Novel water-soluble prodrugs of combretastatin A-4 （5-8） were synthesized and evaluated for their in vitro cytotoxicity against lung carcinoma A549. Compound 5, bearing phosphoryl choline （PC） moiety, showed 90% i...Novel water-soluble prodrugs of combretastatin A-4 （5-8） were synthesized and evaluated for their in vitro cytotoxicity against lung carcinoma A549. Compound 5, bearing phosphoryl choline （PC） moiety, showed 90% inhibition at 32 ktg/mL concentration after 24 h. The findings showed the PC derivative would be a promising candidate for the development of new water-soluble prodrug of cytotoxic combretastatin A-4,展开更多
In variational methods,coupled parameter optimization(CPO) often needs a long minimization time window(MTW) to fully incorporate observational information,but the optimal MTW somehow depends on the model nonlinearity....In variational methods,coupled parameter optimization(CPO) often needs a long minimization time window(MTW) to fully incorporate observational information,but the optimal MTW somehow depends on the model nonlinearity.The analytical four-dimensional ensemble-variational(A-4DEnVar) considers model nonlinearity well and avoids adjoint model.It can theoretically be applied to CPO.To verify the feasibility and the ability of the A-4DEnVar in CPO,“twin” experiments based on A-4DEnVar CPO are conducted for the first time with the comparison of four-dimensional variational(4D-Var).Two algorithms use the same background error covariance matrix and optimization algorithm to control variates.The experiments are based on a simple coupled oceanatmosphere model,in which the atmospheric part is the highly nonlinear Lorenz-63 model,and the oceanic part is a slab ocean model.The results show that both A-4DEnVar and 4D-Var can effectively reduce the error of state variables through CPO.Besides,two methods produce almost the same results in most cases when the MTW is less than 560 time steps.The results are similar when the MTW is larger than 560 time steps and less than 880 time steps.The largest MTW of 4 D-Var and A-4DEnVar are 1 200 time steps.Moreover,A-4DEnVar is not sensitive to ensemble size when the MTW is less than 720 time steps.A-4DEnVar obtains satisfactory results in the case of highly nonlinear model and long MTW,suggesting that it has the potential to be widely applied to realistic CPO.展开更多
Herein a series of combretastatin A-4(CA-4)analogues with aggregation-induced emission characteristics(compounds a1-a19)were rationally designed and synthesized.The research results showed that the mechanism of AIE of...Herein a series of combretastatin A-4(CA-4)analogues with aggregation-induced emission characteristics(compounds a1-a19)were rationally designed and synthesized.The research results showed that the mechanism of AIE of a1-a19 could be attributed to the dual function of the restriction of intramolecular motion(RIM)and J-aggregate formation.Furthermore,the detailed investigation on the action mechanisms revealed that a19 diffused from lysosomes into the cytoplasm,and then targeted the colchicine binding site to induce cell cycle arrest and apoptosis in cancer cells.These results provide new ideas and impetus for the rational design of CA-4 analogues.展开更多
文摘Novel water-soluble prodrugs of combretastatin A-4 （5-8） were synthesized and evaluated for their in vitro cytotoxicity against lung carcinoma A549. Compound 5, bearing phosphoryl choline （PC） moiety, showed 90% inhibition at 32 ktg/mL concentration after 24 h. The findings showed the PC derivative would be a promising candidate for the development of new water-soluble prodrug of cytotoxic combretastatin A-4,
基金The National Key Research and Development Program under contract No.2021YFC3101501the National Natural Science Foundation of China under contract No.41876014。
文摘In variational methods,coupled parameter optimization(CPO) often needs a long minimization time window(MTW) to fully incorporate observational information,but the optimal MTW somehow depends on the model nonlinearity.The analytical four-dimensional ensemble-variational(A-4DEnVar) considers model nonlinearity well and avoids adjoint model.It can theoretically be applied to CPO.To verify the feasibility and the ability of the A-4DEnVar in CPO,“twin” experiments based on A-4DEnVar CPO are conducted for the first time with the comparison of four-dimensional variational(4D-Var).Two algorithms use the same background error covariance matrix and optimization algorithm to control variates.The experiments are based on a simple coupled oceanatmosphere model,in which the atmospheric part is the highly nonlinear Lorenz-63 model,and the oceanic part is a slab ocean model.The results show that both A-4DEnVar and 4D-Var can effectively reduce the error of state variables through CPO.Besides,two methods produce almost the same results in most cases when the MTW is less than 560 time steps.The results are similar when the MTW is larger than 560 time steps and less than 880 time steps.The largest MTW of 4 D-Var and A-4DEnVar are 1 200 time steps.Moreover,A-4DEnVar is not sensitive to ensemble size when the MTW is less than 720 time steps.A-4DEnVar obtains satisfactory results in the case of highly nonlinear model and long MTW,suggesting that it has the potential to be widely applied to realistic CPO.
基金supported by the National Key R&D Programs of China(2017YFC1103603)the National Natural Science Foundation of China(21877049,32171296)+2 种基金Guangdong Natural Science Foundation(2020B1515120043)the Innovation Team Project in Guangdong Colleges and Universities(2019KCXTD008)K.C.Wong Education Foundation。
文摘Herein a series of combretastatin A-4(CA-4)analogues with aggregation-induced emission characteristics(compounds a1-a19)were rationally designed and synthesized.The research results showed that the mechanism of AIE of a1-a19 could be attributed to the dual function of the restriction of intramolecular motion(RIM)and J-aggregate formation.Furthermore,the detailed investigation on the action mechanisms revealed that a19 diffused from lysosomes into the cytoplasm,and then targeted the colchicine binding site to induce cell cycle arrest and apoptosis in cancer cells.These results provide new ideas and impetus for the rational design of CA-4 analogues.
