Author(s): Nakahata, Douglas H. ; de Paiva, Raphael E.F. ; Lustri, Wilton R. ; Ribeiro, Camila M. [UNESP] ; Pavan, Fernando R. [UNESP] ; da Silva, Gisele G. ; Ruiz, Ana L.T.G. ; de Carvalho, João E. ; Corbi, Pedro P.
Date: 2018
Persistent ID: http://hdl.handle.net/11449/180073
Origin: Oasisbr
Subject(s): Anti-M. tuberculosis activity; Antiproliferative activity; Copper(II); Metallonucleases; Sulfonamides
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Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
The bis-(1,10-phenanthroline)copper(I) complex, [Cu(I)(phen)2]+, 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)2] 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−)2(phen)] (1) and [Cu(sdmx−)2(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)2]+, [Cu(I)(sulfa)(N^N)]+ and [Cu(I)(sulfa)2]+ 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.
Institute of Chemistry University of Campinas UNICAMP
Biological and Health Sciences Department University of Araraquara UNIARA
School of Pharmaceutical Sciences São Paulo State University UNESP
Faculty of Pharmaceutical Sciences University of Campinas UNICAMP
Chemical Biological and Agricultural Pluridisciplinary Research Center (CPQBA) University of Campinas – UNICAMP
Department of Physiological Sciences Piracicaba Dental School University of Campinas UNICAMP
School of Pharmaceutical Sciences São Paulo State University UNESP
CNPq: 140466/2014-2
FAPESP: 2015/09833-0
FAPESP: 2015/20882-3
FAPESP: 2015/25114-4
CNPq: 442123/2014-0
