Journal of Enzyme Inhibition and Medicinal Chemistry最新文献_第4页

Fluorinated indeno-quinoxaline bearing thiazole moieties as hypoglycaemic agents targeting α-amylase, and α-glucosidase: synthesis, molecular docking, and ADMET studies. 以α-淀粉酶和α-葡萄糖苷酶为靶标的含噻唑分子的氟化茚喹喔啉类降血糖药：合成、分子对接和 ADMET 研究。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-06-24 DOI: 10.1080/14756366.2024.2367128

Nirvana A Gohar, Eman A Fayed, Yousry A Ammar, Ola A Abu Ali, Ahmed Ragab, Amal M Mahfoz, Moustafa S Abusaif

{"title":"Fluorinated indeno-quinoxaline bearing thiazole moieties as hypoglycaemic agents targeting α-amylase, and α-glucosidase: synthesis, molecular docking, and ADMET studies.","authors":"Nirvana A Gohar, Eman A Fayed, Yousry A Ammar, Ola A Abu Ali, Ahmed Ragab, Amal M Mahfoz, Moustafa S Abusaif","doi":"10.1080/14756366.2024.2367128","DOIUrl":"10.1080/14756366.2024.2367128","url":null,"abstract":"Inhibition of α-glucosidase and α-amylase are key tactics for managing blood glucose levels. Currently, stronger, and more accessible inhibitors are needed to treat diabetes. Indeno[1,2-b] quinoxalines-carrying thiazole hybrids 1-17 were created and described using NMR. All analogues were tested for hypoglycaemic effect against STZ-induced diabetes in mice. Compounds 4, 6, 8, and 16 were the most potent among the synthesised analogues. These hybrids were examined for their effects on plasma insulin, urea, creatinine, GSH, MDA, ALT, AST, and total cholesterol. Moreover, these compounds were tested against α-glucosidase and α-amylase enzymes in vitro. The four hybrids 4, 6, 8, and 16 represented moderate to potent activity with IC50 values 0.982 ± 0.04, to 10.19 ± 0.21 for α-glucosidase inhibition and 17.58 ± 0.74 to 121.6 ± 5.14 μM for α-amylase inhibition when compared to the standard medication acarbose with IC50=0.316 ± 0.02 μM for α-glucosidase inhibition and 31.56 ± 1.33 μM for α-amylase inhibition. Docking studies as well as in silico ADMT were done.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC467095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141446338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

The repertoire of iron superoxide dismutases from Leishmania infantum as targets in the search for therapeutic agents against leishmaniasis. 将婴儿利什曼原虫的铁超氧化物歧化酶作为寻找利什曼病治疗药物的目标。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-07-22 DOI: 10.1080/14756366.2024.2377586

Juan Carlos García-Soriano, Héctor de Lucio, Daniel Elvira-Blázquez, Mercedes Alcón-Calderón, Natalia Sanz Del Olmo, Pedro A Sánchez-Murcia, Paula Ortega, Francisco Javier de la Mata, Antonio Jiménez-Ruiz

{"title":"The repertoire of iron superoxide dismutases from Leishmania infantum as targets in the search for therapeutic agents against leishmaniasis.","authors":"Juan Carlos García-Soriano, Héctor de Lucio, Daniel Elvira-Blázquez, Mercedes Alcón-Calderón, Natalia Sanz Del Olmo, Pedro A Sánchez-Murcia, Paula Ortega, Francisco Javier de la Mata, Antonio Jiménez-Ruiz","doi":"10.1080/14756366.2024.2377586","DOIUrl":"https://doi.org/10.1080/14756366.2024.2377586","url":null,"abstract":"Species of Leishmania and Trypanosoma genera are the causative agents of relevant parasitic diseases. Survival inside their hosts requires the existence of a potent antioxidant enzymatic machinery. Four iron superoxide dismutases have been described in trypanosomatids (FeSODA, FeSODB1, FeSODB2, and FeSODC) that hold a potential as therapeutic targets. Nonetheless, very few studies have been developed that make use of the purified enzymes. Moreover, FeSODC remains uncharacterised in Leishmania. In this work, for the first time, we describe the purification and enzymatic activity of recombinant versions of the four Leishmania FeSOD isoforms and establish an improved strategy for developing inhibitors. We propose a novel parameter [(V*cyt. c - Vcyt. c)/Vcyt. c] which, in contrast to that used in the classical cytochrome c reduction assay, correlates linearly with enzyme concentration. As a proof of concept, we determine the IC50 values of two ruthenium carbosilane metallodendrimers against these isoforms.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141734333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Watermelon: setup and validation of an in silico fragment-based approach. 西瓜：基于片段的硅学方法的设置和验证。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-06-12 DOI: 10.1080/14756366.2024.2356179

