The Research Of Synthesis And Antitumor Activity Of New Ruthenium Complexes

Malignant tumor is one of the main diseases endangering human health.For a long time, Look for the medicine to cure malignant tumor has always been the hot spot of the drug development all over the world, until the 1960 s, people found the antitumor activity of platinum complexes, the situation to change. Nowadays, platinum drugs have been used in 85% of the cancer treatment. Metal ruthenium complexes are considered to be one of the most potential antitumor drugs. Platinum drugs, however, the disadvantages are also growing during the clinical use, such as renal toxicity, bone marrow toxicity, ototoxicity, peripheral nerve toxicity, vomiting and drug resistance caused by use for a long time, and platinum drugs for many tumor does not work, which limit its application. Therefore, other metal complexes of anti-tumor research gradually aroused people’s concern.This topic design and synthesized different kinds of ruthenium metal complexes, to study the biological activity, 14 complexes with strong anticancer activity were filtered. In the process of research, this subject adopts determined by MTT detection, cellular uptake assay, AO/EB dyeing experiments, cell cycle test, reactive oxygen species level test, mitochondrial membrane potential detection, single cell gel electrophoresis detection, Western-blot method. By studying its affection to Bel-7402, Mg-63, A549, SK-BR-3 and Hela cells, the effect of preliminary confirmed these new ruthenium complexes have the function of the induced cancer cells apoptosis, and explore the related mechanism of complexes induce cell apoptosis.The following chapter will introduce the concrete research content.Chapter one, introduction, introduce the current situation of research and application of metal complex, main about the ruthenium complexes.Chapter two synthetic ligands CPIP and five auxiliary ligand bpy, phen, dmb, dip, dmp five ruthenium metal complexes are synthesized C1, C2, C3, C4 and C5. Detection of these complexes on the NIH-3T3, Bel-7402, Mg-63, the cell line A549, SK-BR-3 to five inhibitory activity. Found that these compounds have lower IC50 of Bel-7402 cells. Cellular uptake assay, AO/EB dyeing experiments, detection of mitochondrial membrane potential and the experimental results can preliminary judgment, the complexes into the cell, and apoptosis induced by mitochondrial way.Chapter three synthetic ligands DCPIP and five auxiliary ligand bpy, phen, dmb, dip, dmp five ruthenium metal complexes are synthesized D1, D2, D3, D4, D5.Detection inhibitory activity of these complexes on the five cell lines NIH-3T3, Bel-7402, Mg-63, A549, SK-BR-3. Found that these compounds have lower IC50 of Bel-7402 cells. Endocytosis experiment found that these compounds into Bel-7402 cells inside, reactive oxygen species and mitochondrial membrane potential experiments have shown that these complexes caused the Bel-7402 cell apoptosis through mitochondrial channels.Chapter four synthetic ligands ATATP, with four auxiliary ligand bpy, phen, dmb, dip four ruthenium metal complexes are synthesized M1, M2, M3, M4.Detect the distribution and inhibition for the five cell lines NIH-3T3, Bel-7402, Mg-63, A549,Hela. Found these complexes got lower IC50 for Hela.Staining showed that compounds into the cell, Reactive oxygen species and mitochondrial membrane potential experiment according to the results, these compounds induce apoptosis through mitochondrial pathway.Fifth chapter through the protein immunoblot method and single cell gel electrophoresis method study of C4 and D1 induced the Bel-7402 cell apoptosis related mechanism, research the related mechanism of M1 induced Hela apoptosis. Results show that the Bcl-2, the Bcl-x amount of protein expression, was cut, Caspase-3, Caspase-7, Bax, Bad expression quantity increase. Experiment results have proven that the Bel-7402 cells and Hela is apoptosis through mitochondrial apoptosis channels.