Binucleating Hydrazonic Ligands and Their μ-Hydroxodicopper(II) Complexes as Promising Structural Motifs for Enhanced Antitumor Activity

RADA, JESICA PAOLA; BASTOS, BEATRIZ S. M.; ANSELMINO, LUCIANO; FRANCO, CHRIS H. J.; LANZNASTER, MAURICIO; DINIZ, RENATA; FERNÁNDEZ, CLAUDIO O.; MENACHO-MÁRQUEZ, MAURICIO; PERCEBOM, ANA MARIA; REY, NICOLÁS A.

INORGANIC CHEMISTRY

AMER CHEMICAL SOC

Año: 2019 vol. 58 p. 8800 - 8819

0020-1669

Very few inorganic antineoplastic drugs haveentered the clinic in the last decades, mainly because oftoxicity issues. Because copper is an essential trace element ofubiquitous occurrence, decreased side effects could beexpected in comparison with the widely used platinumanticancer compounds. In the present work, two novelhydrazonic binucleating ligands and their μ-hydroxo dicopper-(II) complexes were prepared and fully characterized. Theydiffer by the nature of the aromatic group present in theiraroylhydrazone moieties: while H3L1 and its complex, 1,possess a thiophene ring, H3L2 and 2 contain the more polar furan heterocycle. X-ray diffraction indicates that bothcoordination compounds are very similar in structural terms and generate dimeric arrangements in the solid state. Positive-ionelectrospray ionization mass spectrometry analyses confirmed that the main species present in a 10% dimethyl sulfoxide(DMSO)/water solution should be [Cu2(HL)(OH)]+ and the DMSO-substituted derivative [Cu2(L)(DMSO)]+. Scatteringtechniques [dynamic light scattering (DLS) and small-angle X-ray scattering] suggest that the complexes and their free ligandsinteract with bovine serum albumin (BSA) in a reversible manner. The binding constants to BSA were determined for thecomplexes through fluorescence spectroscopy. Moreover, to gain insight into the mechanism of action of the compounds, calfthymus DNA binding studies by UV−visible and DLS measurements using plasmid pBR322 DNA were also performed. For thecomplexes, DLS data seem to point to the occurrence of DNA cleavage to Form III (linear). Both ligands and their dicopper(II)complexes display potent antiproliferative activity in a panel of four cancer cell lines, occasionally even in the submicromolarrange, with the complexes being more potent than the free ligands. Our data on cellular models correlate quite well with theDNA interaction experiments. The results presented herein show that aroylhydrazone-derived binucleating ligands, as well astheir dinuclear μ-hydroxodicopper(II) complexes, may represent a promising structural starting point for the development of anew generation of highly active potential antitumor agents.