Synthesis And Properties Of Novel Aryl Ruthenium/Osmium Anticancer Complexes

Platinum-based drugs(e.g.cisplatin,carboplatin,oxaliplatin)have been widely used in cancer chemotherapy,which would result in serious drug resistance and toxic side effects.Hence,it becames urgent to develop new anticancer drugs with the different therapic mechanism from Pt-drugs."Piano-stool" aryl metal complexes(such as Ru,Os,Rh,Ir et al.)have been listed as potent anticancer drugs due to their comparable anticancer effects to Pt-drugs and much lower toxicity to normal cells.Combination of the natural product and the metal-arene center may be a highly effective strategy,because the resulting complexes not only held the function in anticancer but also modified their stability and water solubility of natural product.In addition,the diversity of organic bridge ligands offers the possibility for the construction of polynuclear aryl complexes with higher selectivity and enhancement anticancer activities.This dissertation,nine novel metal-arene antitumor complexes were synthesized and fully characterized by 1H NMR,EA and ESI-MS.The crystal structures of 1 and 7 have been established and solved.The hydrolysis of complexes 1-9 were investigated by UV-Vis spectra.The interactions with CT-DNA,pBR322 were confirmed by UV-Vis spectra,Fluorescence spectra,CD spectra and gel electrophoresis.Cell cytotoxicity of complexes towards various cell lines has been determined in vitro by MTT assay.The distribution and transport of curcumin and complexes 1-3 in A549 cell lines were studied by confocal microscopy.Induced ROS levels elevation of complex 2 towards A549 cell lines were evaluated by confocal microscopy.The impact of complex 9 on A2780 Cell cycle distribution and cell apoptosis were studied by flow cytometry.Three complexes based on natural curcumin 1-3 have been synthesized.Single crystal structure analyses revealed 1 adopted "piano-stool" conformation.MTT assay shows clearly that the complexes 1-3 exhibited better cytotoxicity upon irradiation with visible light than in dark,and the IC50 values of complex 2 towards A549 cell lines were decreased from 135.2 ?M to 5.8 ?M.The confocal microscopy images,indicated the complexes and ligands were mainly located in cytoplasm and co-located with mitochondria.In addition,complexes 2 can lead to elevation of intracellular ROS levels.Hoechst staining assay revealed that 2 can led to nuclear alteration based on apoptosis.And complexes 1-3 show obvious antiangiogenic activity,which suggested its potential to suppress tumor metastasis.In addition,the effects of complexes in mice are also being studied.After that,three complexes including[(?6-arene)Ru/Os(N,N')Cl][Cl][M=Ru(4),Os(5)]and[(?5-Cp*)lr(N,N')Cl][Cl](6)based on pyridine derivative ligand tailed with naproxen(non-steroidal anti-inflammatory drugs)were synthesized.UV spectra showed that the complexes 5,6 were much more water-stable than that of complex 4.Studies have shown that complexes 4,5 could interact with the DNA to a certain extent.On the other hand,only little inhibitory abilities for complexes 4-6 have been observed.Finally,we successfully synthesized and characterized three dinuclear aryl Ru(?)complexes 7-9 based the rigid bidentate imidazole ligand(1,3-bib).The difference between Complexes 8,9 and complex 7 is the inner leaving group and anions Cl were replaced by Br,I,respectively.Single crystal structure analyses of complex 7 revealed that complexes presented "bowl-like" dinuclear conformation.The results suggested that complexes 7-9 cound effectively bind to DNA via intercalation.Complex 9 exhibited even better anticancer activity than cisplatin towards A2780 cells.Moreover,the investigation of gel electrophoresis indicates that complexes 7-9 maybe located in the nucleus,which DNA were extracted from A2780 cells.The choices of central metal,metal atom number,arene group,chelating ligand and counter anions have effect on its solubility in water,cell accumulation and the antitumor activity.This study provided a valuable reference on the relationship between cytotoxicity,cellular uptake and the compound structure.And it provides some detailed guidance of the future work on the design effective anticancer metal drugs with low toxicity.