Síntese de novos complexos de cobalto contendo híbrido de cumarina--cetoéster: investigação da citotoxidade e reatividade em solução

Abstract

In this work it was synthesized novel cobalt complexes of the type [Co(L)(Am)](ClO4)n, where L (ethyl 3-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)-3-oxopropanoate) is a fluorescent hybrid ligand of coumarin--ketoester in its anionic form and Am is the auxiliary amine TPA (Tris(2-pyridylmethyl)amine) or Py2en (bis(2-pyridylmethyl)-1,2-diamine). The synthetic procedure to obtain 1b-CoII, [CoII(L)TPA]ClO4, led to the formation of the CoII specie, which was confirmed by CHN elemental analysis, molar conductivity and X-ray diffraction (XRD). The 1b-CoII ion complex is a cationic hexacoordinated specie in the solid state, containing the coumarin--ketoester in the L1- form, acting as O,O-donor, and a neutral TPA as N,N',N',N'-donor. For analogous complex 2b-CoIII, [CoIII(L)TPA](ClO4)2, the methodology used from cis-[CoIII(TPA)Cl2]ClO4 led to the formation of the CoIII species, however, CHN elemental analysis and 1H NMR also indicated the presence of the precursors in the isolated solid. The complex 2c-CoIII, [CoIII(L)Py2en](ClO4)2, was obtained from the same methodology used for 1b-CoII, however, the presence of a more basic amine (Py2en) favored the CoIII specie. Elemental analysis, molar conductivity, infrared and 1H NMR spectroscopy data indicated a structure of the type [CoIII(L)(Py2en)](ClO4)2, where L1- also interacts with the metal through the carbonyl groups of the -ketoester moiety. DFT calculations showed that the band at 448 nm in the UV-Vis spectra of 1b-CoII, obtained in buffer solution (pH 7,4), refers to the transition centered on L1-, and for 2c-CoIII the band at 455 nm is related to a mixture of and LMCT transitions. Cyclic voltammetry showed that the complexes exhibit a quasi-reversible process associated with the CoIII/CoII pair, with Epc in the order 2c-CoIII < 1b-CoII < 2b-CoIII, which was associated to the electronic properties of the auxiliary amine. The higher -acceptor character of the TPA facilitates the electron gain by the cobalt in 1b-CoII and 2b-CoIII, while Py2en, which has a larger -donor character, leads to a lower potential for 2c-CoIII. HL exhibits a cathodic process associated to the reduction of the carbonyl groups, which did not shift after coordination. Reactivity assays of 2c-CoIII in buffer solution (pH 7,4) monitored by fluorescence spectroscopy indicated that the ligand was released in the presence of a reducing agent (sodium ascorbate) for 8.5 h, which was most pronounced in argon atmosphere, suggesting that dissociation of L1- occurs preferentially after reduction of the metal. 2c-CoIII was stable in buffer solution without reducing agent. The cytotoxicity investigation of HL, 1b-CoII and 2c-CoIII against B16-F10 (metastatic murine melanoma), 4T1 (murine mammary melanoma) and BHK-21 (non-tumor cell of hamster kidney) showed that the free ligand was not active, but the coordination favored its cytotoxicity in most cases. 2c-CoIII exhibited the best overall activity when compared to 1b-CoII, presenting selective cytotoxicity to cancer cells (45.9 ± 5.2 M e 39.1 ± 6.6 M para B16-F10 e 4T1, respectively) and being inactive against normal cells (71.2 ± 6.2 M).