Synthesis, Anticancer and Antibacterial Activity of Some Novel Mononuclear Ru(II) Complexes

Abstract

The success of cisplatin and related platinum complexes as anticancer agents has stimulated a search for other active transition metal complexes, and ruthenium in particular has attracted the researchers.1) Metal complexes of ruthenium containing nitrogen and oxygen donor ligands are found to be effective catalysts for oxidation, reduction, hydrolysis and other organic transformation.2) The coordination environment around ruthenium plays the key role in stabilizing its different oxidation states and hence dictates the redox properties of the control atoms. (areneϭp-cymene, hexamethylbenzene and lϭcarbene or nitrogen containing heterocycles) have been tested for antibacterial and antifungal activity.The tris chelates of the ruthenium with bidentate ligands show intercalate properties with the DNA 13) and bind to Fe(III) sites of the proteins lactoferin and transferrin 14,15) and transferrin is thought to be responsible for the delivery of Ru(III) to cancer cells where it is taken up via receptor mediated endocytosis.16) Transferrin normally transports Fe(III) in the blood but is only about one third occupied by Fe(III), and so there are vacant sites available for Ru(III) binding. Another important step in the mechanism of action of Ru(III) complexes is thought to be in vivo reduction to Ru(II), 17) which is kinetically more reactive than Ru(III). Recently we have reported, N-alkyl and N-aryl substituted thiosemicarbazide complexes with Ru(bpy) 2 Cl 2 and greater antibacterial activity was found in the N-alkyl substituted complexes whereas N-aryl substituted exhibited more antitumor activity.18) In view of the above facts we have investigated the design of a novel range of Ru(II) complexes and the structural features as well as the contribution of the ligands that are responsible for antitumor and antibacterial activity. Results and DiscussionChemistry The ligands nmit (nmitϭN-methyl-isatin-3-thiosemicarbazone) and icpl (icplϭisatin-3-(4-chlorophenyl) thiosemicarbazone) were prepared by reacting Nmethylisatin and isatin with thiosemicarbazide and 4-chlorophenyl thiosemicarbazide in alcohol in presence of glacial acetic acid in 1 : 1 molar ratios respectively. Other ligands like r-tsc (r-tscϭ4-substituted thiosemicarbazides) were prepared according to the literature 19,20) with slight modification (Chart 1). All these ligands were confirmed for their purity by their melting point, elemental analysis and infrared spectra.Ruthenium metal complexes with the ligands nmit, icpl, aze (azeϭacetazolamide) and r-tsc were prepared by the reaction of a stoichiometric quantity of Ru(phen) 2 Cl 2 / Ru(bpy) 2 Cl 2 with the respective ligands in alcohol in presence of nitrogen (Chart 2). The completion of the reaction was monitored by TLC on silica gel.The structures of these ligands, especially nmit, icpl and rtsc in Fig. 1, show that in no case these ligands can exhibit tridentate behavior. There are very few cases in which the thiosemicarbazides act as monodentate ligands binding to the metal centre through the sulfur atom, th...

Synthesis, antineoplastic and cytotoxic activities of some mononuclear Ru(II) complexes

“…FAB mass spectroscopic data clearly suggested that mononuclear complexes had been formed in each case, the first fragment being due to the [Ru(S) 2 respectively (where S = 1,10-phenanthroline/2,2'-bipyridine and K = r-binh, r-btsz). This type of fragmentation has been reported for [Ru(phen) 2 (nmit)]Cl 2 and [Ru(bpy) 2 (ihqs)]Cl 2 (where phen = 1,10-phenanthroline, bpy = 2,2'-bipyridine, nmit = N-methyl isatin thiosemicarbazone, ihqs = 7-iodo-8-hydroxyquinoline-5-sulfonicacid) 33 . In all cases, the loss of chlorine ions was detected where S = 2,2'-bipyridine/1,10-phenanthroline and K = r-binh, r-btsz.…”

“…The Ru(II) compounds are kinetically more reactive than Ru(III) 32 . We have reported that Ru(II) compounds bearing thiosemicarbazides, 8-hydroxyquinolines, and 4-substituted thiopicolinanalides have in vivo anticancer and in vitro antibacterial activity [33][34][35] . Recently, we have reported that Ru(II) compounds bearing isatin thiosemicarbazones and chloro-fluoro-phenyl imino methyl phenol have in vivo anticancer and in vitro cytotoxic activity 36 .…”

Monomeric and dimeric coordinatively saturated and substitutionally inert Ru(ii) polypyridyl complexes as anticancer drug candidates

“…117 After a brief structureactivity relationship, Meggers and co-workers demonstrated that complex 46 showed the highest cytotoxicity when compared with the other tris-heteroleptic complexes tested. [121,122] During the same year Tan and co-workers demonstrated, for the first time, that Ru(II) polypyridyl complexes with β-carboline alkaloids could simultaneously induce autophagy and apoptosis in HeLa cells through a ROS-mediated mechanism (ROS= reactive oxygen species), which led to mitochondrial dysfunction. 116 However, DNA could be the primary target of this nuclear permeable complex since the cytotoxicity of the complexes directly correlated with their DNA binding affinity.…”

Role of chelates in treatment of cancer

“…Tumor inhibition by the ruthenium chelates was followed by improvements in hemoglobin, RBC and WBC values. [4] 2. B i s ( 1 , 1 0 -p h e n a n t h ro l i n e / 2 , 2 ′ -b i p y r i d i n e ) ruthenium(II) complexes contain 1-thiocarbamoyl-3,5-diphenyl-2-pyrazoline, 2-(3,5-diphenyl-4,5-dihydropyrazol-1-yl)-4-phenylthiazole, 2-hydroxyphenyl benzimidazole and benzoin thiosemicarbazone ligands coordinated with the metal through nitrogen, sulfur and oxygen atoms.…”