期刊文献+
共找到150篇文章
< 1 2 8 >
每页显示 20 50 100
High-throughput computational screening and in vitro evaluation identifies 5-(4-oxo-4H-3,1-benzoxazin-2-yl)-2-[3-(4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]-1H-isoindole-1,3(2H)-dione(C3),as a novel EGFR—HER2 dual inhibitor in gastric tumors
1
作者 MESFER AL SHAHRANI REEM GAHTANI +5 位作者 MOHAMMAD ABOHASSAN MOHAMMAD ALSHAHRANI YASSER ALRAEY AYED DERA MOHAMMAD RAJEH ASIRI PRASANNA RAJAGOPALAN 《Oncology Research》 SCIE 2024年第2期251-259,共9页
Gastric cancers are caused primarily due to the activation and amplification of the EGFR or HER2 kinases resulting in cell proliferation,adhesion,angiogenesis,and metastasis.Conventional therapies are ineffective due ... Gastric cancers are caused primarily due to the activation and amplification of the EGFR or HER2 kinases resulting in cell proliferation,adhesion,angiogenesis,and metastasis.Conventional therapies are ineffective due to the intra-tumoral heterogeneity and concomitant genetic mutations.Hence,dual inhibition strategies are recommended to increase potency and reduce cytotoxicity.In this study,we have conducted computational high-throughput screening of the ChemBridge library followed by in vitro assays and identified novel selective inhibitors that have a dual impediment of EGFR/HER2 kinase activities.Diversity-based High-throughput Virtual Screening(D-HTVS)was used to screen the whole ChemBridge small molecular library against EGFR and HER2.The atomistic molecular dynamic simulation was conducted to understand the dynamics and stability of the protein-ligand complexes.EGFR/HER2 kinase enzymes,KATOIII,and Snu-5 cells were used for in vitro validations.The atomistic Molecular Dynamics simulations followed by solvent-based Gibbs binding free energy calculation of top molecules,identified compound C3(5-(4-oxo-4H-3,1-benzoxazin-2-yl)-2-[3-(4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]-1H-isoindole-1,3(2H)-dione)to have a good affinity for both EGFR and HER2.The predicted compound,C3,was promising with better binding energy,good binding pose,and optimum interactions with the EGFR and HER2 residues.C3 inhibited EGFR and HER2 kinases with IC50 values of 37.24 and 45.83 nM,respectively.The GI50 values of C3 to inhibit KATOIII and Snu-5 cells were 84.76 and 48.26 nM,respectively.Based on these findings,we conclude that the identified compound C3 showed a conceivable dual inhibitory activity on EGFR/HER2 kinase,and therefore can be considered as a plausible lead-like molecule for treating gastric cancers with minimal side effects,though testing in higher models with pharmacokinetic approach is required. 展开更多
关键词 dual inhibitor Drug discovery EGFR/HER2 kinase Gastric cancer High-throughput screening
下载PDF
Molecular Modeling of Quinoline-Based Compounds as Potential Dual Inhibitors of Reverse Transcriptase and Integrase of HIV 被引量:1
2
作者 Alberto Cabrera Leonor Huerta Hernández +1 位作者 Daniel Chávez José L. Medina-Franco 《Computational Molecular Bioscience》 2018年第3期122-148,共27页
