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Binucleating Hydrazonic Ligands and Their μ‑Hydroxodicopper(II) Complexes as Promising Structural Motifs for Enhanced Antitumor Activity
journal contribution
posted on 2019-06-17, 00:00 authored by Jesica
Paola Rada, Beatriz S. M. Bastos, Luciano Anselmino, Chris H. J. Franco, Mauricio Lanznaster, Renata Diniz, Claudio O. Fernández, Mauricio Menacho-Márquez, Ana Maria Percebom, Nicolás A. ReyVery few inorganic
antineoplastic drugs have entered the clinic
in the last decades, mainly because of toxicity issues. Because copper
is an essential trace element of ubiquitous occurrence, decreased
side effects could be expected in comparison with the widely used
platinum anticancer compounds. In the present work, two novel hydrazonic
binucleating ligands and their μ-hydroxo dicopper(II) complexes
were prepared and fully characterized. They differ by the nature of
the aromatic group present in their aroylhydrazone 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 both coordination compounds
are very similar in structural terms and generate dimeric arrangements
in the solid state. Positive-ion electrospray 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)]+. Scattering techniques [dynamic light scattering (DLS) and
small-angle X-ray scattering] suggest that the complexes and their
free ligands interact with bovine serum albumin (BSA) in a reversible
manner. The binding constants to BSA were determined for the complexes
through fluorescence spectroscopy. Moreover, to gain insight into
the mechanism of action of the compounds, calf thymus DNA binding
studies by UV–visible and DLS measurements using plasmid pBR322
DNA were also performed. For the complexes, 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 submicromolar range, with the complexes being more potent than
the free ligands. Our data on cellular models correlate quite well
with the DNA interaction experiments. The results presented herein
show that aroylhydrazone-derived binucleating ligands, as well as
their dinuclear μ-hydroxodicopper(II) complexes, may represent
a promising structural starting point for the development of a new
generation of highly active potential antitumor agents.
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Keywords
Positive-ion electrospray ionization mass spectrometry analysesIIIDLSH 3 L 1H 3 L 2HLplasmid pBR 322 DNAEnhanced Antitumor ActivityCu 2cancer cell linesDNA interaction experimentsBinucleating Hydrazonic LigandsBSAUVplatinum anticancer compoundsnovel hydrazonic binucleating ligandsPromising Structural Motifscomplexcalf thymus DNA binding studiesaroylhydrazone-derived binucleating ligandsDMSO
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