Miriana Di Stefano, Salvatore Galati, Lisa Piazza, Francesca Gado, Carlotta Granchi, Marco Macchia, Antonio Giordano, Tiziano Tuccinardi, Giulio Poli

{"title":"Watermelon: setup and validation of an in silico fragment-based approach.","authors":"Miriana Di Stefano, Salvatore Galati, Lisa Piazza, Francesca Gado, Carlotta Granchi, Marco Macchia, Antonio Giordano, Tiziano Tuccinardi, Giulio Poli","doi":"10.1080/14756366.2024.2356179","DOIUrl":"10.1080/14756366.2024.2356179","url":null,"abstract":"We present a new computational approach, named Watermelon, designed for the development of pharmacophore models based on receptor structures. The methodology involves the sampling of potential hotspots for ligand interactions within a protein target's binding site, utilising molecular fragments as probes. By employing docking and molecular dynamics (MD) simulations, the most significant interactions formed by these probes within distinct regions of the binding site are identified. These interactions are subsequently transformed into pharmacophore features that delineates key anchoring sites for potential ligands. The reliability of the approach was experimentally validated using the monoacylglycerol lipase (MAGL) enzyme. The generated pharmacophore model captured features representing ligand-MAGL interactions observed in various X-ray co-crystal structures and was employed to screen a database of commercially available compounds, in combination with consensus docking and MD simulations. The screening successfully identified two new MAGL inhibitors with micromolar potency, thus confirming the reliability of the Watermelon approach.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11232643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Development of certain benzylidene coumarin derivatives as anti-prostate cancer agents targeting EGFR and PI3Kβ kinases. 将某些苯亚甲基香豆素衍生物开发为靶向表皮生长因子受体（EGFR）和 PI3Kβ 激酶的抗前列腺癌药物。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-02-13 DOI: 10.1080/14756366.2024.2311157

Mohamed Elagawany, Lina M A Abdel Ghany, Tarek S Ibrahim, Abdulrhman S Alharbi, Mohamed S Abdel-Aziz, Eman M El-Labbad, Noha Ryad

{"title":"Development of certain benzylidene coumarin derivatives as anti-prostate cancer agents targeting EGFR and PI3Kβ kinases.","authors":"Mohamed Elagawany, Lina M A Abdel Ghany, Tarek S Ibrahim, Abdulrhman S Alharbi, Mohamed S Abdel-Aziz, Eman M El-Labbad, Noha Ryad","doi":"10.1080/14756366.2024.2311157","DOIUrl":"10.1080/14756366.2024.2311157","url":null,"abstract":"Novel coumarin derivatives were synthesised and tested for their cytotoxicity against human cancer cells (PC-3 and MDA-MB-231). Compounds 5, 4b, and 4a possessed potent cytotoxic activity against PC-3 cells with IC50 3.56, 8.99, and 10.22 µM, respectively. Compound 4c displayed cytotoxicity more than erlotinib in the MDA-MB-231 cells with IC50 8.5 µM. Moreover, compound 5 exhibited potent inhibitory activity on EFGR with IC50 0.1812 µM, as well as PI3Kβ inhibitory activity that was twofold higher than LY294002, suggesting that this compound has a dual EGFR and PI3Kβ inhibiting activity. Docking aligns with the in vitro results and sheds light on the molecular mechanisms underlying dual targeting. Furthermore, compound 5 decreased AKT and m-TOR expression in PC-3 cells, showing that it specifically targets these cells via the EGFR/PI3K/Akt/m-TOR signalling pathway. Simultaneously, compound 5 caused cell cycle arrest at S phase and induced activation of both intrinsic and extrinsic apoptotic pathways.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10866054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139722893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Discovery of novel and potent dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment via structure-based pharmacophore modelling, virtual screening, and molecular docking, molecular dynamics simulation studies, and biological evaluation. 通过基于结构的药效学建模、虚拟筛选、分子对接、分子动力学模拟研究和生物学评价，发现治疗结直肠癌的新型强效 AXL/HDAC2 双靶向抑制剂。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2023-12-22 DOI: 10.1080/14756366.2023.2295241

