Objective:Ferroptosis represents a form of cell death characterized by the accumulation of iron dependent lipid peroxidation.This process culminates in membrane damage and cell lysis.One pivotal surveillance mechanism...Objective:Ferroptosis represents a form of cell death characterized by the accumulation of iron dependent lipid peroxidation.This process culminates in membrane damage and cell lysis.One pivotal surveillance mechanism is induced by glutathione peroxidase 4(GPX4).Furthermore,inhibition of GPX4 has been reported to hold a promise effect in cancer therapeutics.Methods:Computer-aided docking and small molecule probe were used for designed compounds.Flow cytometry was used to evaluate the ferroptosis.Animal experiments were taken to evaluate the in vivo effect of two compounds.Results:Based on our prior research,a series of twenty compounds with covalent binding potential was designed and synthesized.Under systematic evaluation,our team identified two small molecules 14 and 16,which significantly stabilized GPX4 thermal denaturation.Further investigations revealed that treatment with compounds14 and 16 led to an increase in lipid peroxidation,oxidative stress,and other markers(C11,Fe^(2+) and ROS)levels also increased.In both in vivo and in vitro experiment,compounds 14 and 16 are found suppression effect on urological cancer cells.Conclusions:Compounds 14 and 16 deserve further works as lead compounds of novel docking models for finally discovering effective anti-tumor drug.Future research is needed to dissect their mechanism and exploits this scaffold for GPX4 inhibitor development.展开更多
Over the past decade many bifunctional amine-thioureas have been developed as active metal-free organocatalysts. Coopera-tive catalysis of these amino-thioureas allows high reaction rates and excellent transfer of ste...Over the past decade many bifunctional amine-thioureas have been developed as active metal-free organocatalysts. Coopera-tive catalysis of these amino-thioureas allows high reaction rates and excellent transfer of stereocbemical information. Despite these impressive advances, the design of new high-performance catalysts for applications in asymmetric catalytic reactions is of ongoing interest in organic chemistry. Herein we describe a cooperative catalyst system consisting of a chiral amine thiourea and an achiral organic acid that promotes the conjugate addition of 4-nonsubstituted pyrazolones to nitroolefins and subsequent dearomative chlorination. The corresponding adducts and the subsequent products were obtained in high to excel lent yields （up to 99%） and high stereoselectivities （up to 99/1 dr, 98% ee） under mild reacton conditions. These transforma tions provide an easy access to enantio-enriched pvrazole derivatives, which could possess Potential oharmaceutical activity.展开更多
基金supported by the Natural Science Foundation of Hubei Province(No.2023AFB1021)。
文摘Objective:Ferroptosis represents a form of cell death characterized by the accumulation of iron dependent lipid peroxidation.This process culminates in membrane damage and cell lysis.One pivotal surveillance mechanism is induced by glutathione peroxidase 4(GPX4).Furthermore,inhibition of GPX4 has been reported to hold a promise effect in cancer therapeutics.Methods:Computer-aided docking and small molecule probe were used for designed compounds.Flow cytometry was used to evaluate the ferroptosis.Animal experiments were taken to evaluate the in vivo effect of two compounds.Results:Based on our prior research,a series of twenty compounds with covalent binding potential was designed and synthesized.Under systematic evaluation,our team identified two small molecules 14 and 16,which significantly stabilized GPX4 thermal denaturation.Further investigations revealed that treatment with compounds14 and 16 led to an increase in lipid peroxidation,oxidative stress,and other markers(C11,Fe^(2+) and ROS)levels also increased.In both in vivo and in vitro experiment,compounds 14 and 16 are found suppression effect on urological cancer cells.Conclusions:Compounds 14 and 16 deserve further works as lead compounds of novel docking models for finally discovering effective anti-tumor drug.Future research is needed to dissect their mechanism and exploits this scaffold for GPX4 inhibitor development.
基金supported by the National Natural Science Foundation of China(21172170 and 21225208)the National Basic Research Program of China(973 Program,2014CB745100)
文摘Over the past decade many bifunctional amine-thioureas have been developed as active metal-free organocatalysts. Coopera-tive catalysis of these amino-thioureas allows high reaction rates and excellent transfer of stereocbemical information. Despite these impressive advances, the design of new high-performance catalysts for applications in asymmetric catalytic reactions is of ongoing interest in organic chemistry. Herein we describe a cooperative catalyst system consisting of a chiral amine thiourea and an achiral organic acid that promotes the conjugate addition of 4-nonsubstituted pyrazolones to nitroolefins and subsequent dearomative chlorination. The corresponding adducts and the subsequent products were obtained in high to excel lent yields （up to 99%） and high stereoselectivities （up to 99/1 dr, 98% ee） under mild reacton conditions. These transforma tions provide an easy access to enantio-enriched pvrazole derivatives, which could possess Potential oharmaceutical activity.
