Organoiridium picolinamidate complexes are promising for intracellular applications because of their biocompatibility,activity in living systems,and ease of derivatization.To shield their metal centers from inhibition...Organoiridium picolinamidate complexes are promising for intracellular applications because of their biocompatibility,activity in living systems,and ease of derivatization.To shield their metal centers from inhibition by biological nucleophiles(e.g.,glutathione),attempts were made to increase the steric bulk of the supporting N-(2,6-R_(2)-phenyl)picolinamidate ligand.It was found that when R=H(Ir1)or methyl(Ir2),the ligand adopts N,N’-coordination to iridium,whereas when R=isopropyl(Ir3)or phenyl(Ir4),N,O-coordination was observed.Based on experimental measurements and density functional theory calculations,it was revealed that the carbon chemical shift of the C(O)NR group can be used as a diagnostic handle to distinguish between the N,N’-and N,O-isomers in solution.Computational studies indicate that the former is favored thermodynamically but the latter is preferred when the R group is overly bulky.Complexes Ir1-Ir4 exhibit differences in lipophilicity,cellular uptake,cytotoxicity,and the propensity to generate reactive oxygen species in living cells.Reaction studies showed that Ir1/Ir2 are more efficient than Ir3/Ir4 in promoting the reduction of aldehydes to alcohols via transfer hydrogenation but both isomer types were susceptible to catalyst poisoning by glutathione.This work has led to new insights into structural isomerism in organoiridium picolinamidate complexes and suggests that steric tuning alone is insufficient to protect the Ir center from poisoning by biological nucleophiles.展开更多
基金the National Institute of General Medicine Sciences of the National Institutes of Health(R01GM129276 to L.H.D.and R35GM133548 to J.I.W.)the Alfred P.Sloan Research Foundation(FG-2020-12811 to J.I.W.)for supporting this research.
文摘Organoiridium picolinamidate complexes are promising for intracellular applications because of their biocompatibility,activity in living systems,and ease of derivatization.To shield their metal centers from inhibition by biological nucleophiles(e.g.,glutathione),attempts were made to increase the steric bulk of the supporting N-(2,6-R_(2)-phenyl)picolinamidate ligand.It was found that when R=H(Ir1)or methyl(Ir2),the ligand adopts N,N’-coordination to iridium,whereas when R=isopropyl(Ir3)or phenyl(Ir4),N,O-coordination was observed.Based on experimental measurements and density functional theory calculations,it was revealed that the carbon chemical shift of the C(O)NR group can be used as a diagnostic handle to distinguish between the N,N’-and N,O-isomers in solution.Computational studies indicate that the former is favored thermodynamically but the latter is preferred when the R group is overly bulky.Complexes Ir1-Ir4 exhibit differences in lipophilicity,cellular uptake,cytotoxicity,and the propensity to generate reactive oxygen species in living cells.Reaction studies showed that Ir1/Ir2 are more efficient than Ir3/Ir4 in promoting the reduction of aldehydes to alcohols via transfer hydrogenation but both isomer types were susceptible to catalyst poisoning by glutathione.This work has led to new insights into structural isomerism in organoiridium picolinamidate complexes and suggests that steric tuning alone is insufficient to protect the Ir center from poisoning by biological nucleophiles.
