ABSTRACT
Two novel unsymmetrical binucleating aroylhydrazonic ligands and four dicopper(II) complexes carrying fluorescent benzopyranothiophene (BPT) or boron dipyrromethene (BODIPY) entities were synthesized and fully characterized. Complex 1, derived from the BPT-containing ligand H3L1, had its crystal structure elucidated through X-ray diffraction measurements. The absorption and fluorescence profiles of all the compounds obtained were discussed. Additionally, the stability of the ligands and complexes was monitored by UV-vis spectroscopy in DMSO and biologically relevant media. All the compounds showed moderate to high cytotoxicity towards the triple negative human breast cancer cell line MDA-MB-231. BPT derivatives were the most cytotoxic, specially H3L1, reaching an IC50 value up to the nanomolar range. Finally, fluorescence microscopy imaging studies employing mitochondria- and nucleus-staining dyes showed that the BODIPY-carrying ligand H3L2 was highly cell permeant and suggested that the compound preferentially accumulates in the mitochondria.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Boron Compounds/chemistry , Copper/chemistry , Thiophenes/pharmacology , Antineoplastic Agents/metabolism , Cell Line, Tumor , Female , Humans , Microscopy, Fluorescence , Molecular Structure , Thiophenes/chemistry , Triple Negative Breast NeoplasmsABSTRACT
This paper reports the design, synthesis and cytotoxicity studies of two new isoxazole-derived aroylhydrazone ligands and their dinuclear copper(II) complexes. Compounds were fully characterized by various spectroscopic and analytical techniques. The molecular structures of four derivatives were confirmed by X-ray crystallography. The stability of the ligands and the complexes in aqueous medium was monitored spectroscopically. Both the ligands and the complexes were shown to interact with calf thymus DNA (ct-DNA). Additionally, structures containing a phenol pendant arm were significantly more cytotoxic than those carrying a pendant pyridine substituent, reaching sub-micromolar IC50 values on the triple-negative human breast cancer cell line MDA-MB-231. The metal chelation and transchelation ability of the compounds towards FeII , FeIII and ZnII ions was explored as a possible mechanism of action of these compounds.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Coordination Complexes/pharmacology , Copper/pharmacology , Hydrazones/pharmacology , Isoxazoles/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Breast Neoplasms/pathology , Cattle , Cell Proliferation/drug effects , Cell Survival/drug effects , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Copper/chemistry , Crystallography, X-Ray , DNA/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Humans , Hydrazones/chemistry , Isoxazoles/chemistry , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
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 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.
