Mixed-ligand copper(ii)–sulfonamide complexes: effect of the sulfonamide derivative on DNA binding, DNA cleavage, genotoxicity and anticancer activity

Abstract

Four ternary complexes, [Cu(L1)2(bipy)] (1) [HL1 = N-(6-chlorobenzo[d]thiazol-2-yl)-4-methylbenzenesulfonamide], [Cu(L2)2(bipy)] (2) [HL2 = N-(benzo[d]thiazol-2-yl)-4-methylbenzenesulfonamide], [Cu(L3)2(bipy)]·1/2H2O (3) [HL3 = N-(5,6-dimethylbenzo[d]thiazol-2-yl)-4-methylbenzenesulfonamide] and [Cu(L4)2(bipy)] (4) [HL4 = N-(5,6-dimethylbenzo[d]thiazol-2-yl)benzenesulfonamide], were prepared and then characterized by X-ray crystallography, spectroscopy and magnetic measurements. Whereas the molecular structure of 1 and 2 consists of a discrete monomeric copper(II) species with a distorted square planar geometry, that of 3 and 4 consists of two independent molecules. In 3, both molecules present a different coordination geometry (distorted square planar and distorted square pyramidal) while in 4 they have an identical coordination environment (distorted square planar). The propensity for binding of 1-4 to calf thymus DNA was studied by thermal denaturation, viscosimetry, and fluorescence measurements. Results indicated that the N-sulfonamide derivative plays an important role in governing the type of interaction with DNA. The ability of the complexes to cleave DNA was studied in vitro with ascorbate activation and was tested by monitoring the expression of the yEGFP gene containing the RAD54 reporter. Moreover, their antiproliferative activity was verified in two cellular models: yeast and human tumor cells in culture. Their DNA cleavage efficiency at the cellular level was found to be: 1 < 3 ~ 4 < 2. The higher propensity of 2 for inflicting DNA damage was related with its higher binding affinity to DNA. The biological studies carried out with human tumor cells, colon adenocarcinoma Caco-2 cells and leukemia Jurkat T lymphocytes confirmed that the compounds produce cell death mainly by apoptosis, the complex 2 being the most effective.

A Useful Route to Metal Complexes of Poorly Coordinating Sulfonamides

“…Among the different classes of sulfonamide drugs, those with nuclease and/or cytotoxic activity are receiving increasing attention in the search for anticancer chemotherapeutic strategies. [9][10][11][12][13] Over recent years, the conformational preferences of sulfonamides have been actively exploited in drug design, as the conformation defines the shape of the molecule, which in turn is a major determinant of its biological and physical properties. [14,15] Many structural studies have been performed on N-tosylsubstituted Schiff bases, because the rigidity of the sulfonamide functional group typically favours crystallisation.…”

Synthesis, CMC determination, and intercalative binding interaction with nucleic acid of a surfactant–copper(II) complex with modified phenanthroline ligand (dpq)

“…This may suggest that conjugation of biologically active peptides with quinoxaline analogs can lead to new therapeutic agents possessing interesting anticancer properties (Ambika et al, 2013;Staszewska, Stefanowicz, & Szewczuk, 2005). In addition, quinoxaline derivatives are reported for their applications in dyes, efficient electroluminescent materials, organic semiconductors, and DNA cleaving agents (González-Álvarez et al, 2013;Srinivas, Kumar, Rao, & Palaniappan, 2008). Surfactants, sometimes called surface-active agents or detergents, are among the most versatile chemicals available.…”

Sulfonamide-containing copper(II) metallonucleases: Correlations with in vitro antimycobacterial and antiproliferative activities

“…González-Álvarez et al, for example, reported copper(II)-bpy complexes with thiazol-sulfonamide derivatives with nuclease activities that correlated with their cytotoxicity on the low micromolar range against human Jurkat T lymphocytes and Caco-2 cell lines. The complexes induced cell death by an apoptotic mechanism [10]. The same research group reported copper complexes of N-substituted sulfonamides that presented DNA photocleavage and remarkable cytotoxicity on sub-micromolar range against Caco-2 cell lines [25].…”

“…Since the introduction of [Cu(phen) 2 ] 2+ , much effort has been dedicated to the development of novel artificial metallonucleases, since metal complexes are endowed with several properties that can be explored to fine-tune the desired nuclease activity. This includes the number and nature of the ligands, structural diversity and electronic properties [5,7,10]. For reviews of artificial copper metallonucleases, the reader is directed to the works of McGivern et al [7] and Pratviel et al [11].…”