As follow-up of our past publication?[1], we propose that quinolones (as part of the pyridinone family) are capable to increase the number of interactions with HIV reverse transcriptase (RT) or integrase (IN) by addin... As follow-up of our past publication?[1], we propose that quinolones (as part of the pyridinone family) are capable to increase the number of interactions with HIV reverse transcriptase (RT) or integrase (IN) by adding a halogen in position C-8 of aromatic portion of the quinolones. This addition could help with the activity of dual inhibitors of RT and IN. In this work, we add a chlorine atom with the rationale to identify in the docking simulations a halogen interaction with the oxygen in the near aminoacids in the binding pockets of RT and IN enzymes. Our docking studies started with RT and 320 structures. Later, we took 73 structures with good results in docking with RT. The structures that we choose contain ester or acids groups in C-3 due the structural similarity with groups in charge to interact with the Mg++ ions in Elvitegravir. In conclusion, we obtained 14 structures that could occupy the allosteric pocket of RT and could inhibit the catalytic activity of IN, for this reason could be dual inhibitors. A major perspective of this work is the synthesis and testing of the potential dual inhibitors designed. 展开更多
关键词 REVERSE Transcriptase INTEGRASE QUINOLONE dual inhibitor DOCKING
下载PDF
Anti-esophagus cancer activity and mechanism of DN3,a novel natural diterpenoid derivative,as a dual inhibitor of glycolysis and oxidative phosphorylation
3
作者 Yong-cheng MA Ying-li ZHU +4 位作者 Xia-xia FAN Ao JIA Ya-fei LI Bei-bei SHAO Ai-feng WANG 《中国药理学与毒理学杂志》 CAS CSCD 北大核心 2018年第4期297-297,共1页
OBJECTIVE To probe into the anti-esophagus cancer activity and mechanisms of DN3,a novel natural diterpenoid derivative.METHODS The anti-tumor activity in vitro of DN3 was evaluated by MTT,and by using human esophagea... OBJECTIVE To probe into the anti-esophagus cancer activity and mechanisms of DN3,a novel natural diterpenoid derivative.METHODS The anti-tumor activity in vitro of DN3 was evaluated by MTT,and by using human esophageal carcinoma cells xenografted into athymic mice model in vivo.The specific mechanisms of DN3,as a dual inhibitor of glycolysis and oxidative phos.phorylation(OXPHOS) were explored through cell and molecular biology techniques.For instance,the manner of cancer cell death induced by DN3 was characterized by hoechst33342,FITC-Annexin V/PI staining and flow cytometric analysis,then these changes of glucose consumption,glucose uptake and lactate production in glycolysis,as well as oxygen consumption rate(OCR) and ATP content in OXPHOS caused by DN3 were performed separately through related kits and SeahorseBioscience XF24 Extra.cellular Flux Analyzer.Furthermore,in order to obtain a clear understanding of the inhibition of DN3 to glycolysis and OXPHOS,these regulatory factors were investigated by Western blot,such as PI3K/AKT,c-Myc and p53 of glycolysis,Bax and HK2 of mitochondrial function.RESULTS DN3 inhibited the growth of esophagus cancer cell EC9706,EC109 and EC1 cells in a dose and time dependent manner,but showed no significant effects on human esophageal epithelial cells(HEECs).DN3 caused significant G2/M arrest of esophagus cancer cell lines and induced apoptosis of these cell lines,which indicated DN3 inhibited the growth of esophagus cancer cell through blocking cell cycle and inducing apoptosis