Design, Synthesis And Detection Of Anticancer Drugs Containing [C, N] Ligands And Semi-sandwich Structures

Eight new organometallic Ir ^?cyclopentadienyl complexes[??⁵-Cp^x?Ir?C^N?Cl]has been prepared to explore the effect of cyclopentadienyl ligands and[C,N]type chelating ligands on their chemical and anticancer activity.{Cp^x=C₅Me₄H,Cp*,tetramethyl?phenyl?cyclopentadienyl(Cp^xph),tetramethyl?biphenyl?cyclopentadienyl N-?4-methoxybenzylidene?aniline?MBIA?}.The complexes were characterized by MS,NMR and elemental analysis,etc.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.The crystal structures of complexes [??⁵-C₅Me₄H?Ir Cl₂]₂?dimer1?,[(?⁵-Cp^xph)Ir?BIMA?Cl]?A3? and [(?⁵-Cp^xph)Ir?MBIA?Cl]?B3? have been characterized by single crystal X-ray diffraction analysis.All complexes A1-B4studied here display high potency toward the human Hela cancer cell,comparable to,and for some complexes even higher than the clinical anticancer drug cisplatin.The anticancer activity can be tuned by varying the cyclopentadienyl ligand,and increased in the order of Cp^xbiph>Cp^xph>C₅Me₄H>Cp*.The most active complex A4 and B4,contains a phenyl substituent on imidazole and biphenyl substituent on cyclopentadienyl ring.The results of viability assay show that the complex A4 and B4is 4 times more potent than cisplatin against Hela cells.In this work,we have shown that halfsandwich cyclopentadienyl Ir ^III complexes?A1-B4?display no nucleobase binding to 9-Et A and 9-Et G,and show slightly unwinding to the p BR322 DNA,suggesting that DNA could not be the main target for these complexes.For all complexes,transfer hydrogenation reactions can be achieved in living cells,using iridium?III?complexes with a chelated C^N ligands to convert coenzyme NADH into NAD⁺.Organometallic complexes are unique for their ability to achieve such redox modulation in living cells.In addition,the iridium complexes A4 and B4 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.