Semi-sandwich Metal Ruthenium Nitrogen Heterocyclic Carbene Anticancer Complex

Recently,the tremendously increasing incidence of cancer has drawn much attention.Cisplatin plays a crucial role in the treatment of various cancers in clinical chemotherapy.However,the actual efficacy and applicability of platinum based drugs have been greatly limited by their severe toxic side-effects.In recent years,researches showed that multi-target iridium anticancer drugs might be more effective and less adaptive to resistance than cisplatin agents.The design of Ir anti-tumor drugs has become one of the major challenges in the research and development of anticancer agents.Half-sandwich iridium anticancer complexes have new mechanisms of action different from clinical used platinum drugs.The iridium complexes can selectively kill cancer cells.A series of N-Heterocyclic carbene(NHC)ligands(L1-L4)and novel bridging silver complexes(1d-4d)have been designed and synthesized through N-methylimidazole,N-ethylimidazole,N-butylimidazole and N-phenylimidazole.By transmetalation reactions of these novel Ag complexes,twelve new Half-sandwich pseudo-octahedral pentamethylcyclopentadienyl IrIII complexes(1A-4C)of the type [(?5-Cpx)Ir(C^C)Cl]PF6,where Cpx is pentamethylcyclopentadienyl(Cp*),or its phenyl(Cpxph = C5Me4C6H5)or biphenyl(Cpxbiph = C5Me4C6H4C6H5)derivatives,and the C^C-chelating ligands are different N-Heterocyclic carbenes(NHCs)ligands have been synthesized and characterized.The complexes were fully characterized by MS,NMR,infrared(IR)spectra and elemental analysis,single crystal structures of complexes 1A,3B and 4A have been characterized by single crystal X-ray diffraction analysis..On the basis of characterization,the recognition mechanism between complexes and nucleic acid was systematically studied by spectroscopy gel electrophoresis method,etc.All complexes were preliminarily tested for their inhibitory activity towards human cervical carcinoma He La by MTT.Flow Cytometry was used to examine the apoptosis assay,cell cycle analysis and the induction of ROS in Hela cancer cells.1H NMR spectra and UV-Vis spectra were used to examine the catalytic activity of these complexes about NADH.Except 1A,all the rest complexes have not been reported in literature.All complexes 1A-4C undergo hydrolysis and their kinetics was studied,the hydrolysis have been characterized by UV-vis and 1H NMR spectra.The structure of complexes make a key role in their hydrolysis.It is easier to hydrolyze when the leaving group stays in opening environment.The extent of formation of nucleobase adducts by these complexes based on 1H NMR peak integrals was studied,no reaction with 9-Et A or 9-Et G was observed for 1A-4C.Gel electrophoresis studies suggested that DNA binding appears not to be the major mechanism of action.Except for Cp* complex 1A,the rest eleven complexes 1B-4C all showed potent cytotoxicity,with IC50 values ranging from 2.9 to 46.3 ?M toward Hela human cervical cancer cells.Potency toward Hela cells increased with additional phenyl substitution on Cp*: Cpxbiph > Cpxph > Cp*,and increased with the size of chain substitution on C^C-ligand in the order: ph > butyl > ethyl > methyl.Complex [(?5-C5Me4C6H4C6H5)Ir(L4)Cl]PF6(4C)displayed the highest potency,about 3 times more active than the clinical platinum drug cisplatin.The ability of these iridium complexes to catalytic hydride transfer from the coenzyme NADH to NAD+ is studied.Complexes [(?5-C5Me4C6H4C6H5)Ir(L2)Cl]PF6(2C)and [(?5-C5Me4C6H4C6H5)Ir(L3)Cl]PF6(3C)cause cell apoptosis and arrest cell cycles at G1 phase and G2/M phase when Hela cancer cells were treated with different IC50 concentrations of complexes,and increase the reactive oxygen species(ROS)dramatically,which appears to contribute to the anticancer activity.This class of organometallic Ir complexes has unusual features worthy of further exploration in the design of novel anticancer drugs.