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Thioether and sulfoxide complexes of ruthenium : preliminary in vitro studies of water-soluble species Cheu, Elizabeth Lai Shuen


Water-soluble ruthenium chemotherapeutic agents require further investigation. One approach is to study the coordination chemistry of a series of Ru-disulfoxide complexes, and preliminary in vitro surveys of the effects of these complexes in C H O (Chinese hamster ovary) cells are included. Other approaches, including the metallation of some free-base porphyrins, were investigated as well. Dithioethers and disulfoxides were synthesized using the well established chemistry outlined below: (chemical reactions) The disulfoxide and dithioethers were reacted with Ru precursors to yield complexes characterized generally by a combination of elemental analyses, NMR, IR and UV-Visible spectroscopies, as well as conductivity, magnetic measurements and thermal. gravimetric analyses; fifteen Ru complexes were also characterized by X-ray crystallography. The Ru-sulfoxide complexes contained only S-bonded sulfoxides (except jwer-RuCl₃(DPSO)₂(DPSO) where O and S represent O- and S-bonded diphenylsulfoxide, respectively). The following new, mononuclear, non-water-soluble, disulfoxide complexes were synthesized and characterized: frcms-RuCl₂ (BESE) ₂ (BESE = 1,2- bis(ethylsulfinyl)ethane), cw-RuCl2(BBSE) ₂ , c/s-RuCl₂ (BPeSE) ₂ , c«-RuCl₂ (BCySE) ₂ and c«-RuCl₂ (BESP) ₂ . RuCl₂ (DMSO)(L) (where L = 3,6,9,14-tetrathiabicyclo[9.2.1]tetradeca- 11,13-diene), and the water-soluble [Ru(12-S-4)(DMSO)(H20)][OTfJ2 (where 12-S-4 = 1,4,7,10-tetrathiacyclododecane and OTf = CF3SO3 ⁻), were synthesized to determine how the macrocyclic ligand might affect the in vitro properties of the Ru-sulfoxide moiety. Novel, water-soluble, dinuclear* Ru(II)-disulfoxide complexes [RuCl(BESE)(H20)]2(μ -Cl) ₂ , [RuCl(BPSE)(H20)]2(μ -Cl)2 (BPSE = 1,2- bis(propylsulfinyl)ethane) and [RuCl(BBSE)(H20)]2(μ -Cl)2 were characterized, and a new type of water-soluble, dinuclear, mixed-valence Ru(II)/Ru(III)-disulfoxide complex, [RuCl(BPSP)] ₂ (μ-Cl) ₃, was characterized and its aqueous chemistry studied. Two mononuclear, dithioether complexes (/ra»s-RuCl₂ (BPhTE) ₂ and -RuCl₂ (BCyTE) ₂ , where BPhTE = l,2-bis(phenylthio)ethane and BCyTE = 1,2- bis(cyclohexylthio)ethane), and four dinuclear, Ru(III)/Ru(III) dithioether complexes ([RuCl₂ (BETP)] ₂( μ -Cl) ₂, [RuCl2(BPTP)] ₂ (μ -Cl) ₂ , [RuCl₂ (BBTP)] ₂ (μ Cl) ₂ and [RuCl₂ (BPeTP)] ₂ (μ -Cl) ₂, where BETP = l,3-bis(ethylthio)propane, BPTP = 1,3- bis(propylthio)propane, BBTP = l,3-bis(butylthio)propane and BPeTP = 1,3- bis(pentylthio)propane) were also synthesized. The purpose of their synthesis was to determine whether the ligand set would retain its geometry at the Ru after oxidation of the coordinated S-atom to S = 0 , but such an oxidation was not affected. A procedure involving the metallation of the water-soluble, free-base porphyrin TSPhP (the dianion of 5,10,15,20-tetrakis(4-sulfonato)phenylporphyrin), using [Ru(DMF)₆][Otf]₃ as the precursor, to give Na ₄[Ru(TSPhP)(CO)]-4H₂0 was also shown to be effective for metallation of several non-water-soluble, free-base porphyrins with formation of Ru(CO)(Porp) species, where Porp = TPhP (the dianion of 5,10,15,20- tetraphenylporphyrin), BPhP (dianion of 5,15-bis(phenyl)porphyrin), TrPhPyNO (dianion of 5,10,15-triphenyl-20-(4-pyridyl-A/-oxide)porphyrin), and OEP (dianion of 2,3,7,8,12,13,17,18-octaethylporphyrin). The water-soluble [RuCl(S-S)(H₂0) ] ₂ (μ-Cl)₂ (S-S = BESE, BPSE or BBSE), [RuCl(BPSP)]₂(μ-Cl)₃ and [Ru(12-S-4)(DMSO)(H₂0)][OTf]₂ complexes were examined in vitro using Chinese hamster ovary (CHO) cells. Toxicity, cell accumulation and D N A - binding assays were used to examine the ability of these complexes to traverse the cell membrane and bind to DNA. The biological data indicate that all five complexes are nontoxic but accumulate in CHO cells, with no difference in hypoxia. Of major interest [RuCl(BPSP)]₂(μ-Cl)₃ and [RuCl(BESE)(H₂0) ]₂ ( μ - Cl )₂ bind to DNA to a greater degree than cis- or trans-RuCl₂(DMSO)₄, both of which are known to exhibit anti-cancer activity. The preliminary biological data strongly encourage further investigations into the use of water-soluble, dinuclear Ru-disulfoxide complexes as DNA-binding agents.

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