Studies of the interaction between bis(dithiocarbamato)copper(II) complexes with nitric oxide in aqueous solution and biological applications

Abstract

Three new bis(dithiocarbamato)copper(II) complexes have been prepared and characterized by elemental analysis, UV–Vis, and IR spectroscopy: bis(4-piperidonedithiocarbamato)copper(II), [Cu(Pdtc) 2] 2 ( 1), bis(piperidinedithiocarbamato)copper(II), [Cu(Ppdtc) 2] 2 ( 2), and bis[(2-piperidinecarboxy)dithiocarbamato]copper(II), Cu(Ppidtc) 2 ( 3). The crystal structures of the complexes 1 and 2 have been determined using X-ray diffraction methods and they are dimeric. The coordination sphere of copper(II) ions is described as a distorted square-pyramid: the axial Cu–S bond distances 2.7 and 2.8 Å for 1 and 2, respectively, are longer than the equatorial Cu–S ones (2.3 Å). Complexes 1 and 2 are not soluble in water. In contrast, 3 is water soluble. The interaction of 3, the previously prepared bis[ N-(dithiocarboxy)sarcosine]copper(II), Cu(Sdtc) 2 ( 4), and bis[(dicarboxymethyl)dithiocarbamato]copper(II), Cu(Idadtc) 2 ( 5), with nitric oxide in aqueous solution at pH 7.4 and 20 °C was spectrophotometrically studied and the experimental data were analysed by means of the spefo-letagrop and hyperquad programs, respectively. The stability constants of the complexes CuL 2(NO) and CuL 2(NO) 2 [L = dithiocarbamate] were determined. The interaction of 1 and 2 with nitric oxide was theoretically studied by molecular mechanics methods. Complexes 3, 4 and 5 and the previously studied bis[(dihydroxyethyl)dithiocarbamato]copper(II), Cu(Deadtc) 2 ( 6), decrease the NO produced in vitro either by sodium nitroprusside (NPS) or by cultured murine macrophages J774 stimulated with lipopolysaccharide (LPS) and interferon-γ (IFNγ). Inducible nitric oxide synthase (iNOS) activity was determined by measuring the stable NO end product, nitrite, using a colorimetric assay.