in a dose and time-dependent manner.Importantly,8 μM DN3 decreased the extracellular acidification rate(ECAR) by 45% in EC109,which indicated glycolysis was inhibited by DN3.Mean.while,DN3 decreased the oxygen consumption rate(OCR) and the OCR linked to intracellular ATP production in EC109 cells,but that was not obvious in HEECs,so which indicated that DN3 could selec.tively block OXPHOS of cancer cells.In addition,the accumulation of reactive oxygen species(ROS)and the drop of mitochondrial membrane potential(MMP) were also observed in EC109 incubated by DN3,which suggested mitochondrial biological function was disturbed.Furthermore,the expression of PI3K/AKT,c-Myc and HK2 related to glycolysis were down-regulated by DN3,but the p53 and Bax were up-regulated in esophageal carcinoma cells.The changes of these enzymes accounted for the decreased glycolysisand OXPHOS in esophageal carcinoma cells treated by DN3.CONCLUSION The new compound DN3 has a strong anti-esophageal carcinoma activity,and it is tolerable that DN3 is seen as a dual inhibitor of glycolysis and oxidative phosphorylation. 展开更多
关键词 天然二萜衍生物 食管癌 治疗方法 临床分析
下载PDF
Evodiamine-inspired dual inhibitors of histone deacetylase 1(HDAC1) and topoisomerase 2(TOP2) with potent antitumor activity 被引量:5
4
作者 Yahui Huang Shuqiang Chen +2 位作者 Shanchao Wu Guoqiang Dong Chunquan Sheng 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2020年第7期1294-1308,共15页
A great challenge in multi-targetingdrug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations.Inspired by our previous efforts in designing ... A great challenge in multi-targetingdrug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations.Inspired by our previous efforts in designing antitumor evodiamine derivatives,herein selective histone deacetylase 1(HDAC1)and topoisomerase 2(TOP2)dual inhibitors were successfully identified,which showed potent in vitro and in vivo antitumor potency.Particularly,compound 30 a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model(TGI=75.2%,150 mg/kg,p.o.)without significant toxicity,which was more potent than HDAC inhibitor vorinostat,TOP inhibitor evodiamine and their combination.Taken together,this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents. 展开更多
关键词 EVODIAMINE Histone deacetylase TOPOISOMERASE dual inhibitors Antitumor activity
原文传递
Discovery of 4-Thiazol-N-(pyridin-2-yl)pyrimidin-2-amine as Novel Cyclin-dependent Kinases 4 and 6 Dual Inhibitors via 3D-QSAR and Molecular Simulation 被引量:2
5
作者 FU Le ZHAO Li-Nan +6 位作者 GUO Hong-Mei YU Na QUAN Wen-Xuan CHEN Yi SHU Mao WANG Rui LIN Zhi-Hua 《Chinese Journal of Structural Chemistry》 SCIE CAS CSCD 2022年第3期108-124,I0010,共18页
Cyclin D dependent kinases 4/6 regulate the entry of cells into S phase and are effective target for the discovery of anticancer drugs.In this article,3D-QSAR modeling including comparative molecular field analy-sis(C... Cyclin D dependent kinases 4/6 regulate the entry of cells into S phase and are effective target for the discovery of anticancer drugs.In this article,3D-QSAR modeling including comparative molecular field analy-sis(CoMFA)and comparative molecular similarity indices analysis fields(CoMSIA)was implemented on 52 dual CDK4/6 inhibitors.As a result,we