Synthesis And Biological Activity Of Ionic Half-sandwich Complexes Of Iridium, Rhodium And Rutheniu

Although a series of platinum antitumor drugs such as cisplatin and its derivatives have been applied in clinical practice,the serious side effects have made scientists commit themselves to searching for more efficient and less toxic antitumor drugs.We synthesized a series of novel cationic and zwitterionic half-sandwich platinum group metal-based anticancer complexes through rational design and optimization of ligand.The anticancer mechanism has been systematically studied.It is hoped to solve the key scientific problems such as resistance and side effects of commercial anticancer drugs.1.Herein,we investigated the different coordination modes of half-sandwich iridium（III）and rhodium（III）complexes based on pyridine-amine ligands.The pyridyl-amine iridium（III）and rhodium（III）complexes,the corresponding oxidation pyridyl-imine products and 16-electron pyridyl-amido complexes can be obtained through the change in reaction conditions（nitrogen/adventitious oxygen atmosphere,reaction time and solvents）and structural variations in the metal and ligand.The reaction of pyridine-amine ligands with[（η⁵-C₅（CH₃）₅）MCl₂]₂（M=Ir or Rh）in the presence of adventitious oxygen afforded the oxidized pyridyl-imine complexes.The possible mechanism for the oxidation of iridium（III）and rhodium（III）amine complexes was confirmed by the detection of the byproduct hydrogen peroxide.Moreover,the formation of pyridyl-amine complexes was favored when non-polar solvent CH₂Cl₂ was used instead of CH₃OH.The rarely reported complex with[（η⁵-Cp^*）Ir Cl₃]anion can also be obtained without the addition of NH₄PF₆.The introduction of sterically bulky i-Bu group on the bridge carbon of the ligand led to the formation of stable 16-elcetron pyridyl-amido complexes.The pyridyl-amine iridium（III）and rhodium（III）complexes were also synthesized under a N₂ atmosphere.The aqueous solution stability and in vitro cytotoxicity toward A549 and He La cancer cells of these complexes were systematically evaluated.No obvious selectivity was observed for cancer cells versus normal cells with these complexes.Notably,the represented complex 11 can promote an increase in the reactive oxygen species level and induce cell death via apoptosis.2.The synthesis and biological assessment of neutral or cationic platinum group metal-based anticancer complexes have been extremely studied,whereas there are few reports on the corresponding zwitterionic complexes.Herein,the synthesis,characterization,and bioactivity of zwitterionic half-sandwich phosphine-imine iridium（III）,rhodium（III）,and ruthenium（II）complexes were presented.The solution stability of these complexes and their spectral properties were also determined.Almost all of these complexes showed the enhanced anticancer activity against model He La and A549 cancer cells than the corresponding zwitterionic pyridyl-imine N,N-chelating iridium（III）and ruthenium（II）complexes,which have exhibited inactive or low active in our previous work.The increase in the lipophilic property and intracellular uptake levels of these zwitterionic P,N-chelating complexes appeared to be associated with their superior cytotoxicity.In addition,these complexes showed biomolecular interactions with bovine serum albumin（BSA）.The flow cytometry studies indicated that the representative complex 14 could induce early-stage apoptosis in A549 cells.Further,confocal microscopy imaging analysis displayed that 14 entered A549 cells through the energy-dependent pathway,targeted lysosome,and could cause lysosomal damage.In particular,these complexes could impede cell migration in A549 cells.