title: Mixed ligand-silver(I) complexes with anti-inflammatory agents which can bind to lipoxygenase and calf-thymus DNA, modulating their function and inducing apoptosis.
abstract: A new mixed ligand-silver(I) complex of formula [Ag(tpp)(2)(p-Hbza)] (1) (p-HbzaH = 4-hydroxybenzoic acid and tpp = triphenylphosphine) has been synthesized and characterized by elemental analysis, mp, vibrational spectroscopy (mid- and far-FT-IR), (1)H-NMR, UV-vis, ESI-MS spectroscopic techniques and X-ray crystallography. Complex 1 and the already known mixed ligand-silver(I) complexes of formulae [Ag(tpp)(2)(salH)] (2) (salH(2) = salicylic acid or 2-hydroxy-benzoic acid) and {[Ag(tpp)(3)(asp)](dmf)} (3) (aspH = o-acetylsalicylic acid) were used for the clarification of the cytostatic activity mechanism. Thus, 1-3 were tested for their in vitro cytotoxic activity against leiomyosarcoma (LMS) and human breast adenocarcinoma (MCF-7) cells with trypan blue and Thiazolyl Blue Tetrazolium Bromide (MTT) assays. For both cell lines, complexes 1-3 were found to be more active than cisplatin. Due to the morphology of the LMS cells after incubation with 1-3, the type of cell death was evaluated by flow cytometry assay and DNA fragmentation. The results show that LMS cells undergo programmed cell death (apoptosis). DNA binding tests indicate the ability of complexes 1-3 to modify the activity of the cells. The binding constants of 1-3 towards calf-thymus DNA (CT-DNA) ((27.7 ± 7.9) × 10(4) (1), (13.3 ± 6.5) × 10(4) (2) and (11 ± 2.8) × 10(4) (3) M(-1)) indicate strong interaction. Moreover, the influence of complexes 1-3 on the catalytic peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX) was kinetically studied. Finally, docking studies on DNA binding interactions were performed.
authors.affiliation: Inorganic and Analytical Chemistry, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece.
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: Poyraz
authors.forename: M
authors.initials: M
authors.lastname: Kubicki
authors.forename: K
authors.initials: K
authors.lastname: Charalabopoulos
authors.forename: S K
authors.initials: SK
authors.lastname: Hadjikakou
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D002417:Cattle; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007700:Kinetics; D019787:Linoleic Acid / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008084:Lipoxygenase / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D008958:Models, Molecular; D009943:Organophosphorus Compounds / Q000737:chemistry; D010226:Parabens / Q000737:chemistry; D011485:Protein Binding; D012834:Silver / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D056831:Coordination Complexes; D009943:Organophosphorus Compounds; D010226:Parabens; C061896:triphenylphosphine; D012834:Silver; D004247:DNA; C427203:calf thymus DNA; D019787:Linoleic Acid; D008084:Lipoxygenase; C038193:4-hydroxybenzoic acid