimuzzaman Sharif, Md Omor Farque, Md Habibur Rahaman, Md Arafat Hossen, Mohammed Akhter Hossain, Mohammad A Halim","doi":"10.1039/d5md00528k","DOIUrl":"10.1039/d5md00528k","url":null,"abstract":"Bicyclic peptides have emerged as promising inhibitors due to their high binding affinity and selectivity for target receptors. While peptide inhibitors are highly target-specific and exhibit strong protein-binding capabilities, their potential is often limited by challenges such as proteolytic instability and flexible secondary structures, which can reduce their efficacy and bioavailability. This study focuses on designing and synthesizing bicyclic peptides and their molecular dynamics insights using scaffolds like 1,3,5-tris(bromomethyl)benzene (TBMB) and 1,3,5-triacryloylhexahydro-1,3,5-triazine (TATA) to enhance their stability and efficacy. The inhibitory activity of these peptides was assessed by targeting the main protease (Mpro), a key enzyme in viral replication of SARS-CoV-2. Mass spectrometry confirmed the purity of these peptides, and their inhibitory activity was evaluated using fluorescence resonance energy transfer (FRET) and selected ion monitoring (SIM)-based LC-MS assays. Computational modeling and molecular dynamics (MD) simulations revealed the structural basis of peptide-Mpro interactions, highlighting improved conformational stability and binding mechanisms. Bicyclic peptides demonstrated superior inhibition compared to linear analogs, with constraints significantly improving peptide stability and binding properties. Our findings highlight the potential of bicyclic peptides as a robust platform for developing next-generation therapeutics with enhanced pharmacokinetic and pharmacodynamic profiles.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12419469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145041401","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}

引用次数: 0

Parallel synthesis of 5'-amino-5'-deoxy-adenosine derivatives for focused chemical space exploration and their application as methyltransferase inhibitors. 平行合成5′-氨基-5′-脱氧腺苷衍生物及其作为甲基转移酶抑制剂的应用

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2025-08-12 DOI: 10.1039/d5md00376h

Sabrina N Hoba, Marvin Schwickert, Luis Kammerer, Mark Sabin, Annabelle C Weldert, Zarina Nidoieva, J Laurenz Meidner, Fabian Barthels, Tanja Schirmeister, Christian Kersten

{"title":"Parallel synthesis of 5'-amino-5'-deoxy-adenosine derivatives for focused chemical space exploration and their application as methyltransferase inhibitors.","authors":"Sabrina N Hoba, Marvin Schwickert, Luis Kammerer, Mark Sabin, Annabelle C Weldert, Zarina Nidoieva, J Laurenz Meidner, Fabian Barthels, Tanja Schirmeister, Christian Kersten","doi":"10.1039/d5md00376h","DOIUrl":"10.1039/d5md00376h","url":null,"abstract":"Parallel syntheses and their throughput capabilities are powerful tools for the rapid generation of molecule libraries, making them highly beneficial for accelerating hit identification in early-stage drug discovery. Utilizing chemical spaces and virtual libraries enhances time and cost efficiency, enabling the faster exploitation of chemically diverse compounds. In this study, a parallel synthesis method for rapidly generating a 5'-amino-5'-deoxy adenosine-based amide and sulfonamide library of 42 compounds is described with high yields and purity, which is economical and ecological due to the reduced requirements for extensive purification. Methyltransferases recently emerged as promising drug targets. The adenosine-derived library was screened using a fluorescence polarization (FP) assay against model enzymes human DNMT2 and METTL3/14, and SARS-CoV-2 nsp14/10, resulting in the identification of three compounds binding with nanomolar affinity to nsp14/10 and three compounds binding METTL3/14 with low micromolar affinity. To demonstrate the accessibility of a broad variety of adenosine derivatives, a focused virtual chemical space of 25 241 5'-amino-5'-deoxy adenosine amides and sulfonamides, which are accessible via the described synthetic procedure, was generated. This chemical space was further investigated for potential biological applications through virtual screening against nsp14/10 which led to the identification of four additional ligands with low micromolar affinities.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12412055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016137","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}