obtained a pretty good 3D-QSAR model,which is CoMFACDK4 with q2 to be 0.543 and r^(2) to be 0.967;CoMSIACDK4 with q2 being 0.518 and r^(2) being 0.937;CoMFACDK6 with q2 to be 0.624 and r^(2) to be 0.984;CoMSIACDK6 with q2 being 0.584 and r^(2) being 0.975.Molecular docking confirmed the important residues for interactions.Molecular dynamics simulation further confirmed binding affinity with key residues of protein,such as Lys22,Lys35,Val96 for CDK4 and Lys43,His100,Val101 for CDK6 at the active sites.Then these results offered new directions to explore new inhibitors of CDK4/6.Finally,we designed 10 novel compounds with promising expected activity and ADME/T properties,and provided referable synthetic routes. 展开更多
关键词 cyclin-dependent kinases 4 and 6 dual inhibitors 3D-QSAR drug design molecular simulation
原文传递
Development of peptidomimetic hydroxamates as PfA-M1 and PfA-M17 dual inhibitors: Biological evaluation and structural characterization by cocrystallization
6
作者 Anil Kumar Marapaka Priyanka Sankoju +8 位作者 Guozhen Zhang Yongzheng Ding Chunhua Ma Vijaykumar Pillalamarri Renu Sudhakar Bharati Reddi Puran Singh Sijwali Yingjie Zhang Anthony Addlagatta 《Chinese Chemical Letters》 SCIE CAS CSCD 2022年第5期2550-2554,共5页
Plasmodium parasites causing malaria have developed resistance to most of the antimalarials in use,in-cluding the artemisinin-based combinations,which are the last line of defense against malaria.This ne-cessitates th... Plasmodium parasites causing malaria have developed resistance to most of the antimalarials in use,in-cluding the artemisinin-based combinations,which are the last line of defense against malaria.This ne-cessitates the discovery of new targets and the development of novel antimalarials.Plasmodium falciparum alanyl aminopeptidase(PfA-M1)and leucyl aminopeptidase(PfA-M17)belong to the M1 and M17 family of metalloproteases respectively and play critical roles in the asexual erythrocytic stage of development.These enzymes have been suggested as potential antimalarial drug targets.Herein we describe the devel-opment of peptidomimetic hydroxamates as PfA-M1 and PfA-M17 dual inhibitors.Most of the compounds described in this study display inhibition at sub-micromolar range against the recombinant PfA-M1 and PfA-M17.More importantly,compound 26 not only exhibits potent malarial aminopeptidases inhibitory activities(PfA-M1 K i=0.11±0.0002μmol/L,PfA-M17 K_(i)=0.05±0.005μmol/L),but also possesses remarkable selectivity over the mammalian counterpart(pAPN K_(i)=17.24±0.08μmol/L),which endows 26 with strong inhibition of the malarial parasite growth and negligible cytotoxicity on human cell lines.Crystal structures of PfA-M1 at atomic resolution in complex with four different compounds including compound 26 establish the structural basis for their inhibitory activities.Notably,the terminal ureidoben-zyl group of 26 explores the S2' region where differences between the malarial and mammalian enzymes are apparent,which rationalizes the selectivity of 26.Together,our data provide important insights for the rational and structure-based design of selective and dual inhibitors of malarial aminopeptidases that will likely lead to novel chemotherapeutics for the treatment of malaria. 展开更多
