Estudos de complexos metálicos de ligantes bioativos derivados de estilbeno e de benzo-gama-pirona

Abstract

The present work comprised an investigation on copper(II) and silver(I)complexes containing bioactive ligands derived from stilbene and benzo-Y-pyrone. Trans-4-stilbenecarboxaldehyde-acetylhydrazone HStAc (1), trans-4-stilbenecarboxaldehyde-phenylhydrazone HStPh (2), trans-4-stilbenecarboxaldehydepara-chloro-phenylhydrazone HStpClPh (3), trans-4-stilbenecarboxaldehyde-paranitro-phenylhydrazone HStpNO2Ph (4), trans-4-stilbenecarboxaldehyde-para-toluichydrazoneHStpT (5), trans-4-stilbenecarboxaldehyde-benzylhydrazone HStBz (6) and trans-4-stilbenecarboxaldehyde-para-hydroxy-phenylhydrazone HStpOHPh (7) were prepared, as well as complexes [Cu(HStAc)2Cl2] (8), [Cu(HStpClPh)2Cl2] (9), [Cu(HStpNO2Ph)2Cl2] (10), [Cu(HStpT)2Cl2] (11), [Cu(HStBz)2Cl2] (12) and [Cu(HStpOHPh)2Cl2] (13). Due to the small differences in energy of the possible isomers theoretical calculations did not allow to determine the exact geometry of thecomplexes. The ligands (1-7) and complexes (8-13) showed weak antimicrobial activity against bacteria and fungi as well as poor cytotoxic effects against tumor cells. The hydrazones and their complexes demonstrated in vitro free radical scavenging activity for reactive oxygen and nitrogen species. Complexes (12) and (13) interact with bovine (BSA) and human serum (HSA), albumin indicating that they could be transported by these proteins.Complexes Cu(Nar)(Fen)(OH2)]22ClO4·2H2O (17) and [Cu(Hsp)(Fen)(OH2)]22ClO4 (18) containing naringenin (Nar) or hesperetin (Hsp ) and 1,10-phenanthroline as co-ligand were synthesized. The EPR spectra of complexes (17-18) in powder suggested formation of binuclear species. However, in DMSO solution the monomeric species should be largely predominant at 37 oC in DMSO/water. The cytotoxic activities of complexes (17) and (18) were evaluated against A549lung adenocarcinoma cells, normal lung fibroblasts (LL-24) and human umbilical vein endothelial cells (HUVEC). Complex (18) exhibited higher cytotoxic activity against A549 cells than complex (17). Both complexes promoted typical apoptotic morphological changes in A549 cells. A549 cells treated with the complexes did not show reduced mitochondrial membrane potential indicating that apoptosis induced bythe complexes is not associated to mitochondrial depolarization. A549 cells treated with the complexes showed reduction of ROS production, indicating that the compounds have antioxidant activity. The two complexes interact with DNA and with BSA and HSA. Thus, these complexes should be investigated as promising antineoplastic drugs candidates for the treatment of human lung adenocarcinoma.In addition, in the present work, 3-formyl-6-methylchromone-phenyl hydrazone (HCrPh, 19) and 3-formyl-6-methylchromone-para-chloro-phenyl hydrazone(HCrpClPh, 20) were also obtained. Hydrazones (19) and (20) did not present antimicrobial activity and showed low cytotoxic activity against on B16-F10 (metastatic melanoma) and Melan-a (nontumorigenic melanocyte) cells. However, upon coordination to silver(I), with formation of [Ag(HCrPh)2]NO32H2O (21) and [Ag(HCrpClPh)2]NO3 (22) improved antifungal activity was observed. Complexes (20)and (21) were more cytotoxic than the free ligands against B16-F10 cells, promoting reduction in cell viability of 25% and 40% respectively. Under the same conditions cisplatin and silver nitrate induced a reduction in cell viability of 11% and 9%, respectively. Hence, complexation of 3-formyl-6-methylchromone derived-hydrazones with silver(I) improves cytotoxic activity against tumor cells. The silver(I) complexes were less active on non-malignant Melan-a cells than cisplatin, indicating that they induced less cell damage in normal cells, which is a very important characteristic of new chemotherapeutic drug candidates. Hence, coordination of the hydrazones to silver(I) constituted an important strategy for increasing cytotoxic activity against solid tumorcells without increasing cytotoxic effects against normal cells. Complex (22) interacts with DNA and with BSA and HSA.