title: Novel metallo-therapeutics of the NSAID naproxen. Interaction with intracellular components that leads the cells to apoptosis.
abstract: Two new mixed ligand-silver(I) complexes of the anti-inflammatory drug naproxen (naprH) and triphenylphosphine (tpp) or tri(p-tolyl)phosphine (tptp) of formulae {[Ag(tpp)3(napr)](H2O)} (1) and [Ag(tptp)2(napr)] (2) have been synthesized and characterized by m.p., vibrational spectroscopy (mid-FT-IR), Raman, (1)H-NMR, UV-Vis, ESI-MS spectroscopic techniques and X-ray crystallography. The complexes show high photo-sensitivity to UVC light. Photolysis of 1-2 was studied and the results showed monotonic degradation of the complexes with simultaneous triarylphosphine oxide formation. The complexes 1-2 were tested for their antiproliferative activity against human breast adenocarcinoma (MCF-7) cells. Complexes 1-2 were more active than cisplatin against cells. UVC light increases the effectiveness of complexes 1-2 on MCF-7 cells by 13% and 38% respectively. Due to the morphology of the MCF-7 cells, which were incubated with the complexes 1-2, the cell death was ascribed to apoptosis. Electrophoresis to genomic DNA of MCF-7 cells confirmed the apoptosis through DNA fragmentation. The binding affinity of 1-2 towards the intracellular molecules CT-DNA and lipoxygenase (LOX) was studied for the evaluation of the mechanism of cell death. Thus, the binding constants (K(b)) of 1-2 towards CT-DNA calculated by UV-Vis spectra are 32.8 ± 8.5 × 10(4) (1) and 4.7 ± 1.8 × 10(4) (2) M(-1), respectively. Changes in fluorescent emission light of ethidium bromide (EB) in the presence of DNA suggest intercalation or electrostatic interactions into DNA of both complexes 1-2 in the minor groove. The corresponding apparent binding constants (K(app)) of 1-2 towards CT-DNA calculated through fluorescence spectra are 2.9 ± 0.3 × 10(4) (1) and 1.6 ± 0.4 × 10(4) (2) M(-1) respectively. Docking studies on DNA-complexes interactions show the binding of 1 in the major groove and the corresponding one of 2 in the minor one. Moreover, the influence of complexes 1-2 on the catalytic peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX) was kinetically and theoretically studied. Only 1 inhibits lipoxygenase activity (IC50 = 5.1 (1), >30 (2) μM).
authors.affiliation: Section of Inorganic and Analytical Chemistry, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece. shadjika@uoi.gr.
authors.forename: C N
authors.initials: CN
authors.lastname: Banti
authors.forename: A D
authors.initials: AD
authors.lastname: Giannoulis
authors.forename: N
authors.initials: N
authors.lastname: Kourkoumelis
authors.forename: A M
authors.initials: AM
authors.lastname: Owczarzak
authors.forename: M
authors.initials: M
authors.lastname: Kubicki
authors.forename: S K
authors.initials: SK
authors.lastname: Hadjikakou
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation / Q000379:methods; D009288:Naproxen / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D012834:Silver / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D012834:Silver; D009288:Naproxen