Journal of Enzyme Inhibition and Medicinal Chemistry最新文献_第6页

Synthesis and biological evaluation of ortho-phenyl phenylhydroxamic acids containing phenothiazine with improved selectivity for class IIa histone deacetylases. 对 IIa 类组蛋白去乙酰化酶具有更好选择性的含吩噻嗪的正苯基苯基羟肟酸的合成和生物学评价。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-09-24 DOI: 10.1080/14756366.2024.2406025

Kai-Cheng Hsu, Yun-Yi Huang, Jung-Chun Chu, Yu-Wen Huang, Jing-Lan Hu, Tony Eight Lin, Shih-Chung Yen, Jing-Ru Weng, Wei-Jan Huang

{"title":"Synthesis and biological evaluation of ortho-phenyl phenylhydroxamic acids containing phenothiazine with improved selectivity for class IIa histone deacetylases.","authors":"Kai-Cheng Hsu, Yun-Yi Huang, Jung-Chun Chu, Yu-Wen Huang, Jing-Lan Hu, Tony Eight Lin, Shih-Chung Yen, Jing-Ru Weng, Wei-Jan Huang","doi":"10.1080/14756366.2024.2406025","DOIUrl":"10.1080/14756366.2024.2406025","url":null,"abstract":"Class IIa histone deacetylases (HDACs) have been linked to tumorigenesis in various cancers. Previously, we designed phenylhydroxamic acid LH4f as a potent class IIa HDAC inhibitor. However, it also unselectively inhibited class I and class IIb HDACs. To enhance the compound's selectivity towards class IIa HDACs, the ortho-phenyl group from the selective HDAC7 inhibitor 1 is incorporated into ortho position of the phenylhydroxamic acid in LH4f. Compared to LH4f, most resulting compounds displayed substantially improved selectivity towards the class IIa HDACs. Notably, compound 7 g exhibited the strongest HDAC9 inhibition with an IC50 value of 40 nM. Molecular modelling further identified the key interactions of compound 7 g bound to HDAC9. Compound 7 g significantly inhibited several human cancer cells, induced apoptosis, modulated caspase-related proteins as well as p38, and caused DNA damage. These findings suggest the potential of class IIa HDAC inhibitors as lead compounds for the development of cancer therapeutics.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2406025"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307872","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, and biological evaluation of (thio)urea derivatives as potent Escherichia coli β-glucuronidase inhibitors. 作为强效大肠杆菌β-葡糖醛酸酶抑制剂的（硫代）脲衍生物的设计、合成和生物学评价。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-08-14 DOI: 10.1080/14756366.2024.2387415

Keren Xu, Leyi Ying, Titi Ying, Qihao Wu, Lin Du, Yanlei Yu, Youmin Ying, Bin Wei, Hong Wang, Zhikun Yang

{"title":"Design, synthesis, and biological evaluation of (thio)urea derivatives as potent Escherichia coli β-glucuronidase inhibitors.","authors":"Keren Xu, Leyi Ying, Titi Ying, Qihao Wu, Lin Du, Yanlei Yu, Youmin Ying, Bin Wei, Hong Wang, Zhikun Yang","doi":"10.1080/14756366.2024.2387415","DOIUrl":"10.1080/14756366.2024.2387415","url":null,"abstract":"EcGUS has drawn considerable attention for its role as a target in alleviating serious GIAEs. In this study, a series of 72 (thio)urea derivatives were designed, synthesised, and biologically assayed. The bioassay results revealed that E-9 (IC50 = 2.68 μM) exhibited a promising inhibitory effect on EcGUS, surpassing EcGUS inhibitor D-saccharic acid-1,4-lactone (DSL, IC50 = 45.8 μM). Additionally, the inhibitory kinetic study indicated that E-9 (Ki = 1.64 μM) acted as an uncompetitive inhibitor against EcGUS. The structure-activity relationship revealed that introducing an electron-withdrawing group into the benzene ring at the para-position is beneficial for enhancing inhibitory activity against EcGUS. Furthermore, molecular docking analysis indicated that E-9 has a strong affinity to EcGUS by forming interactions with residues Asp 163, Tyr 472, and Glu 504. Overall, these results suggested that E-9 could be a potent EcGUS inhibitor, providing valuable insights and guidelines for the development of future inhibitors targeting EcGUS.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2387415"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11328603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975775","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

