Nitroimidazole and glucosamine conjugated heteroscorpionate ligands and related copper(II) complexes. Syntheses, biological activity and XAS studies.

New nitroimidazole and glucosamine conjugated heteroscorpionate ligands, namely 2,2-bis(3,5-dimethyl-1H-pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide (L(MN)) and 1,3,4,6-tetra-O-acetyl-2-{[bis(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]amino}-2-deoxy-β-D-glucopyranose (L(DAC)), respectively, were synthesized by direct coupling of preformed side chain acid and amine components. The related copper(II) complexes {[(L(MN))(2)Cu]Cl(2)}, and {[(L(DAC))(2)Cu]Cl(2)} have been prepared from the reaction of CuCl(2)2H(2)O with L(MN) or L(DAC) ligand in methanol solution. Single crystal structural characterization was undertaken for the L(MN) ligand. In the absence of a coordinated metal core, the overall arrangement of the ligand is determined by some loose intra- and inter-molecular nonbonding contacts. X-Ray Absorption Spectroscopy (XAS) has been used to probe the local structure of the two copper(II) complexes, {[(L(MN))(2)Cu]Cl(2)} and {[(L(DAC))(2)Cu]Cl(2)}. The EXAFS analysis has permitted the identification of the local environment of the copper site. Copper interacts with 2 units of ligand in both complexes, and it is found to be 6-fold coordinated. Its local structure is described by four Cu-N and two Cu-O interactions to form a pseudo-octahedron core, with a 0.14 Å lengthening of the Cu-O bond length in the case of L(DAC) complex with respect to the L(MN) one, likely due to the higher steric hindrance of the glucosamine moiety. The XANES analysis agrees with these results, also confirming the Cu(II) formal copper oxidation state for both complexes. The new copper(II) complexes {[(L(MN))(2)Cu]Cl(2)} and {[(L(DAC))(2)Cu]Cl(2)} as well as the corresponding uncoordinated ligands were evaluated for their cytotoxic activity towards a panel of several human tumour cell lines. The results reported here indicate that both copper(II) complexes show similar spectra of cytotoxicity and very low resistance factors (RF < 2) against C13 ovarian cancer cells which have acquired resistance to cisplatin.