关键词 AMINOPEPTIDASE dual inhibitor ANTIMALARIA PEPTIDOMIMETIC Plasmodium falciparum
原文传递
Novel dual inhibitors against FP-2 and PfDHFR as potential antimalarial agents: Design, synthesis and biological evaluation
7
作者 Wenhua Chen Xue Yao +8 位作者 Zhenghui Huang Fei Mao Longfei Guan Yun Tang Hualiang Jiang Jian Li Jin Huang Lubin Jiang Jin Zhu 《Chinese Chemical Letters》 SCIE CAS CSCD 2019年第1期250-254,共5页
Resistance to malaria parasites has quickly developed to almost all used antimalarial drugs. Cysteine protease falcipain-2(FP-2) and Plasmodium falciparum dihydrofolate reductase(PfDHFR) have crucial roles, which are ... Resistance to malaria parasites has quickly developed to almost all used antimalarial drugs. Cysteine protease falcipain-2(FP-2) and Plasmodium falciparum dihydrofolate reductase(PfDHFR) have crucial roles, which are absolutely necessary, in the parasite life cycle. In this study, based on the uniform pharmacophores of reported PfDHFR inhibitors and the first-generation dual inhibitors against FP-2 and PfDHFR, we identified a novel series of dual inhibitors through fragments assembly. Lead optimization led to the identification of 14, which showed potent inhibition against FP-2 and PfDHFR enzyme(IC_(50)= 6.8 + 1.8 mmol/L and IC_(50)= 8.8 + 0.3 mmol/L) and P. falciparum 3D7 strain(IC50= 2.9mmol/L).Additionally, 14 exhibited more potent inhibition to the proliferation of chloroquine-resistant P.falciparum Dd2 strain(IC_(50)= 1.1 mmol/L) than pyrimethamine(IC_(50)>10 mmol/L), and 14 displayed micromolar inhibitory activities against two clinical isolated strains Fab9(IC_(50)= 2.6 mmol/L) and GB4(IC_(50)= 1.0 mmol/L). Collectively, these data demonstrated that 14 might be a good lead compound for the treatment of malaria. 展开更多
关键词 ANTIMALARIAL DRUG PLASMODIUM FALCIPARUM FP-2 PfDHFR dual inhibitor
原文传递
Evidence for using a dual COX 1/2 and 5-LOX inhibitor in neurodegenerative diseases
8
作者 Natasha Irrera Alessandra Bitto 《Neural Regeneration Research》 SCIE CAS CSCD 2017年第7期1077-1078,共2页
A complex network of factors contributes to neuroinflammation,such as infections,brain injuries and accumulation of toxic metabolites(Gendelman,2002).Eicosanoids and several cytokines are the main mediators of infla... A complex network of factors contributes to neuroinflammation,such as infections,brain injuries and accumulation of toxic metabolites(Gendelman,2002).Eicosanoids and several cytokines are the main mediators of inflammatory process;in fact,when an inflammatory condition persists,it can be responsible for the progression of degenerative diseases, 展开更多
关键词 COX LOX in Evidence for using a dual COX 1/2 and 5-LOX inhibitor in neurodegenerative diseases for
下载PDF
BTK/JAK3双靶点抑制剂的设计合成和生物活性评价
9
作者 岑丽芳 程铭 +5 位作者 任玮杰 叶柳 王禄华 郭维博 张强 徐云根 《中国药科大学学报》 CAS CSCD 北大核心 2024年第1期73-86,共14页
以课题组前期发现的XL-12为先导化合物,通过末端苯环的结构修饰,进一步提高化合物的抗炎活性。设计并合成了12个目标化合物。所有目标化合物的结构经^(1)H NMR、^(13)C NMR和HRMS确证。体外活性测试结果显示大部分化合物对布鲁顿型酪氨... 以课题组前期发现的XL-12为先导化合物,通过末端苯环的结构修饰,进一步提高化合物的抗炎活性。设计并合成了12个目标化合物。所有目标化合物的结构经^(1)H NMR、^(13)C NMR和HRMS确证。体外活性测试结果显示大部分化合物对布鲁顿型酪氨酸激酶(Bruton’s tyrosine,BTK)和Janus激酶3(JAK3)具有较好的酶抑制活性,化合物I-3对Daudi细胞和BaF3-JAK3细胞显示中等的细胞增殖抑制活性。在体外抗炎活性评价中,化合物I-3能有效抑制炎症因子IL-6的产生。此外,在小鼠二甲苯致耳廓肿胀模型中,化合物I-3显示出优于阳性药依鲁替尼(ibrutinib)的抗炎活性。 展开更多
