Design,Synthesis And Antitumor Activity Evaluation Of Novel Arene-ruthenium(Ⅱ) Complexes

Organometallic compounds have been widely used in the field of catalysis,materials and medicine.The discovery of cisplatin was a great breakthrough for treatment of cancers as metal-based drugs.Since then organometallic compounds have attracted much attention and a large number of organometallic complexes have been reported.Among these organometallic compounds,arene-ruthenium(Ⅱ)complexes were widely synthesized and tested because of their biological advantages,such as low side-effect,high selectivity,amphiphilic nature provided by hydrophilic metal center and hydrophobic aromatic ligands,and some other vital anticancer properties such as anti-metastasis and anti-angiogenesis activity.In this paper,we had prepared two series of novel ruthenium(Ⅱ)-cymene complexes.Their stereochemical structure are similar,and their arene parts are cymenes.Only difference between these two ruthenium(Ⅱ)-cymene complexes is their ligands.Due to the change of ligand,their biological features are quite different.In the first part,a series of novel ruthenium(Ⅱ)-cymene complexes[Ru(η6-p-cymene)(L)Cl]Cl(L = N,N-chelating derivatives)(1-8)containing pyridyl-thiazole ligands have been synthesized and characterized by elemental analysis,IR,1H NMR and 13 C NMR spectroscopies.All these complexes display remarkable cytotoxicity in vitro against three different human cancer cell lines(Hela,A549 and MDA-MB-231).We can see that these compounds show similar cytotoxicity against Hela(2.02-7.49 μΜ),and compound 5,6,7 show nearly three times or more higher cytotoxicity against A549(1.58-4.98 μΜ)and MDA-MB-231(2.42-5.31 μΜ)than that of cisplatin.Besides,they also exhibit promising anti-metastatic activity at its sub-cytotoxic concentrations.Cell cycle analysis shows that the growth inhibition was mainly caused by cell cycle arrest at S-phase,accompanied by decrease in the percentage of cells at G2/M phase which is different from the phase-nonspecific chemotherapeutics drug cisplatin.Further protein level analysis suggests that compound 5 may exert their antitumor activity via ap53-independent mechanism which is different from cisplatin.These results hold a promise for treatment of cancers that are drug-resistant due to their mutated p53 or p53-null status.In the second part,another series of novel ruthenium(Ⅱ)-cymene complexes Ru(η6-p-cymene)(L)Cl(a-c)containing β-ketoxime ligands have been synthesized and characterized by elemental analysis,IR,1H NMR and 13 C NMR spectroscopies.The crystal structures of a was determined by single cystal X-ray diffractometer and clearly revealed that the ruthenium(Ⅱ)-cymene complex adopt the similar three-legged piano-stool coordination geometry around the ruthenium ion.Different from the previous series of ruthenium(Ⅱ)-cymene complexes,these complexes display much lower cytotoxicity in vitro against all three different human cancer cell lines(Hela,A549 and MDA-MB-231),and exhibit weak anti-metastatic activity.However,HUVECs experiments indicate that complex a shows obvious anti-angiogenesis activity.Due to promising anti-angiogenesis properties with little side effect,compound a deserves to be further investigated.