Synthesis, Crystal Structure, Spectroscopic Characterization, DFT Calculations and Cytotoxicity Assays of a New Cu(II) Complex with an Acylhydrazone Ligand Derived from Thiophene

Abstract

A new Cu(II) complex is synthetized by the reaction of copper nitrate and a N-acylhydrazone ligand obtained from the condensation of o-vanillin and 2-thiophecarbohydrazide (H2L). The solid-state structure of [Cu(HL)(H2O)](NO3)·H2O, or CuHL for simplicity, was determined by X-ray diffraction. In the cationic complex, the copper center is in a nearly squared planar environment with the nitrate interacting as a counterion. CuHL was characterized by spectroscopic techniques, including solid-state FTIR, Raman, electron paramagnetic resonance (EPR) and diffuse reflectance and solution UV-Vis electronic spectroscopy. Calculations based on the density functional theory (DFT) assisted the interpretation and assignment of the spectroscopic data. The complex does not show relevant antioxidant activity evaluated by the radical cation of 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) method, being even less active than the free ligand as a radical quencher. Cytotoxicity assays of CuHL against three human tumor cell lines, namely MG-63, A549 and HT-29, revealed an important enhancement of the effectiveness as compared with both the ligand and the free metal ion. Moreover, its cytotoxic effect was remarkably stronger than that of the reference metallodrug cisplatin in all cancer cell lines tested, a promissory result in the search for new metallodrugs of essential transition metals.

Anticancer Activity and Mechanism of Action Evaluation of an Acylhydrazone Cu(II) Complex toward Breast Cancer Cells, Spheroids, and Mammospheres

“…Our previous results showed that CuHL displayed wide anticancer activity over lung, colon and bone cancer cells with IC 50 between 2-7 μM. [27] In another work on related compounds, our results with a copper(II)-ONO acylhydrazone ligand derived from 4-hydroxy-benzohydrazide and o-vanillin showed important anticancer properties on leukemia, lung, breast and bone cancer cells with IC 50 between 5-12 μM. [30] More recent results showed that another copper(II)-hydrazone ligand derived from 4-methoxybenzohydrazide with o-vanillin displayed similar IC 50 values on breast cancer cells.…”

“…This band can be assigned to ligand-to-metal charge transfer (LMCT) transitions according to our previous published results. [27] Upon monitoring this solution with time (0.25, 0.5, 1, 3, 6 and 24 h), no changes were observed in the UV vis signals, and the integrity of the compound in PBS was conserved within the time-frame of the anticancer activity assays. These results suggest that CuHL is stable over time.…”

“…The compound was synthetized from ethanolic solutions of the reactants (H 2 L and copper nitrate) according to the procedure described in our previous work. [27] It was obtained as green crystals of the nitrate salt of the cationic complex and it was fully characterized in solid state and in DMSO solution by different physicochemical techniques.…”

“…We have previously reported the synthesis and physicochemical characterization, including DFT studies, of the 2acetylthiophene-2-hydroxy-3-methoxybenzohydrazone monohydrate [26] and its copper(II) complex, of stoichiometry [Cu(HL)(H 2 O)](NO 3 )•H 2 O [27] (H 2 L and CuHL, respectively, for short). The copper center is coordinated by the deprotonated tridentate ligand (HL À ) and a water molecule, in a nearly squared environment.…”

A Review on the Advancements in the Field of Metal Complexes with Schiff Bases as Antiproliferative Agents

“…Schiff bases, as well as diarylureas [8][9][10], have been defined as "privileged" ligands in organic synthesis, thanks to their affordability, easy synthesis and different biological activities and ability to form complexes with almost all metals [11][12][13]. Actually, they may form complexes with transition metals, platinum group metals (PGM) [14], lanthanides [15,16], and actinides [17,18] and many of them have been extensively described in the literature [19,20]. Metal complexes bearing in the structure a Schiff base are known for their numerous applications and biological activities including antimicrobial [21], antioxidant [22], antitumor [23], antinflammatory [24], and ureases inhibitors [25], and occupy a central role in the development of coordination chemistry [26][27][28].…”