Synthesis,Characterization And In Vitro Cytotoxicity Study Of Ruthenium (Ⅱ) Arene Complexs Of Curcumin Derivatives

Cancer is an uncontrolled proliferation of abnormal cells with increasing mortality of the individual.In this quest,enormous research efforts have been dedicated to search for new anticancer agents.Ruthenium(Ⅱ)-arene complexes with high efficacy,low toxicity and specificity to target tumor,have recieved the widespread attention.In this paper,28 novel ruthenium(Ⅱ)-arene complexes with curcuminoids were synthesized.The complexs were fully characterized by 1H NMR,13 C NMR,ESI-MS and Elemental analysis.Two of the complexs have also been confirmed by single crystal X-ray diffraction.The stability and the Log P of selected complexs were studied by NMR and UV-vis.A series of experiments were taken to evaluate the bioactivity of the complexs,such as MTT,Annexin V-PI staining,cell cycle analysis,DCFH-DA assay,JC-1 mitochondrial membrane potential assay,wound scratch assay and spectroscopic methods.The main works are shown as follows:In Chapter 1,the background and the significance of metallodrugs in cancer therapy was described.At the same time,the development of the ruthenium(Ⅱ)-arene complexes were systemic introduced and its antitumor action mechanism were also detailed reviewed.With these mentioned,the research purpose of this article are suggested.In Chapter 2,a series of organoruthenium(Ⅱ)chlorido complexes with curcuminoids [(η6-p-cymene)Ru(curcuminoids)Cl](3a–3g,6a-6h)and their respective PTA derivatives [(η6-p-cymene)Ru(curcuminoids)pta]PF6(4a–4g,7a-7h)were synthesized.These complexes have been characterized by 1H NMR,13 C NMR,ESI-MS and Elemental analysis.Crystal structures of 3e,7b have also been determined by X-ray diffraction analysis.The stability and the Log P of 3f,4f,6f and 7f were studied by NMR.The results indicate that the ruthenium(Ⅱ)-arene complexes with chlorido ligand undergo fast hydrolysis and release the β-Diketonates ligands partially,but the complexs with PTA quite resistant to hydrolysis.Meanwhile,The log P value for 3f,4f,6f,7f have been estimated to be in the range of 0.5-1.28 which lies in the following order as 7f > 6f > 4f > 3f.In Chapter 3,the newly synthesized ruthenium(Ⅱ)-arene complexes were tested for their inhibitory activity towards Hela,MCF-7,A549,MGC-803 and MDA-MB-231 cancer cell lines by MTT assay.Ruthenium(Ⅱ)-arene complexes with the half-curcumin ligands showed low cytotoxicity,while the ruthenium(Ⅱ)-arene complexes bearing the curcumin ligands especially with PTA ligand were noticeably much higher.The growth inhibitory effects of the 6a,7a,7b and 7c were found to be significant effective against the reference drugcisplatin(CDDP)with low micromolar range.Further investigations on the mechaism revealed that 6a and 7c induce a concentration-dependent increase apoptosis.But,the mode-of-action of 6a and 7c were drastically different.6a provoked the generation of reactive oxygen species,caused arrest in the G2/M phase,induced the loss of ΔΨm.The antiproliferative activity of 6a is greatly enhanced by the antioxidant nacetyl cysteine(NAC)and the activation of migration is blocked by NAC effectively,but 7a is negative in the DCFDA assay.It could be associated with the G0/G1 arrest and loss of ΔΨm.Moreover,the impact of NAC does not effective.In Chapter 4,the reactivity toward the calf thymus DNA(ct-DNA)and bovine serum albumin(BSA)of 6a and 7c were studied by UV-vis spectroscopy,fluorescent spectrum and circular dichroism spectroscopy.Preliminary results indicate that 6a displayed higher affinity to CT-DNA and BSA than 7c.The difference is 6a showed the interaction with the major groove of DNA and 7c was with minor groove of DNA.