Considering the undesirable metabolic stability of our recently identified NNRTI 5(t1/2=96 min)in human liver microsomes,we directed our efforts to improve its metabolic stability by introducing a new favorable hydrox...Considering the undesirable metabolic stability of our recently identified NNRTI 5(t1/2=96 min)in human liver microsomes,we directed our efforts to improve its metabolic stability by introducing a new favorable hydroxymethyl side chain to the C-5 position of pyrimidine.This strategy provided a series of novel methylol-biphenyl-diarylpyrimidines with excellent anti-HIV-1 activity.The best compound 9g was endowed with remarkably improved metabolic stability in human liver microsomes(t1/2=2754 min),which was about 29-fold longer than that of 5(t1/2=96 min).This compound conferred picomolar inhibition of WT HIV-1(EC50=0.9 nmol/L)and low nanomolar activity against five clinically drug-resistant mutant strains.It maintained particularly low cytotoxicity(CC50=264μmol/L)and good selectivity(SI=256,438).Molecular docking studies revealed that compound 9g exhibited a more stable conformation than 5 due to the newly constructed hydrogen bond of the hydroxymethyl group with E138.Also,compound 9g was characterized by good safety profiles.It displayed no apparent inhibition of CYP enzymes and h ERG.The acute toxicity assay did not cause death and pathological damage in mice at a single dose of 2 g/kg.These findings paved the way for the discovery and development of new-generation anti-HIV-1 drugs.展开更多
In this paper,dual-stabilizer-capped CdTe quantum dots were used as modulated photoluminescence(PL)sensors for the subpicomolar level detection of copper(II)(Cu^(2+))and mercury(II)(Hg^(2+))ions in aqueous solution fo...In this paper,dual-stabilizer-capped CdTe quantum dots were used as modulated photoluminescence(PL)sensors for the subpicomolar level detection of copper(II)(Cu^(2+))and mercury(II)(Hg^(2+))ions in aqueous solution for the first time.The dual-stabilizer-capped CdTe quantum dots were synthesized using mercaptopropionic acid(MPA)and sodium hexametaphosphate(SHMP)as surface-modified ligands via a convenient hydrothermal process.The researches showed a low interference response of the MPASHMP-capped CdTe quantum dots towards other metal ions.The highly efficient PL quenching ability in the presence of Hg^(2+)or Cu^(2+)ions due to the formed nonfluorescent metal complexes via robust Hg^(2+)–O interaction with the carboxy oxygen elements of surface ligands of MPA,and on the basis of the competitive binding of the mercapto groups of the MPA between the CdTe quantum dots and the Cu^(2+)ions,respectively,which allowed the analysis of Hg^(2+)or Cu^(2+)ions down to the picomolar levels.Under optimal conditions,the response of the MPA-SHMP-capped CdTe quantum dot PL intensity is linearly proportional to the Cu^(2+)and Hg^(2+)ion concentration ranging from 0.1 to 1000 and 0.3 to 1000 nM with a detection limit of 41.6 and 97.0 pM,respectively.The diagnostic capability and potential in practical applications of this method have been demonstrated by detecting Cu^(2+)and Hg^(2+)ions in environmental water samples.展开更多
基金financially supported by National Natural Science Foundation of China(No.22077018)。
文摘Considering the undesirable metabolic stability of our recently identified NNRTI 5(t1/2=96 min)in human liver microsomes,we directed our efforts to improve its metabolic stability by introducing a new favorable hydroxymethyl side chain to the C-5 position of pyrimidine.This strategy provided a series of novel methylol-biphenyl-diarylpyrimidines with excellent anti-HIV-1 activity.The best compound 9g was endowed with remarkably improved metabolic stability in human liver microsomes(t1/2=2754 min),which was about 29-fold longer than that of 5(t1/2=96 min).This compound conferred picomolar inhibition of WT HIV-1(EC50=0.9 nmol/L)and low nanomolar activity against five clinically drug-resistant mutant strains.It maintained particularly low cytotoxicity(CC50=264μmol/L)and good selectivity(SI=256,438).Molecular docking studies revealed that compound 9g exhibited a more stable conformation than 5 due to the newly constructed hydrogen bond of the hydroxymethyl group with E138.Also,compound 9g was characterized by good safety profiles.It displayed no apparent inhibition of CYP enzymes and h ERG.The acute toxicity assay did not cause death and pathological damage in mice at a single dose of 2 g/kg.These findings paved the way for the discovery and development of new-generation anti-HIV-1 drugs.
基金the National Natural Science Foundation of China(21575022,21535003),the National High Technology Research and Development Program(“863”Program)of China(2015AA020502)the Fundamental Research Funds for the Central Universities,Qing Lan Project and A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.And we greatly appreciate the support of the National Natural Science Foundation of China(21575123,21675139,21705140)+1 种基金the Natural Science Foundation of Jiangsu Province(BK20170474)the Industry-University-Research Cooperative Innovation Foundation of Jiangsu Province(BY2015057-17).
文摘In this paper,dual-stabilizer-capped CdTe quantum dots were used as modulated photoluminescence(PL)sensors for the subpicomolar level detection of copper(II)(Cu^(2+))and mercury(II)(Hg^(2+))ions in aqueous solution for the first time.The dual-stabilizer-capped CdTe quantum dots were synthesized using mercaptopropionic acid(MPA)and sodium hexametaphosphate(SHMP)as surface-modified ligands via a convenient hydrothermal process.The researches showed a low interference response of the MPASHMP-capped CdTe quantum dots towards other metal ions.The highly efficient PL quenching ability in the presence of Hg^(2+)or Cu^(2+)ions due to the formed nonfluorescent metal complexes via robust Hg^(2+)–O interaction with the carboxy oxygen elements of surface ligands of MPA,and on the basis of the competitive binding of the mercapto groups of the MPA between the CdTe quantum dots and the Cu^(2+)ions,respectively,which allowed the analysis of Hg^(2+)or Cu^(2+)ions down to the picomolar levels.Under optimal conditions,the response of the MPA-SHMP-capped CdTe quantum dot PL intensity is linearly proportional to the Cu^(2+)and Hg^(2+)ion concentration ranging from 0.1 to 1000 and 0.3 to 1000 nM with a detection limit of 41.6 and 97.0 pM,respectively.The diagnostic capability and potential in practical applications of this method have been demonstrated by detecting Cu^(2+)and Hg^(2+)ions in environmental water samples.