Identification of novel PD-1/PD-L1 small molecule inhibitors: virtual screening, synthesis and in vitro characterisation. 新型 PD-1/PD-L1 小分子抑制剂的鉴定：虚拟筛选、合成和体外表征。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-06-17 DOI: 10.1080/14756366.2024.2353711

Tingting Wu, Hu Cheng, Lijie Sima, Zhongyuan Wang, Weiwei Ouyang, Jianta Wang, Yunlei Hou, Dongsheng Zhao, Weike Liao, Chujiao Hu

{"title":"Identification of novel PD-1/PD-L1 small molecule inhibitors: virtual screening, synthesis and in vitro characterisation.","authors":"Tingting Wu, Hu Cheng, Lijie Sima, Zhongyuan Wang, Weiwei Ouyang, Jianta Wang, Yunlei Hou, Dongsheng Zhao, Weike Liao, Chujiao Hu","doi":"10.1080/14756366.2024.2353711","DOIUrl":"10.1080/14756366.2024.2353711","url":null,"abstract":"The PD-1/PD-L1 pathway is considered as one of the most promising immune checkpoints in tumour immunotherapy. However, researchers are faced with the inherent limitations of antibodies, driving them to pursue PD-L1 small molecule inhibitors. Virtual screening followed by experimental validation is a proven approach to discover active compounds. In this study, we employed multistage virtual screening methods to screen multiple compound databases to predict new PD-1/PD-L1 ligands. 35 compounds were proposed by combined analysis of fitness scores, interaction pattern and MM-GBSA binding affinities. Enzymatic assay confirmed that 10 out of 35 ligands were potential PD-L1 inhibitors, with inhibitory rate higher than 50% at the concentration of 30 µM. Among them, ZDS20 was identified as the most effective inhibitor with low micromolar activity (IC50 = 3.27 μM). Altogether, ZDS20 carrying novel scaffold was identified and could serve as a lead for the development of new classes of PD-L1 inhibitors.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2353711"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11232653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141419415","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

Expanding the antiprotozoal activity and the mechanism of action of n-butyl and iso-butyl ester of quinoxaline-1,4-di-N-oxide derivatives against Giardia lamblia, Trichomonas vaginalis, and Entamoeba histolytica. An in vitro and in silico approach. 拓展喹喔啉-1,4-二-N-氧化物正丁酯和异丁酯衍生物对蓝氏贾第鞭毛虫、阴道毛滴虫和组织溶解恩塔莫阿巴的抗原虫活性和作用机制。体外和硅学方法。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-10-29 DOI: 10.1080/14756366.2024.2413018

Alonzo González-González, Oscar Sánchez-Sánchez, Lilián Yépez-Mulia, Timoteo Delgado-Maldonado, Lenci K Vázquez-Jiménez, Gabriel López-Velázquez, José Ignacio de la Mora-de la Mora, Sebastian Pacheco-Gutierrez, Laura Chino-Ríos, Diego Arias, Adriana Moreno-Rodríguez, Alma Paz-González, Eyra Ortíz-Pérez, Gildardo Rivera

{"title":"Expanding the antiprotozoal activity and the mechanism of action of n-butyl and iso-butyl ester of quinoxaline-1,4-di-N-oxide derivatives against Giardia lamblia, Trichomonas vaginalis, and Entamoeba histolytica. An in vitro and in silico approach.","authors":"Alonzo González-González, Oscar Sánchez-Sánchez, Lilián Yépez-Mulia, Timoteo Delgado-Maldonado, Lenci K Vázquez-Jiménez, Gabriel López-Velázquez, José Ignacio de la Mora-de la Mora, Sebastian Pacheco-Gutierrez, Laura Chino-Ríos, Diego Arias, Adriana Moreno-Rodríguez, Alma Paz-González, Eyra Ortíz-Pérez, Gildardo Rivera","doi":"10.1080/14756366.2024.2413018","DOIUrl":"10.1080/14756366.2024.2413018","url":null,"abstract":"In this study, n-butyl and iso-butyl quinoxaline-7-carboxylate-1,4-di-N-oxide derivatives were evaluated in vitro against Giardia lamblia (G. lamblia), Trichomonas vaginalis (T. vaginalis), and Entamoeba histolytica (E. histolytica). The potential mechanism of action determination was approached by in silico analysis on G. lamblia and T. vaginalis triosephosphate isomerase (GlTIM and TvTIM, respectively), and on E. histolytica thioredoxin reductase (EhTrxR). Enzyme inactivation assays were performed on recombinant GlTIM and EhTrxR. Compound T-167 showed the best giardicidal activity (IC50 = 25.53 nM) and the highest inactivation efficiency against GlTIM without significantly perturbing its human homolog. Compounds T-142 and T-143 showed the best amoebicidal (IC50 = 9.20 nM) and trichomonacidal (IC50 = 45.20 nM) activity, respectively. Additionally, T-143 had a high activity as giardicial (IC50 = 29.13 nM) and amoebicidal (IC50 = 15.14 nM), proposing it as a broad-spectrum antiparasitic agent. Compounds T-145, and T-161 were the best EhTrxR inhibitors with IC50 of 16 µM, and 18 µM, respectively.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2413018"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11523249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521985","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

