Synthesis,Charactrization,and Antitumor Activity Of Novel Monofunctional N-heterocyclic Carbine Platinum(?) Complexes

DNA is the target of classic platinum-based drugs.Such platinum-based drugs can block the rapid proliferation of cancer cells and induce apoptosis,and are widely used in the chemotherapy of cancer.However,classic cisplatin drugs have many unpleasant side effects and drug resistance,which limit their further clinical applications.Therefore,many non-classical platinum drugs have been developed for anti-tumor activity studies.Among them,monofunctional platinum complexes have attracted the attention of pharmaceutical chemists due to their unique mechanism of action and strong biological activity.The structural features and DNA binding modes of monofunctional platinum complexes are different from those of cisplatin but still display an impressive antitumor activity,most of them have no cross-resistance compared to cisplatin.And they have good water-solubility.Consequently,it is still of great importance to study monofunctional platinum complexes.Because of their unique stability,easy modification,easy synthesis,nitrogen heterocyclic carbene metal complexes have always been the focus of organic chemistry,especially in the field of catalyst.Nitrogen heterocyclic carbene metal complexes are gradually applied to the field of medicinal chemistry these years.Scientists have found that many nitrogen heterocyclic carbene metal complexes have good antibacterial or antitumor activity.The strong Pt–C_carbene bond?s?renders the platinum?II?complexes to display unique photophysical properties and enhanced stability against biological reduction and ligand exchange reactions.The introduction of C^N ligand has great influence on the optical properties of phosphorescent metal complexes such as platinum,ruthenium,palladium and other metal complexes.Hence,cyclometalated platinum complexes may be used as fluorescent probes,bioimaging,etc.This article designed and synthesized analogous 11 anticancer platinum?II?complexes.The structure of these complexes has been characterized by ¹H-NMR,LC-MS,elemental analysis and single crystal X-ray diffraction.The results showed that none of pyridine nitrogen atom and thioether sulfur atom of the nitrogen heterocyclic carbene side chain of complex 1-9 was coordinated with platinum,and instead of the platinum atom,a chlorine anion was coordinated.Eventually resulting in nine complexes that are both neutral monofunctional platinum complexes.Compared to cisplatin,they all have stronger antitumor activity in vitro.For complexes 1-5,all of them have definite DNA insertion ability to effectively compete with the nucleic acid binding site of EB.In the cell cycle arrest experiment,it was found that the complexes could cause cell cycle arrest in a concentration-dependent manner to produce anticancer activity.In addition,during the synthesis,we also isolated two biscarbapentin complexes.They have almost no killing effect on cancer cells,and thus it can be proved that the presence of a leaving group chloride ion has a great impact on the anticancer activity of the complexes.This study expands the exploration field of monofunctional platinum complexes and provides a new idea for the rational design of platinum drugs with target and novel structure.