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

Abstract

Very 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 H 3 L1 and its complex, 1, possess a thiophene ring, H 3 L2 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 [Cu 2 (HL)(OH)] + and the DMSO-substituted derivative [Cu 2 (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.

Isoxazole‐Derived Aroylhydrazones and Their Dinuclear Copper(II) Complexes Show Antiproliferative Activity on Breast Cancer Cells with a Potentially Alternative Mechanism Of Action

“…The K b constants for 1-4 are comparable to those reported for other copper(II) complexes. [40][41][42] The calculated K b values for the ligands and complexes were smaller than the binding constant of the conventional DNA intercalator ethidium bromide, EB (in the order of~10 5 M À 1 ). [43] Both ligands presented an emission band at 530 nm for H 3 L1 and 503 nm for H 2 L2 upon excitation at 350 nm).…”

“…We have shown in a previous study that dinuclear copper(II) complexes with hydrazonic ligands display very promising activities on the triple negative breast cancer cell line MDA-MB-231. [28] To confirm this trend, cytotoxicity evaluations in the present study were carried out only on this cancer cell line. Cells were incubated with medium containing different concentrations of each ligand or copper(II) complex during a period of 72 h. Cytotoxicity was evaluated as the ability of the compounds to inhibit cell growth using the MTT assay.…”

“…[39] Moreover, ligands H 3 L1 and H 2 L2 showed a higher DNA affinity than our previously reported HBPAMFF-aroylhydrazone ligands containing non-coordinating furan or thiophene groups. [28] Thus the presence of the planar isoxazole fragment clearly increases the affinity for ct-DNA. The K b constants for 1-4 are comparable to those reported for other copper(II) complexes.…”

“…Not only the complexes, but the free ligands as well, displayed high cytotoxic activity on a board of cancer cell lines. [28] Herein, we wish to report two new unsymmetrical binucleating ligands, namely, H 3 L1 and H 2 L2, for which an isoxazole group was appended to the aroylhydrazone moiety. Indeed, isoxazoles and hydrazones are very useful pharmacophores and have become popular in the design of potent new drugs, including anticancer drugs.…”

Physico-Chemical Optimization and Structure-Activity Relationship Studies of Aldehyde-Derived N-Acylhydrazones: Towards the Improvement of Moderate Metal Chelators as a Strategy Against Metal-Enhanced Aggregopathies

“…This chelating power is exploited in a wide spectrum of pharmacological applications. Hydrazones are commonly associated with a number of biological uses (Thota et al, 2018), such as analgesics (Lima et al, 2000), antihypertensives, anticonvulsants, anti-inflammatories (Kajal et al, 2014), anti-tuberculosis agents, antitumor agents (El-Hawash et al, 2006;Vicini et al, 2006;Rada et al, 2019;Rada et al, 2020), antiretrovirals (Savini et al, 2004;Vicini et al, 2009), antimalarials, antidepressants and vasodilators (Silva et al, 2005).…”