Anti-cancer activity and cellular uptake of 7,3',4'- and 7,8,4'-trihydroxyisoflavone in HepG2 cells under hypoxic conditions. 缺氧条件下 7,3',4'- 和 7,8,4'- 三羟基异黄酮在 HepG2 细胞中的抗癌活性和细胞吸收。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2023-12-28 DOI: 10.1080/14756366.2023.2288806

Wen-Sheng Tzeng, Wei-Lin Teng, Pao-Hsien Huang, Feng-Lin Yen, Yow-Ling Shiue

{"title":"Anti-cancer activity and cellular uptake of 7,3',4'- and 7,8,4'-trihydroxyisoflavone in HepG2 cells under hypoxic conditions.","authors":"Wen-Sheng Tzeng, Wei-Lin Teng, Pao-Hsien Huang, Feng-Lin Yen, Yow-Ling Shiue","doi":"10.1080/14756366.2023.2288806","DOIUrl":"10.1080/14756366.2023.2288806","url":null,"abstract":"Transarterial chemoembolisation (TACE) is used for unresectable hepatocellular carcinoma (HCC) treatment, but TACE-induced hypoxia leads to poor prognosis. The anti-cancer effects of soybean isoflavones daidzein derivatives 7,3',4'-trihydroxyisoflavone (734THIF) and 7,8,4'-trihydroxyisoflavone (784THIF) were evaluated under hypoxic microenvironments. Molecular docking of these isomers with cyclooxygenase-2 (COX-2) and vascular endothelial growth factor receptor 2 (VEGFR2) was assessed. About 40 μM of 734THIF and 784THIF have the best effect on inhibiting the proliferation of HepG2 cells under hypoxic conditions. At a concentration of 40 μM, 784THIF significantly inhibits COX-2 expression in pre-hypoxia conditions compared to 734THIF, with an inhibition rate of 67.73%. Additionally, 40 μM 784THIF downregulates the expression of hypoxic, inflammatory, and metastatic-related proteins, regulates oxidative stress, and inhibits the expression of anti-apoptotic proteins. The uptake by HepG2 confirmed higher 784THIF level and slower degradation characteristics under post- or pre-hypoxic conditions. In conclusion, our results showed that 784THIF had better anti-cancer effects and cellular uptake than 734THIF.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2288806"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10763887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139048863","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 novel ALOX15 inhibitors combining dual machine learning filtering and fragment substitution optimisation approaches, molecular docking and dynamic simulation methods. 结合双重机器学习过滤和片段置换优化方法、分子对接和动态模拟方法，开发新型 ALOX15 抑制剂。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-01-12 DOI: 10.1080/14756366.2024.2301756

Yinglin Liao, Peng Cao, Lianxiang Luo

引用次数: 0

Effects of thymoquinone and the curcumin analog EF-24 on the activity of the enzyme paraoxonase-1 in human glioblastoma cells U87MG. 胸腺醌和姜黄素类似物 EF-24 对人胶质母细胞瘤细胞 U87MG 中副氧合酶-1 活性的影响。

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: 10.1080/14756366.2024.2339901

Ender Simsek, Asuman Sunguroglu, Ahmet Kilic, Nurbanu Özgültekin, O Ozensoy Guler

引用次数: 0

Cloning, expression, and purification of an α-carbonic anhydrase from Toxoplasma gondii to unveil its kinetic parameters and anion inhibition profile. 从弓形虫中克隆、表达和纯化一种α-碳酸酐酶，以揭示其动力学参数和阴离子抑制曲线。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-06-07 DOI: 10.1080/14756366.2024.2346523