关键词 类风湿性关节炎 BTK抑制剂 JAK3抑制剂 双靶点抑制剂 抗炎
下载PDF
含吡唑酮基团的喹唑啉衍生物的合成及其作为EGFR/VEGFR-2双靶标酪氨酸激酶抑制剂
10
作者 许佳敏 魏洪磊 +3 位作者 李亚鑫 杨磊夫 莫善雁 胡利明 《合成化学》 CAS 2024年第3期250-260,281,共12页
双靶标酪氨酸激酶抑制剂在克服药物抗性和减少药物毒副作用方面具有重要作用,本文设计并合成了含有吡唑酮基团的喹唑啉衍生物作为EGFR/VEGFR-2双靶标酪氨酸激酶抑制剂。目标化合物由喹唑啉中间体和吡唑酮中间体通过亲核取代反应合成。... 双靶标酪氨酸激酶抑制剂在克服药物抗性和减少药物毒副作用方面具有重要作用,本文设计并合成了含有吡唑酮基团的喹唑啉衍生物作为EGFR/VEGFR-2双靶标酪氨酸激酶抑制剂。目标化合物由喹唑啉中间体和吡唑酮中间体通过亲核取代反应合成。喹唑啉中间体以2,3,4-三羟基苯甲酸为原料,通过酯化、硝化、还原、氯化和环化等反应合成;吡唑酮中间体以4-取代苯基肼盐酸盐为原料,通过甲基化和氧化等反应合成。目标化合物通过^(1)H NMR、^(13)C NMR和HR-MS进行结构鉴定。分别采用ADP-Glo激酶活性检测方法和CCK-8法测定了目标化合物对EGFR和VEGFR-2的抑制活性以及对Hela细胞、A549细胞、HUVEC细胞的抗增殖活性,其对EGFR和VEGFR-2抑制活性IC_(50)值为10~899 nM,15~712 nM;对部分在分子水平测定表现出较高活性的化合物进行了抗增殖活性测定,所选定的化合物对人肺癌A549细胞的半抑制浓度IC_(50)值为10~267 nM,对人脐静脉内皮细胞HUVEC的半抑制浓度IC_(50)值为11~433 nM,对人宫颈癌细胞Hela细胞几乎没有表现出抑制活性。对在细胞和分子水平测试均表现出良好活性的化合物5l通过分子对接研究发现其能够很好地结合在EGFR激酶和VEGFR-2激酶的活性口袋中。本研究为发现EGFR和VEGFR-2双靶标小分子酪氨酸激酶抑制剂奠定了良好的基础。 展开更多
关键词 二噁烷并喹唑啉 吡唑酮 双靶标抑制剂 酪氨酸激酶 抗肿瘤活性
下载PDF
白藜芦醇衍生物作为新型LSD1/HDAC双靶点抑制剂的计算模拟研究
11
作者 鲁文凤 路嘉瑞 +2 位作者 韩迪 高云龙 徐永涛 《化学研究与应用》 CAS 北大核心 2024年第3期572-580,共9页
本研究选择前期设计出来的6个白藜芦醇衍生物LSD1抑制剂R1~R6,通过分子对接、分子动力学模拟、分子力学/广义玻恩表面积(MM/GBSA)等计算模拟方法探索了这些衍生物与HDAC8的相互作用模式以及结合自由能。以HDAC8的共晶配体CRA-A作为参考... 本研究选择前期设计出来的6个白藜芦醇衍生物LSD1抑制剂R1~R6,通过分子对接、分子动力学模拟、分子力学/广义玻恩表面积(MM/GBSA)等计算模拟方法探索了这些衍生物与HDAC8的相互作用模式以及结合自由能。以HDAC8的共晶配体CRA-A作为参考,结果显示,白藜芦醇衍生物R1~R6均能以双齿配位的形式与Zn^(2+)结合,与HDAC8有效结合。在分子动力学模拟的过程中,小分子的羟肟酸基团的两个氧原子始终与Zn^(2+)双齿配位,且6个白藜芦醇衍生物始终在HDAC8的疏水腔内。R1~R6与HDAC8的结合自由能计算结果表明,R1和R3与HDAC8的结合能力最强(分别为-200.00 kcal·mol^(-1)和-202.62 kcal·mol^(-1)),和其与LSD1的结合能力一致。其中,静电相互作用是主要的稳定因素。能量分解结果揭示ASP164、ASP253和HIS166是小分子与HDAC8结合过程中的关键氨基酸。 展开更多
关键词 组蛋白去乙酰化酶 白藜芦醇衍生物 分子对接 分子动力学模拟 双靶点抑制剂
下载PDF
点击化学制备AChE/MAO-B双抑制剂及活性评价
12
作者 贾朝 梁旭华 +2 位作者 周伟 潘婷婷 李世玺 《化学试剂》 CAS 2024年第5期112-120,共9页
通过点击化学(Click)设计、合成了22个香豆素衍生物。多数化合物在微摩尔范围内表现出良好的AChE和MAO-B双抑制活性,具有良好的生物相容性。尤其是一种名为A2B5的化合物,对AChE和MAO-B的IC_(50)分别为(0.23±0.02)、(0.31±0.03... 通过点击化学(Click)设计、合成了22个香豆素衍生物。多数化合物在微摩尔范围内表现出良好的AChE和MAO-B双抑制活性,具有良好的生物相容性。尤其是一种名为A2B5的化合物,对AChE和MAO-B的IC_(50)分别为(0.23±0.02)、(0.31±0.03)μmol/L,是最佳的AChE/MAO-B双抑制剂。实验结果表明香豆素基团是一类有效的AChE和MAO-B双抑制活性基团,羟基取代苯环的存在能够增强抑制活性。分子对接研究发现A2B5是双位点抑制剂,苯基部分结合到AChE的CAS位点,香豆素结合到PAS位点,三氮唑环占据两个活性位点的中间峡谷。A2B5的香豆素部分结合到MAO-B的入口空腔,苯基部分结合到底物空腔,并嵌入到Tyr435、Tyr398和FAD形成的“芳香笼”。总之,香豆素C7位置取代衍生物可以被开发为AChE/MAO-B双抑制剂,为进一步开发抗阿尔茨海默病的双靶点药物提供一个新的起点。 展开更多
关键词 阿尔茨海默病(AD) 点击化学 香豆素 AChE/MAO-B双抑制剂 分子对接 生物相容性
下载PDF
抗痛风双靶标抑制剂研究进展
13
作者 黄冬倩 郑明 +2 位作者 束福 李诗健 刘根炎 《化学与生物工程》 CAS 北大核心 2024年第6期7-12,共6页
痛风是由尿酸单钠晶体沉积在关节和非关节结构处引起的常见代谢类疾病。治疗痛风的单靶标药物通常伴有严重不良反应,而双靶标药物具有更好的疗效和更低的毒性,因此开发能够降低体内血清尿酸水平的双靶标抑制剂是近年来抗痛风药物的研究... 痛风是由尿酸单钠晶体沉积在关节和非关节结构处引起的常见代谢类疾病。治疗痛风的单靶标药物通常伴有严重不良反应,而双靶标药物具有更好的疗效和更低的毒性,因此开发能够降低体内血清尿酸水平的双靶标抑制剂是近年来抗痛风药物的研究热点。系统综述了具有降尿酸作用双靶标抑制剂及其衍生物的研究进展,为新型抗痛风双靶标药物的研发提供了参考。 展开更多
关键词 尿酸 痛风 双靶标抑制剂
下载PDF
LSD1、HDAC及其双靶点抑制剂在抗肿瘤应用中的研究进展
14
作者 延秋铭 叶理 +1 位作者 陈念 查晓明 《山东化工》 CAS 2024年第15期146-149,152,共5页
表观遗传学调控因其可逆性及在疾病进程中的关键作用,已成为肿瘤治疗的重要靶点。组蛋白赖氨酸特异性去甲基化酶(LSD1)与组蛋白去乙酰化酶(HDAC)是调控癌细胞基因表达的重要靶点,抑制这两种蛋白可以显示出显著的肿瘤治疗效果。本综述聚... 表观遗传学调控因其可逆性及在疾病进程中的关键作用,已成为肿瘤治疗的重要靶点。组蛋白赖氨酸特异性去甲基化酶(LSD1)与组蛋白去乙酰化酶(HDAC)是调控癌细胞基因表达的重要靶点,抑制这两种蛋白可以显示出显著的肿瘤治疗效果。本综述聚焦于LSD1和HDAC的单靶点及双靶点抑制剂的研究进展,探讨了这些抑制剂在抗肿瘤治疗中的应用。双靶点抑制剂通过同时抑制LSD1和HDAC活性,提供了超越单一抑制剂的抗癌效果,展示了改善治疗效果的潜力。文章细致回顾了这些抑制剂在临床前研究和临床试验中的表现,指出其优势与挑战,并对未来研究方向进行了展望。 展开更多
关键词 LSD1 HDAC 双靶点 抑制剂
下载PDF
