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The synthesis and characterization of ruthenium disulfoxide complexes and their preliminary in vitro examination as potential chemotherapeutic agents Huxham, Lynsey Anne

Abstract

The anti-cancer activity of the water-soluble complexes cis- and trans- RuCl2(DMSO)4 has led, in this laboratory, to further investigation of disulfoxide complexes of Ru as potential chemotherapeutic agents. The dithioether precursors and disulfoxides were synthesized in this work following literature procedures. The disulfoxides used were of the formula RS(O)(CH2)nS(O)R, where R = Et (BESE) or Ph (BPhSE) for n = 2; and R = Et (BESP) or Pr (BPSP) for n = 3, and the dithioether used was BPTP (l,3-bis(propylthio)propane). These compounds/ligands were reacted with Ru precursors to yield complexes characterized mainly by NMR, elemental analysis, IR, and conductivity, while three complexes were also characterized by X-ray crystallography. A mixed sulfoxide/disulfoxide complex, cis-RuCl2(DMSO)2(BESE), was isolated during this thesis work. The water-soluble complex was characterized by X-ray crystallography, the solution chemistry was studied, and preliminary in vitro tests were performed. The crystal structure shows cis chlorides, one O-bound DMSO, one S-bound DMSO, and S-bound BESE. The complex does not exhibit significant host toxicity toward CHO (Chinese hamster ovarian) cells below 1.1 mM, and was found to have essentially no anti-cancer activity, at concentrations up to 3 mM, toward human mammary cancer cells. The known complex [RuCl(BESE)(H2O)]2(μ-Cl)2 ionizes in aqueous solution to generate 2 equiv. of H+ and 2 equiv. Cl per mole of complex, and sulfoxide exchange reactions with the in situ formed species (thought to be [Ru(BESE)(OH)(H2O)]2(μ-Cl)2) were briefly studied. In an attempt to synthesize the previously characterized, dinuclear complex [RuCl2(BPTP)]2(μ-Cl)2 , trans-RuCl2(BPTP)2 was isolated and characterized by NMR, and elemental analysis. The synthesis of thioether complexes was performed to attempt a subsequent oxidation of the coordinated dithioether while retaining the geometry about the Ru. This thesis work led to the isolation of three Ru disulfoxide-bridged complexes. One such complex, [RuCl3(BPhSE)](μ-BPhSE), was characterized by elemental analysis, IR, and mass spectrometry, and two Ru(p-cymene) complexes with bridging sulfoxides were also isolated. The first, [RuCl2(p-cymene)]2(μ-BESE), was characterized by X-ray crystallography and contains S-bound sulfoxide, while the other, [RuCl2(p-cymene)]2(μ- BESP), characterized by NMR, elemental analysis, and IR, appears to be chemically similar to the μ-BESE complex. [RuCl2(p-cymene)]2(μ-BESE) was shown in vitro to exhibit no significant host toxicity below concentrations of 1.1 mM, but did exhibit, in the concentration range 345-360 μM, anti-cancer activity against human mammary cancer cells. A third p-cymene complex, [RuCl(p-cymene)(BESE)]PF6 , was characterized by X-ray crystallography and shown to have S-bound sulfoxide. [Scientific formulae used in this abstract could not be reproduced.]

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