引用次数: 0

Analysis of the structural diversity of heterocycles amongst European medicines agency approved pharmaceuticals (2014–2023) 2014-2023年欧洲药品管理局批准的药品中杂环结构多样性分析。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2025-08-11 DOI: 10.1039/D5MD00403A

Matthew Ward and Niamh M. O'Boyle

{"title":"Analysis of the structural diversity of heterocycles amongst European medicines agency approved pharmaceuticals (2014–2023)","authors":"Matthew Ward and Niamh M. O'Boyle","doi":"10.1039/D5MD00403A","DOIUrl":"10.1039/D5MD00403A","url":null,"abstract":"This review presents a detailed analysis of the heterocycle diversity amongst medicines with new active substances (NAS) approved by the European Medicines Agency (EMA) in the 10 years from 2014–2023. A total of 380 medicines were approved that contain a NAS, of which 160 are small molecule products that contained one or more NAS with a heterocycle (164 NAS in total). Of the 164 heterocycle-containing NAS, 76% contained more than one heterocycle. The majority (59%) of the 164 active substances contained at least one fused heterocycle. The most common bicyclic rings were quinoline, benzimidazole, indole, and pyrrolopyrimidine. Tricyclic and polycyclic fused rings were observed but were rare. There were 28 distinct monocyclic heterocycles, consisting of 3, 4, 5, and 6 membered rings. 5-Membered rings were the most diverse as 15 of the 28 heterocycles are 5-membered rings. 6-Membered rings ranked second with 12 heterocycles. There was one 3-membered ring and one 4-membered ring seen. Nitrogen was by far the most common heteroatom in both monocyclic and fused heterocycles. Oxygen, sulfur and boron appeared in monocyclic heterocycles, whilst oxygen, sulfur and phosphorous were noted in fused heterocycles. The most common monocyclic heterocycles were pyridine, piperidine, pyrrolidine, piperazine, pyrimidine, pyrazole, triazole, imidazole and tetrahydropyran. This analysis provides valuable information on the structural diversity of heterocycles that were present in EMA approved medicines between 2014–2023. It highlights heterocycle occurrences, diversity, substitution patterns, and trends. The information detailed will be of interest to organic chemists, researchers, regulatory agencies, and the pharmaceutical industry as it demonstrates how common heterocycles are seen amongst EMA approved medicines for a wide range of therapeutic areas.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 10","pages":" 4540-4570"},"PeriodicalIF":3.6,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12359206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144967086","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}

引用次数: 0

Electrostatic interactions influence diazabicyclooctane inhibitor potency against OXA-48-like β-lactamases. 静电相互作用影响重氮杂环辛烷抑制剂对抗oxa -48样β-内酰胺酶的效力。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2025-08-08 DOI: 10.1039/d5md00512d

Joseph F Hoff, Kirsty E Goudar, Karina Calvopiña, Michael Beer, Philip Hinchliffe, John M Shaw, Catherine L Tooke, Yuiko Takebayashi, Andrew F Cadzow, Nicholas J Harmer, Adrian J Mulholland, Christopher J Schofield, James Spencer

