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

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 1–5 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 1–5 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 1–5 was further studied by (i) the binding affinity of 1–5 toward the calf thymus (CT) DNA, (ii)
the inhibitory activity of 1–5 against
lipoxygenase (an enzyme that oxidizes polyunsaturated fatty acids
to leukotrienes or prostaglandins), and (iii) the catalytic activity
of 1–5 on the oxidation of linoleic
acid (an acid that partakes in membrane fluidity, membrane enzyme
activities, etc.) to hyperoxolinoleic acid by oxygen.