Metal complexes of[NiL_(2)(NO_(3))_(2)](1),[CuL_(2)(NO_(3))_(2)](2)and[ZnL_(2)(NO_(3))_(2)](3)with the 1-trifluoroethoxyl-2,9,10-trimethoxy-7-oxoaporphine(L)ligand were synthesized.We discovered that complexes 1-3 exh...Metal complexes of[NiL_(2)(NO_(3))_(2)](1),[CuL_(2)(NO_(3))_(2)](2)and[ZnL_(2)(NO_(3))_(2)](3)with the 1-trifluoroethoxyl-2,9,10-trimethoxy-7-oxoaporphine(L)ligand were synthesized.We discovered that complexes 1-3 exhibited considerable anticancer activity in vitro via simultaneously targeting microtubules and mitochondria.Complexes 1-3 impaired mitochondrial bioenergetic function by causing ATP depletion and mitochondrial membrane depolarization.They also triggered excessive generation of intracellular ROS and Ca^(2+),activated caspase-3 and caspase-9,and triggered mitochondria-dependent apoptosis pathways.In addition,complexes 1-3 were shown by SPR and CETSA assays to have a good binding affinity forβ-tubulin.Tubulin polymerization analysis suggested that complexes 1-3 promoted tubulin polymerization into microtubules,and disrupted the microtubule cytoskeleton network,which caused cell cycle arrest in the G2/M phase.Complexes 1-3 ultimately activated a strongly apoptotic response.Complexes 1 and 2 displayed high cancer growth inhibition efficacy in mice bearing T-24 xenografts,and had a good in vivo safety profile.Complexes 1-3 have the potential to become anticancer agents through targeting microtubule and mitochondria.展开更多
基金National Natural Science Foundation of China(Grant 22077022)IRT_16R15+1 种基金Natural Science Foundation of Guangxi Province of China(Grants 2016GXNSFGA380005 and AD17129007)“BAGUI Scholar”program of Guangxi Province of China。
文摘Metal complexes of[NiL_(2)(NO_(3))_(2)](1),[CuL_(2)(NO_(3))_(2)](2)and[ZnL_(2)(NO_(3))_(2)](3)with the 1-trifluoroethoxyl-2,9,10-trimethoxy-7-oxoaporphine(L)ligand were synthesized.We discovered that complexes 1-3 exhibited considerable anticancer activity in vitro via simultaneously targeting microtubules and mitochondria.Complexes 1-3 impaired mitochondrial bioenergetic function by causing ATP depletion and mitochondrial membrane depolarization.They also triggered excessive generation of intracellular ROS and Ca^(2+),activated caspase-3 and caspase-9,and triggered mitochondria-dependent apoptosis pathways.In addition,complexes 1-3 were shown by SPR and CETSA assays to have a good binding affinity forβ-tubulin.Tubulin polymerization analysis suggested that complexes 1-3 promoted tubulin polymerization into microtubules,and disrupted the microtubule cytoskeleton network,which caused cell cycle arrest in the G2/M phase.Complexes 1-3 ultimately activated a strongly apoptotic response.Complexes 1 and 2 displayed high cancer growth inhibition efficacy in mice bearing T-24 xenografts,and had a good in vivo safety profile.Complexes 1-3 have the potential to become anticancer agents through targeting microtubule and mitochondria.
