RESUMEN
The title copper complex, [Cu(H(2)P(2)O(7))(C(15)H(11)N(3))](2)·4.5H(2)O, consists of two very similar independent Cu(Tpy)H(2)P(2)O(7) monomeric units (Tpy is 2,2':6',2''-terpyridine) plus four and a half water molecules of hydration, some of which are disordered. Tpy units bind through the usual triple bite via their N atoms, and the H(2)P(2)O(7)(2-) anions coordinate through two O atoms from two different phosphate units. Each independent CuN(3)O(2) chromophore can be described as a slightly deformed square pyramid, with one of them having a sixth, semicoordinated, O atom from a centrosymmetrically related CuN(3)O(2) unit in a weakly bound second apical position suggesting an octahedral environment for the cation and weak dimerization of the molecule. The two independent complex molecules are connected via two strong O-H···O interactions between the phosphate groups to form hydrogen-bonded dinuclear units, further linked into [111] columns, resulting in a very complex three-dimensional supramolecular structure through a variety of classical and nonclassical hydrogen bonds, as well as π-π interactions.
Asunto(s)
Cobre/química , Iones/química , Compuestos Organometálicos/química , Piridinas/química , Cristalografía por Rayos X , Dimerización , Ditiocarba/análogos & derivados , Enlace de Hidrógeno , Estructura MolecularRESUMEN
Since diethyl dithiocarbamate (DEDTC) forms complexes with either zinc or copper, and 8-hydroxyquinoline (8-OHQ) also complexes with copper, we now compared the cytotoxic activity of Cu[DEDTC]2, Zn[DEDTC]2 and Cu[8-OHQ]2. This report shows that at nanomolar levels, only copper-[DEDTC]2, suppresses proliferation and clonogenicity of SKBR3 human breast carcinoma, concurrently with induction of apoptosis-associated PARP fragmentation. Susceptibility to these agents was paralleled by reactive oxygen generation (ROS) and greater expression of anti-oxidant enzymes like MnSOD and catalase, with no comparable effect on Cu/Zn superoxide dismutase. The lethal effects of Cu[DEDTC]2 manifested when adding the two separate aqueous components or the preformed synthetic complexes in DMSO, was prevented by N-acetyl cysteine or glutathione, with no comparable protection afforded by non-thiol anti-oxidants like mannitol or DMSO. Exogenously added catalase also protected cells from Cu[DEDTC]2, suggesting that this complex may kill after the levels of superoxide anion [O2*-] dismutated by MnSOD increase hydrogen peroxide-related stress. Cu[DEDTC]2 also induced p21WAF1, a cdk inhibitor usually not inducible in mutant p53 tumors like SKBR3 carcinoma, correlating with dephosphorylation of the Sp1 transcription factor. Concentrations of Cu[DEDTC]2 cytotoxic for SKBR3 carcinoma did not induce comparable damage versus normal diploid human WI-38 fibroblasts. In contrast to the cytotoxic effect of nM levels of Cu[DEDTC]2 against SKBRR3 cells, no response was seen in the same cells exposed to 20 microM cis-platin. Since neither DEDTC bound to zinc, nor copper bound to 8-OHQ showed comparable cytotoxicity, our results suggest that the greater activity of copper-DEDTC reflects a specific structure-activity relationship for the active complex. Since Cu[DEDTC]2 shows more effectiveness than other metal-chelator complexes, it may be worth further investigation as an alternative to cancer therapies.