Xiao Qiao, Xiangyu Wu, Shutong Chen, Miao-Miao Niu, Huilian Hua, Yan Zhang

{"title":"Discovery of novel and potent dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment via structure-based pharmacophore modelling, virtual screening, and molecular docking, molecular dynamics simulation studies, and biological evaluation.","authors":"Xiao Qiao, Xiangyu Wu, Shutong Chen, Miao-Miao Niu, Huilian Hua, Yan Zhang","doi":"10.1080/14756366.2023.2295241","DOIUrl":"10.1080/14756366.2023.2295241","url":null,"abstract":"Colorectal cancer (CRC) is one of the most common cancers worldwide. Nowadays, owing to the complex mechanism of tumorigenesis, simultaneous inhibition of multiple targets is an important anticancer strategy. Recent studies have demonstrated receptor tyrosine kinase AXL (AXL) and histone deacetylase 2 (HDAC2) are closely associated with colorectal cancer. Herein, we identified five hit compounds concurrently targeting AXL and HDAC2 using virtual screening. Inhibitory experiments revealed these hit compounds potently inhibited AXL and HDAC2 in the nanomolar range. Among them, Hit-3 showed the strongest inhibitory effects which were better than that of the positive control groups. Additionally, MD assays showed that Hit-3 could bind stably to the AXL and HDAC2 active pockets. Further MTT assays demonstrated that Hit-3 showed potent anti-proliferative activity. Most importantly, Hit-3 exhibited significant in vivo antitumor efficacy in xenograft models. Collectively, this study is the first discovery of dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10763849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138885025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

o-Vanillin binds covalently to MAL/TIRAP Lys-210 but independently inhibits TLR2. o-香兰素与 MAL/TIRAP Lys-210 共价结合，但独立抑制 TLR2。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-02-28 DOI: 10.1080/14756366.2024.2313055

Md Habibur Rahaman, Sara J Thygesen, Michael J Maxwell, Hyoyoung Kim, Prerna Mudai, Jeffrey D Nanson, Xinying Jia, Parimala R Vajjhala, Andrew Hedger, Irina Vetter, Thomas Haselhorst, Avril A B Robertson, Brian Dymock, Thomas Ve, Mehdi Mobli, Katryn J Stacey, Bostjan Kobe

{"title":"o-Vanillin binds covalently to MAL/TIRAP Lys-210 but independently inhibits TLR2.","authors":"Md Habibur Rahaman, Sara J Thygesen, Michael J Maxwell, Hyoyoung Kim, Prerna Mudai, Jeffrey D Nanson, Xinying Jia, Parimala R Vajjhala, Andrew Hedger, Irina Vetter, Thomas Haselhorst, Avril A B Robertson, Brian Dymock, Thomas Ve, Mehdi Mobli, Katryn J Stacey, Bostjan Kobe","doi":"10.1080/14756366.2024.2313055","DOIUrl":"10.1080/14756366.2024.2313055","url":null,"abstract":"Toll-like receptor (TLR) innate immunity signalling protects against pathogens, but excessive or prolonged signalling contributes to a range of inflammatory conditions. Structural information on the TLR cytoplasmic TIR (Toll/interleukin-1 receptor) domains and the downstream adaptor proteins can help us develop inhibitors targeting this pathway. The small molecule o-vanillin has previously been reported as an inhibitor of TLR2 signalling. To study its mechanism of action, we tested its binding to the TIR domain of the TLR adaptor MAL/TIRAP (MALTIR). We show that o-vanillin binds to MALTIR and inhibits its higher-order assembly in vitro. Using NMR approaches, we show that o-vanillin forms a covalent bond with lysine 210 of MAL. We confirm in mouse and human cells that o-vanillin inhibits TLR2 but not TLR4 signalling, independently of MAL, suggesting it may covalently modify TLR2 signalling complexes directly. Reactive aldehyde-containing small molecules such as o-vanillin may target multiple proteins in the cell.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10903754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139990277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Druggable cavities and allosteric modulators of the cell division cycle 7 (CDC7) kinase. 细胞分裂周期 7 (CDC7) 激酶的药腔和异位调节剂。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-01-11 DOI: 10.1080/14756366.2024.2301767

Elisa Rojas-Prats, Loreto Martinez-Gonzalez, Carmen Gil, David Ramírez, Ana Martinez

引用次数: 0

Design, synthesis, and evaluation of novel stilbene derivatives that degrade acidic nucleoplasmic DNA-binding protein 1 (And1) and synergize with PARP1 inhibitor in NSCLC cells. 设计、合成和评估能降解酸性核质 DNA 结合蛋白 1 (And1) 并与 PARP1 抑制剂协同作用于 NSCLC 细胞的新型二苯乙烯衍生物。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-07-29 DOI: 10.1080/14756366.2024.2383886