{"title":"Electrostatic interactions influence diazabicyclooctane inhibitor potency against OXA-48-like β-lactamases.","authors":"Joseph F Hoff, Kirsty E Goudar, Karina Calvopiña, Michael Beer, Philip Hinchliffe, John M Shaw, Catherine L Tooke, Yuiko Takebayashi, Andrew F Cadzow, Nicholas J Harmer, Adrian J Mulholland, Christopher J Schofield, James Spencer","doi":"10.1039/d5md00512d","DOIUrl":"10.1039/d5md00512d","url":null,"abstract":"Carbapenemases, β-lactamases hydrolysing carbapenem antibiotics, challenge the treatment of multi-drug resistant bacteria. The OXA-48 carbapenemase is widely disseminated in Enterobacterales, necessitating new treatments for producer strains. Diazabicyclooctane (DBO) inhibitors, including avibactam and nacubactam, act on a wide range of enzymes to overcome β-lactamase-mediated resistance. Here we describe investigations on how avibactam and nacubactam inhibit OXA-48 and two variants, OXA-163 and OXA-405, with deletions in the β5-β6 loop neighbouring the active site that modify activity towards different β-lactam classes. Nacubactam is ∼80-fold less potent than avibactam towards OXA-48, but this difference reduces in OXA-163 and OXA-405. Crystal structures and molecular dynamics simulations reveal electrostatic repulsion between Arg214 on the OXA-48 β5-β6 active-site loop and nacubactam, but not avibactam; effects absent from simulations of OXA-163 and OXA-405, which lack Arg214. Crystallographic and mass spectrometry data demonstrate that all three enzymes support desulfation of the bound DBOs. The results indicate that interactions with Arg214 affect DBO potency, suggesting that sequence variation in OXA-48-like β-lactamases affects reactivity towards inhibitors as well as β-lactam substrates.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12415477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145030692","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}

引用次数: 0

Naphthalimide–organometallic hybrids as multi-targeted anticancer and luminescent cellular imaging agents 萘酰亚胺-有机金属杂合体作为多靶点抗癌和发光细胞显像剂。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2025-08-08 DOI: 10.1039/D5MD00205B

David C. Magri and Alex D. Johnson

引用次数: 0

Bio-reductive Co(iii)-doxorubicin complex for cancer cell-selective delivery of doxorubicin and potent anticancer activity. 生物还原性Co(iii)-阿霉素复合物用于癌细胞选择性递送阿霉素和有效的抗癌活性。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2025-08-07 DOI: 10.1039/d5md00360a

Sharmila Wahengbam, Himanshi Sharma, Phamdom Romabai Chanu, Neha Masarkar, Sukhes Mukherjee, Manoj B Menon, Chandi Charan Malakar, Mithun Roy

{"title":"Bio-reductive Co(iii)-doxorubicin complex for cancer cell-selective delivery of doxorubicin and potent anticancer activity.","authors":"Sharmila Wahengbam, Himanshi Sharma, Phamdom Romabai Chanu, Neha Masarkar, Sukhes Mukherjee, Manoj B Menon, Chandi Charan Malakar, Mithun Roy","doi":"10.1039/d5md00360a","DOIUrl":"10.1039/d5md00360a","url":null,"abstract":"The utility of bio-reductive prodrugs in cancer research has emerged as an attractive strategy. We synthesized and characterized a couple of cobalt(iii)-Schiff base complexes of general molecular formula Co(L1)(L2) [Co(iii)-dione] and Co(L1)(dox) [Co(iii)-dox], where L1 and L2 are N,N-(ethane-1,2-diyl)bis(1-(pyridine-2-yl)methanimine) and 1-phenyl-1,3-butanedione, and dox = doxorubicin, as bio-reductive prodrugs. UV-vis and fluorescence spectroscopic assays confirmed the reductive release of doxorubicin from the complex [Co(iii)-dox] in a GSH-dependent manner under physiological conditions, showing its potential for in vitro drug release. The rate of doxorubicin release was found to be 8.20 min-1 at pH 5.5 in the presence of 10 mM GSH. The complex [Co(iii)-dox] primarily targets mitochondria and displayed remarkable anticancer effects against A549, hypoxic A549, HT29, and MDA-MB-231 cells with IC50 values in the range of 9.88-17.89 μM (24 h incubation), suggesting its ability to overcome multidrug resistance (MDR) and reduce side effects associated with traditional doxorubicin therapy. The IC50 value determined against HaCaT cells was >30 μM. The colony formation, wound healing, and invasion assays revealed the capacity of the complex [Co(iii)-dox] to inhibit tumor growth, migration, and invasion. Furthermore, RT-PCR analysis showed notable downregulation of key hypoxia-adaptive genes (HIF-1α, VEGF, and GLUT-1), disrupting tumor survival mechanisms. Overall, the complex [Co(iii)-dox] emerged as an excellent bio-reductive prodrug for safer and potent anticancer activity.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016124","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}

引用次数: 0