Viviana De Luca, Simone Giovannuzzi, Clemente Capasso, Claudiu T Supuran

{"title":"Cloning, expression, and purification of an α-carbonic anhydrase from Toxoplasma gondii to unveil its kinetic parameters and anion inhibition profile.","authors":"Viviana De Luca, Simone Giovannuzzi, Clemente Capasso, Claudiu T Supuran","doi":"10.1080/14756366.2024.2346523","DOIUrl":"10.1080/14756366.2024.2346523","url":null,"abstract":"Toxoplasmosis, induced by the intracellular parasite Toxoplasma gondii, holds considerable implications for global health. While treatment options primarily focusing on folate pathway enzymes have notable limitations, current research endeavours concentrate on pinpointing specific metabolic pathways vital for parasite survival. Carbonic anhydrases (CAs, EC 4.2.1.1) have emerged as potential drug targets due to their role in fundamental reactions critical for various protozoan metabolic processes. Within T. gondii, the Carbonic Anhydrase-Related Protein (TgCA_RP) plays a pivotal role in rhoptry biogenesis. Notably, α-CA (TcCA) from another protozoan, Trypanosoma cruzi, exhibited considerable susceptibility to classical CA inhibitors (CAIs) such as anions, sulphonamides, thiols, and hydroxamates. Here, the recombinant DNA technology was employed to synthesise and clone the identified gene in the T. gondii genome, which encodes an α-CA protein (Tg_CA), with the purpose of heterologously overexpressing its corresponding protein. Tg_CA kinetic constants were determined, and its inhibition patterns explored with inorganic metal-complexing compounds, which are relevant for rational compound design. The significance of this study lies in the potential development of innovative therapeutic strategies that disrupt the vital metabolic pathways crucial for T. gondii survival and virulence. This research may lead to the development of targeted treatments, offering new approaches to manage toxoplasmosis.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2346523"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11163988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141283871","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

Novel dual-targeting inhibitors of NSD2 and HDAC2 for the treatment of liver cancer: structure-based virtual screening, molecular dynamics simulation, and in vitro and in vivo biological activity evaluations. 新型NSD2和HDAC2双靶向抑制剂治疗肝癌:基于结构的虚拟筛选、分子动力学模拟和体内外生物活性评价

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2023-12-07 DOI: 10.1080/14756366.2023.2289355

Xing Jin, Yuting Wang, Jing Chen, Miaomiao Niu, Yang Yang, Qiaoxuan Zhang, Guangyu Bao

{"title":"Novel dual-targeting inhibitors of NSD2 and HDAC2 for the treatment of liver cancer: structure-based virtual screening, molecular dynamics simulation, and in vitro and in vivo biological activity evaluations.","authors":"Xing Jin, Yuting Wang, Jing Chen, Miaomiao Niu, Yang Yang, Qiaoxuan Zhang, Guangyu Bao","doi":"10.1080/14756366.2023.2289355","DOIUrl":"10.1080/14756366.2023.2289355","url":null,"abstract":"Liver cancer exhibits a high degree of heterogeneity and involves intricate mechanisms. Recent research has revealed the significant role of histone lysine methylation and acetylation in the epigenetic regulation of liver cancer development. In this study, five inhibitors capable of targeting both histone lysine methyltransferase nuclear receptor-binding SET domain 2 (NSD2) and histone deacetylase 2 (HDAC2) were identified using a structure-based virtual screening approach. Notably, DT-NH-1 displayed a potent inhibition of NSD2 (IC50 = 0.08 ± 0.03 μM) and HDAC2 (IC50 = 5.24 ± 0.87 nM). DT-NH-1 also demonstrated a strong anti-proliferative activity against various liver cancer cell lines, particularly HepG2 cells, and exhibited a high level of biological safety. In an experimental xenograft model involving HepG2 cells, DT-NH-1 showed a significant reduction in tumour growth. Consequently, these findings indicate that DT-NH-1 will be a promising lead compound for the treatment of liver cancer with epigenetic dual-target inhibitors.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2289355"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11721945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138498512","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

3-aryl-4-(3,4,5-trimethoxyphenyl)pyridines inhibit tubulin polymerisation and act as anticancer agents. 3-芳基-4-(3,4,5-三甲氧基苯基)吡啶抑制微管蛋白聚合，可作为抗癌剂。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2023-12-11 DOI: 10.1080/14756366.2023.2286939

Chao Wang, Yujing Zhang, Shanbo Yang, Lingyu Shi, Yutao Xiu, Yudong Wu, Hongfei Jiang

引用次数: 0