Reviews of gas hydrate inhibitors in gas-dominant pipelines and application of kinetic hydrate inhibitors in China 被引量:15
15
作者 Yanhong Wang Shuanshi Fan Xuemei Lang 《Chinese Journal of Chemical Engineering》 SCIE EI CAS CSCD 2019年第9期2118-2132,共15页
During the development and application of natural gas,hydrate plugging the pipelines is a very important issue to solve.Currently,adding thermodynamic hydrate inhibitors(THIs)and kinetic hydrate inhibitors(KHIs)in gas... During the development and application of natural gas,hydrate plugging the pipelines is a very important issue to solve.Currently,adding thermodynamic hydrate inhibitors(THIs)and kinetic hydrate inhibitors(KHIs)in gas-dominated pipelines is a main way to prevent hydrate plugging of flow lines.This paper mainly reviews the efforts to develop THIs and KHIs in the past 20 years,compare the role of various THIs,such as methanol,ethylene glycol and electrolyte,and give the tips in using.The direction of KHIs is toward high efficiency,low toxicity,low pollution and low cost.More than a hundred inhibitors,including polymers,natural products and ionic liquids,have been synthesized in the past decade.Some of them have better performance than the current commercial KHIs.However,there are still few problems,such as the complex synthesis process,high cost and low solubility,impeding the commercialization of these inhibitors.The review also summarized some application of KHIs in China.Research of KHIs in China began late.There are no KHIs used in gas pipelines.Only a few field tests have been carried out.In the end of this paper,the field test of self-developed KHIs by China is summarized,and the guidance is given according to the application results. 展开更多
关键词 Gas HYDRATE Thermal HYDRATE inhibitor KINETIC HYDRATE inhibitor dual-effect inhibitor Field testing
下载PDF
COX-2/sEH双抑制剂PTUPB抑制肝星型细胞活化减轻小鼠肝纤维化
16
作者 马玲 洪洁茹 +4 位作者 金玲 刘昱镳 杨金桐 周勇 张晨宇 《中国临床解剖学杂志》 CSCD 北大核心 2023年第1期58-63,71,共7页
目的探讨花生四烯酸(ARA)经细胞色素P450(CYPs)及环氧合酶2(COX-2)代谢途径在非酒精性脂肪肝(NAFLD)相关肝纤维化中的作用,并从肝星形细胞(HSC)活化的角度探讨其机制。方法采用雄性C57BL/6J小鼠为研究对象,高糖高脂饲养(HFD)诱导小鼠NA... 目的探讨花生四烯酸(ARA)经细胞色素P450(CYPs)及环氧合酶2(COX-2)代谢途径在非酒精性脂肪肝(NAFLD)相关肝纤维化中的作用,并从肝星形细胞(HSC)活化的角度探讨其机制。方法采用雄性C57BL/6J小鼠为研究对象,高糖高脂饲养(HFD)诱导小鼠NAFLD相关肝纤维化模型。给予小鼠每天皮下注射COX-2/可溶性环氧化物水解酶(sEH)双抑制剂PTUPB(5 mg/kg)。12周后观察COX-2/sEH双抑制对小鼠NAFLD相关肝纤维化的影响。记录小鼠体重变化;检测小鼠葡萄糖耐受性;HE染色观察小鼠肝组织病理损伤;油红O染色观察小鼠肝组织脂质堆积;Masson染色及Western blot法检测肝组织胶原含量;Real-time PCR法检测小鼠肝组织基质金属蛋白酶抑制因子相关基因表达;Western blot法检测PTUPB对棕榈酸(PA)诱导的肝星形细胞JS1活化的影响。结果PTUPB可显著降低HFD小鼠的体重,提高小鼠葡萄糖耐受性,减轻肝组织病理损伤、脂质堆积和胶原沉积;PTUPB亦可降低HFD小鼠肝组织基质金属蛋白酶抑制因子Timp1及Timp2的基因表达;在细胞水平观察到PTUPB可降低PA诱导的JS1细胞的活化。结论抑制ARA的COX-2/sEH代谢可减轻HFD诱导的小鼠NAFLD相关肝纤维化,其机制与抑制HSC的活化有关。 展开更多
关键词 NAFLD 肝纤维化 COX-2/sEH双抑制剂 肝星形细胞
下载PDF
Treatment with clopidogrel and proton pump inhibitors in combination: a review of emerging evidence
17
作者 David A. Johnson Danial E. Baker 《Open Journal of Internal Medicine》 2011年第3期45-55,共11页
