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

Abstract

The bis-(1,10-phenanthroline)copper(I) complex, [Cu(I)(phen)], was the first copper-based artificial nuclease reported in the literature. The biological and ligand-like properties of sulfonamides make them good candidates for fine-tuning the reactivity of the [Cu(phen)] motif with biomolecules. In this context, we developed three novel copper(II) complexes containing the sulfonamides sulfameter (smtrH) and sulfadimethoxine (sdmxH) and (N^N)-bidentate ligands (2,2'-biyridine or 1,10-phenantroline). The compounds were characterized by chemical and spectroscopic techniques and single-crystal X-ray crystallography. When targeting plasmid DNA, the phen-containing compounds [Cu(smtr)(phen)] (1) and [Cu(sdmx)(phen)] (2) demonstrated nuclease activity even in the absence of reducing agents. Addition of ascorbic acid resulted in a complete cleavage of DNA by 1 and 2 at concentrations higher than 10 μM. Experiments designed to evaluate the copper intermediates involved in the nuclease effect after reaction with ascorbic acid identified at least the [Cu(I)(N^N)], [Cu(I)(sulfa)(N^N)] and [Cu(I)(sulfa)] species. The compounds interact with DNA via groove binding and intercalation as verified by fluorescence spectroscopy, circular dichroism (CD) and molecular docking. The magnitude and preferred mode of binding are dependent on the nature of both N^N ligand and the sulfonamide. The potent nuclease activity of compounds 1 and 2 are well correlated with their antiproliferative and anti-M. tuberculosis profiles. The results presented here demonstrated the potential for further development of copper(II)-sulfonamide-(N^N) complexes as multipurpose metallodrugs.

Copper(II) Complexes with Mixed Heterocycle Ligands as Promising Antibacterial and Antitumor Species

“…In a separate line of research, it was found that copper(II) complexes with N-N-chelating heterocycle and sulfonamide antibiotics were active against Mycobacterium tuberculosis [ 21 ] and Pseudomonas aeruginosa [ 22 ] strains. In addition, complexes with phen and quinolone antibiotics [ 23 , 24 ] proved to be active on various Escherichia coli strains, showing promising potential for the development of effective antimicrobials against antibiotic-resistant strains.…”

Metal–Peptide Complexes as Promising Antibiotics to Fight Emerging Drug Resistance: New Perspectives in Tuberculosis

“…Sulfonamide copper complexes presented antibacterial activity; their general formula is as follows: [Cu(sulfa − ) 2 (NˆN)], where sulfa is the anionic form of a sulfonamide ligand (sulfameter (mtrH) or sulfadimethoxine (sdmx)) and NˆN is bipy or phen; they exhibit different geometry and oligomeric state depending on ligand hindrance and demonstrated the ability to bind DNA [112] and good anti-Mtb activity in the micromolar range [113].…”

Nuclease-like metalloscissors: Biomimetic candidates for cancer and bacterial and viral infections therapy

“…Metal complexes possess rich structural and electronic properties as well as redox-active centers which enable them to cleave nucleic acids through hydrolysis [27] , [28] and/or by generating reactive oxygen species (ROS) (oxidative cleavage and photocleavage) [29] , [30] , [31] , [32] , [33] . A rich library of DNA/RNA–cleaving metal complexes have been prepared and submitted to pharma studies as novel therapeutic candidates for the treatment of diseases such as cancer [13] , [14] , [34] , [35] , [36] , [37] , [38] , [39] , bacterial [13] , [14] , [39] , [40] , [41] , [42] , [43] , [44] , [45] and viral infections [13] , [14] , [46] , [47] , [48] , [49] , and gene therapy [50] , [51] . Moreover, metal complexes are considered as suitable photosensitizers for photodynamic therapy (PDT) of cancer and microbial infections due to their efficient in vitro DNA photocleavage [52] , [53] , [54] , [55] .…”