Leyuan Chen, Zhonghao Ren, Yunze Zhang, Wenbin Hou, Yiliang Li

{"title":"Design, synthesis, and evaluation of novel stilbene derivatives that degrade acidic nucleoplasmic DNA-binding protein 1 (And1) and synergize with PARP1 inhibitor in NSCLC cells.","authors":"Leyuan Chen, Zhonghao Ren, Yunze Zhang, Wenbin Hou, Yiliang Li","doi":"10.1080/14756366.2024.2383886","DOIUrl":"10.1080/14756366.2024.2383886","url":null,"abstract":"Specifically inducing the degradation of acidic nucleoplasmic DNA-binding protein 1 (And1) is a promising antitumor strategy. Our previous study identified Bazedoxifene (BZA) and CH3 as specific And1 degraders and validated their activity in reversing radiotherapy resistance in vitro and in vivo. However, unelucidated structure-activity relationships and moderate activity have limited their application. In this study, 27 novel CH3 derivatives were designed and synthesised based on the cavity topology of the WD40 domain of And1. Among them, A15 with a \"V\" conformation significantly induced And1 degradation in NSCLC cells. In addition, this study demonstrated a potential synthetic lethal effect of And1 degraders and PARP1 inhibitors. 1 µM of Olaparib in combination with 5 µM of A15 significantly inhibited the proliferation of A549 and H460 cells. Overall, these compounds are valuable tools for elucidating And1 biology, and their special spatial conformation make them promising candidates for future optimisation studies.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11288208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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, in vitro and in vivo biological evaluation of pterostilbene derivatives for anti-inflammation therapy. 用于抗炎治疗的紫檀芪衍生物的设计、合成、体外和体内生物学评价。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-02-29 DOI: 10.1080/14756366.2024.2315227

Liuzeng Chen, Ke Wang, Xiaohan Liu, Lifan Wang, Hui Zou, Shuying Hu, Lingling Zhou, Rong Li, Shiying Cao, Banfeng Ruan, Quanren Cui

{"title":"Design, synthesis, in vitro and in vivo biological evaluation of pterostilbene derivatives for anti-inflammation therapy.","authors":"Liuzeng Chen, Ke Wang, Xiaohan Liu, Lifan Wang, Hui Zou, Shuying Hu, Lingling Zhou, Rong Li, Shiying Cao, Banfeng Ruan, Quanren Cui","doi":"10.1080/14756366.2024.2315227","DOIUrl":"10.1080/14756366.2024.2315227","url":null,"abstract":"Pterostilbene (PST) is a naturally derived stilbene compound in grapes, blueberries, and other fruits. It is also a natural dietary compound with a wide range of biological activities such as antioxidant, anti-inflammatory, antitumor, and so on. Structural modifications based on the chemical scaffold of the pterostilbene skeleton are of great importance for drug discovery. In this study, pterostilbene skeletons were used to design novel anti-inflammatory compounds with high activity and low toxicity. A total of 30 new were found and synthesised, and their anti-inflammatory activity and safety were screened. Among them, compound E2 was the most active (against NO: IC50 = 0.7 μM) than celecoxib. Further studies showed that compound E2 exerted anti-inflammatory activity by blocking LPS-induced NF-κB/MAPK signalling pathway activation. In vivo experiments revealed that compound E2 had a good alleviating effect on acute colitis in mice. In conclusion, compound E2 may be a promising anti-inflammatory lead compound.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10906133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139990276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Click estradiol dimers with novel aromatic bridging units: synthesis and anticancer evaluation. 具有新型芳香族桥接单元的点击雌二醇二聚体：合成与抗癌评估。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-06-21 DOI: 10.1080/14756366.2024.2367139

Jiří Řehulka, Michal Jurášek, Pavel Dráber, Aleksandra Ivanová, Soňa Gurská, Kateřina Ječmeňová, Olena Mokshyna, Marián Hajdúch, Pavel Polishchuk, Pavel B Drašar, Petr Džubák

{"title":"Click estradiol dimers with novel aromatic bridging units: synthesis and anticancer evaluation.","authors":"Jiří Řehulka, Michal Jurášek, Pavel Dráber, Aleksandra Ivanová, Soňa Gurská, Kateřina Ječmeňová, Olena Mokshyna, Marián Hajdúch, Pavel Polishchuk, Pavel B Drašar, Petr Džubák","doi":"10.1080/14756366.2024.2367139","DOIUrl":"10.1080/14756366.2024.2367139","url":null,"abstract":"Estradiol dimers (EDs) possess significant anticancer activity by targeting tubulin dynamics. In this study, we synthesised 12 EDs variants via copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction, focusing on structural modifications within the aromatic bridge connecting two estradiol moieties. In vitro testing of these EDs revealed a marked improvement in selectivity towards cancerous cells, particularly for ED1-8. The most active compounds, ED3 (IC50 = 0.38 μM in CCRF-CEM) and ED5 (IC50 = 0.71 μM in CCRF-CEM) demonstrated cytotoxic effects superior to 2-methoxyestradiol (IC50 = 1.61 μM in CCRF-CEM) and exhibited anti-angiogenic properties in an endothelial cell tube-formation model. Cell-based experiments and in vitro assays revealed that EDs interfere with mitotic spindle assembly. Additionally, we proposed an in silico model illustrating the probable binding modes of ED3 and ED5, suggesting that dimers with a simple linker and a single substituent on the aromatic central ring possess enhanced characteristics compared to more complex dimers.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC467089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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