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Nimesulide Silver Metallodrugs, Containing the Mitochondriotropic, Triaryl Derivatives of Pnictogen; Anticancer Activity against Human Breast Cancer Cells

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posted on 11.08.2016, 00:00 by Christina N. Banti, Constantina Papatriantafyllopoulou, Maria Manoli, Anastasios J. Tasiopoulos, Sotiris K. Hadjikakou
Novel silver­(I) metallo-drugs of the nonsteroidal anti-inflammatory drug nimesulide (nim) and the mitochondriotropic triaryl derivatives of pnictogen ligands (tpE, E = P (tpp, tptp, or totp), As (tpAs), Sb (tpSb)) with the formulas {[Ag­(nim) (tpp)2]­DMF} (1), [Ag­(nim) (tptp)2] (2), [Ag­(nim) (totp)] (3), [Ag­(nim) (tpAs)2] (4), and [Ag­(nim) (tpSb)3] (5) ((tpp = triphenyphosphine, tptp = tri­(p-tolyl)­phosphine, totp = tri­(o-tolyl)­phosphine, tpAs = triphenylarsine, tpSb = triphenylantimony, and DMF = dimethylformamide) were synthesized and characterized by melting point, vibrational spectroscopy (mid-Fourier transform IR), 1H NMR, UV–visible spectroscopic techniques, and X-ray crystallography. The in vitro cytotoxic activity of 15 against human breast adenocarcinoma cancer cell lines: MCF-7 (estrogen receptor (ER) positive) and MDA-MB-231 (ER negative) was determined. The genotoxicity on normal human fetal lung fibroblast cells (MRC-5) caused by 15 was evaluated by fluorescence microscopy. The absence of micronucleus in MRC-5 cells confirms the in vitro non toxicity behavior of the compounds. Because of the morphology of the cells, an apoptotic pathway was concluded for the cell death. The apoptotic pathway, especially though the mitochondrion damage, was confirmed by DNA fragmentation, cell cycle arrest, and permeabilization of the mitochondrial membrane tests. The molecular mechanism of action of 15 was further studied by (i) the binding affinity of 15 toward the calf thymus (CT) DNA, (ii) the inhibitory activity of 15 against lipoxygenase (an enzyme that oxidizes polyunsaturated fatty acids to leukotrienes or prostaglandins), and (iii) the catalytic activity of 15 on the oxidation of linoleic acid (an acid that partakes in membrane fluidity, membrane enzyme activities, etc.) to hyperoxolinoleic acid by oxygen.

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