Proton pump inhibitors often are prescribed in combination with clopidogrel to decrease risk of gastrointestinal bleeding after acute coronary syndrome. Clopidogrel is a prodrug that has to be metabolized in the liver... Proton pump inhibitors often are prescribed in combination with clopidogrel to decrease risk of gastrointestinal bleeding after acute coronary syndrome. Clopidogrel is a prodrug that has to be metabolized in the liver to generate the active metabolite. Both medications are metabolized largely by the CYP2C19 enzyme;therefore, concerns exist that a drug-drug interaction during concomitant treatment with clopidogrel and a proton pump inhibitor may result in reduction of platelet inhibition. We have reviewed observational and randomized control studies that have evaluated the potential influence of proton pump inhibitors on the platelet inhibitory effect of clopidogrel, along with cardiovascular outcomes. We also have summarized regulatory and academic guidelines for treatment of patients in which concomitant therapy with clopidogrel and proton pump inhibitors may be indicated. Confounding issues, including differential effects of individual proton pump inhibitors on the pharmacodynamics of clopidogrel and variation in clopidogrel metabolism mediated by CYP2C19 gene polymorphisms, also are discussed. 展开更多
关键词 Proton Pump inhibitors CLOPIDOGREL dual ANTIPLATELET Therapy Drug-Drug Interaction Gastrointestinal BLEEDING Myocardial INFARCTION PERCUTANEOUS Coronary Intervention
下载PDF
PARP-1/PI3K双靶点抑制剂的设计、合成与生物活性
18
作者 黄至诚 叶柳 +4 位作者 杜宇 古宏峰 高凡云 朱启华 徐云根 《中国药科大学学报》 CAS CSCD 北大核心 2023年第4期450-460,共11页
磷脂酰肌醇3-激酶(phosphatidylinositol-3-kinase,PI3K)抑制剂可以增加肿瘤细胞对聚腺苷酸二磷酸核糖聚合酶-1(poly ADP-ribose polymerase-1,PARP-1)抑制剂的敏感性,因此,同时抑制PARP-1和PI3K活性有望克服PARP-1抑制剂的耐药性。本... 磷脂酰肌醇3-激酶(phosphatidylinositol-3-kinase,PI3K)抑制剂可以增加肿瘤细胞对聚腺苷酸二磷酸核糖聚合酶-1(poly ADP-ribose polymerase-1,PARP-1)抑制剂的敏感性,因此,同时抑制PARP-1和PI3K活性有望克服PARP-1抑制剂的耐药性。本课题组前期获得了两个对PARP-1和PI3K均具有优良抑制活性的化合物XW-1和WZ-1,但是由于水溶性差限制其进一步研究。本研究以XW-1和WZ-1为先导化合物,通过连接脲基团引入成盐位点以提高化合物的水溶性,设计合成了11个目标化合物。所有目标化合物的结构经1 H NMR、13C NMR和HRMS确认。测定了化合物对PARP-1和PI3K的酶抑制活性,结果显示,大部分化合物对PARP-1和PI3K的抑制活性均较好。在此基础上,采用MTT法测定了化合物8b、8e和8f对MDA-MB231、MDA-MB-468、HCC1937、HCT116以及对奥拉帕尼耐药的HCT116R等5种肿瘤细胞的增殖抑制活性,并进行了构效关系讨论。结果显示,3个化合物都具有优异的抗肿瘤细胞增殖活性。其中,化合物8f对5种肿瘤细胞的抗增殖活性都显著强于阳性药奥拉帕尼,并与BKM120相当。选择化合物8b和8f制成相应的盐酸盐,并测定其水溶性,结果显示两个化合物的水溶性都得到了显著性提升。本研究为进一步研发成药性好且抑制活性强的PARP-1/PI3K双靶点抑制剂提供了实验依据。 展开更多
关键词 PARP-1抑制剂 PI3K抑制剂 双靶点 抗肿瘤 成药性优化
下载PDF
基于计算机辅助药物设计的VEGFR2和PD-L1双靶点抑制剂的筛选
19
作者 郑伟 童荣生 +1 位作者 何俊 师健友 《合成化学》 CAS 2023年第5期321-328,共8页
肝细胞癌(HCC)是世界上最具侵袭性的实体恶性肿瘤之一,尽管近几十年来在肝切除术、射频消融和肝移植等方面取得了显著进展,但HCC患者的愈后仍不乐观,主要原因是HCC的高复发率和转移率以及该疾病对化疗和靶向治疗的耐受性。VEGFR2和PD-L... 肝细胞癌(HCC)是世界上最具侵袭性的实体恶性肿瘤之一,尽管近几十年来在肝切除术、射频消融和肝移植等方面取得了显著进展,但HCC患者的愈后仍不乐观,主要原因是HCC的高复发率和转移率以及该疾病对化疗和靶向治疗的耐受性。VEGFR2和PD-L1抑制剂联合应用能对小鼠体内的HCC肿瘤进行显著抑制并延长其寿命,因此开发VEGFR2与PD-L1双靶点抑制剂对HCC的治疗具有十分重要的意义。本文基于计算机辅助药物设计(CADD),经过以分子对接为基础的虚拟筛选、MM-GBSA和ADMET评价以及QSAR模型预测,得到了一系列VEGFR2和PD-L1的双靶点活性化合物,有望为后续抑制剂的开发提供思路和方向。 展开更多
关键词 VEGFR2 PD-L1 双靶点 计算机辅助药物设计 虚拟筛选 MM-GBSA QSAR
下载PDF
粮饲兼用大豆新品种东农饲豆1的培育及栽培技术
20
作者 刘欢 蒙何 +4 位作者 王绍东 王遂 佟晓红 李远明 姜妍 《大豆科技》 2023年第5期49-54,共6页
为适应畜牧企业需求,提高牛奶蛋白质含量,亟需选育饲用型或粮饲兼用型大豆新品种。东农饲豆1是东北农业大学2013年以黑龙江省主栽高产优质大豆品种合丰50为母本,以胰蛋白酶抑制剂缺失高世代品系HZ6009为父本进行有性杂交,经系谱法及胰... 为适应畜牧企业需求,提高牛奶蛋白质含量,亟需选育饲用型或粮饲兼用型大豆新品种。东农饲豆1是东北农业大学2013年以黑龙江省主栽高产优质大豆品种合丰50为母本,以胰蛋白酶抑制剂缺失高世代品系HZ6009为父本进行有性杂交,经系谱法及胰蛋白酶抑制剂缺失检测分子辅助方法选育而成的产量及品质性状优异且Kunitz型胰蛋白酶抑制剂缺失的大豆新品种。该品种高油、高产,中抗灰斑病,适宜黑龙江省第二积温带≥10℃活动积温2400℃以上区域种植。该品种的育成满足了粮油、青贮、优质饲料等多种用途,应用前景广阔。2023年通过黑龙江省品种审定委员会审定,审编号为黑审豆2023Z0006。 展开更多
关键词 胰蛋白酶抑制剂缺失 粮饲兼用 大豆 东农饲豆1
下载PDF
上一页 1 2 8 下一页 到第
使用帮助 返回顶部