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
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
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
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
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
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
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
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
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
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
文摘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.
文摘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.
基金supported by National Natural Science Foundation of China(81502952)
文摘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.
基金supported by National Natural Science Foundation of China(grants 81872742 to Guoqiang Dong and 81725020 to Chunquan Sheng)the National Key R&D Program of China(grant 2017YFA0506000 to Chunquan Sheng)the Innovation Program of Shanghai Municipal Education Commission(Grant 2019-01-07-00-07-E00073 to Chunquan Sheng,China)
文摘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.
基金supported by the key project of Chongqing Natural Science Foundation (cstc2015jcyj BX0080)
文摘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.
基金supported by University Grants Commission (UGC), New Delhi, India and Bharati Reddi by Department of Science and Technology, New Delhi, India for their research fellowshipsCSIR-IICT manuscript number is IICT/Pubs./2018/299+6 种基金Anthony Addlagatta thanks Science and Engineering Research Board (SERB), New Delhi, India for research grants (Nos. EMR/2015/000461 and CRG/2019/006013)Natural Science Foundation of Shandong Province (No. ZR2018QH007, China)Key Research and Development Program of Shandong Province (No. 2017CXGC1401, China)Young Scholars Program of Shandong University (No. YSPSDU, 2016WLJH33, China) for research fellowshipsRenu Sudhakar is the recipient of the fellowship from the Department of Biotechnology (India)Puran Singh Sijwali lab is supported with funds from the Department of Biotechnology, India (Nos. SR/SO/BB/-0124/2012 and BT/COE/34/SP15138/2015)the Council of Scientific & Industrial Research, India
文摘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.
基金Financial support for this research provided by the National Natural Science Foundation of China (Nos. 21372001 and 21672064)the "Shu Guang" Project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (No. 14SG28)
文摘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.
文摘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,
基金Supported by the National Key R&D Program of China(2016YFC0304006 and 2017YFC0307302/03)National Natural Science Foundation of China(51576069,51876069)+1 种基金the Natural Science Foundation of Guangdong Province(2016A030313488)Fundamental Research Funds for the Central Universities
文摘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.
文摘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.
