New ruthenium(II) complexes with N-alkylphenothiazines: Synthesis, structure, in vivo activity as free radical scavengers and in vitro cytotoxicity

Abstract

Three new complexes of the general formula L[RuCl3(DMSO)(3)] (1-3), where L = chlorpromazine hydrochloride, trifluoroperazine dihydrochloride or thioridazine hydrochloride, were prepared and characterized by elemental analysis and spectroscopic methods (FT-IR, UV-Vis, H-1 NMR and C-13 NMR). In addition, the crystal structure of the complex 2 containing trifluoroperazine dihydrochloride was solved by single crystal X-ray diffraction. The complex crystallizes in the monoclinic system, space group P2(1)/n, with a = 10.4935(7) angstrom, b = 18.6836(12) angstrom, c = 19.9250(13) angstrom, beta = 98.448(2)degrees, V = 3864.0(4) angstrom(3). The structure was refined to the agreement factors of R = 4.79%, R-w = 11.23%. The effect of three different doses (0.4, 4.5 and 90.4 mu M/kg bw) of complex 2 on superoxide dismutase (SOD) and catalase (CAT) activity was investigated under physiological conditions. Influence on nitrite production (NO2-) and the level of erythrocytes malondialdehyde (MDA) in rats blood was also evaluated. Complex 2 did not affect the CAT enzyme activity in vivo and did not cause the hydroxyl radicals production. In the 0.4 and 4.5 mu M/kg bw doses it showed almost the same or lower SOD activity and nitrite levels, while the dose of 90.4 mu M/kg bw significantly increased these parameters. Finally, the cytotoxicity of complexes were assayed in four human carcinoma cell lines MCF-7, MDA-MB-453 (breast carcinoma), SW-480 (colon adenocarcinoma) and IM9 (myeloma multiple cells). Antiproliferative activity in vitro with low IC50 during 48 h of treatment was observed.