title: A novel silver iodide metalo-drug: experimental and computational modelling assessment of its interaction with intracellular DNA, lipoxygenase and glutathione.
abstract: The new mixed ligand silver(I) complex of formula [AgI(TPP)2(MBZT)] (1) was obtained by reacting 2-mercapto-benzothiazole (MBZT) with triphenylphosphine (TPP). The complex was characterized by m.p., vibrational spectroscopy (FT-IR), (1)H NMR, UV-vis, ESI-MS spectroscopic techniques and its structure was confirmed by X-ray crystallography. Mixed ligand complexes of silver(I) iodide with thiones and phosphines are very rare in the literature and to the best of our knowledge compound 1 is the first of this kind exhibiting significant biological effects. Complex 1 was evaluated for its in vitro cytotoxic activity (cell viability) under irradiation with UV light and without irradiation against human cancer cell lines: MCF-7 (breast, ER positive), MDA-MB-231 (breast, ER negative), Caki-1 (renal), A549 (lung), OAW-42 (ovarian), HeLa (cervical) and additionally against the normal human lung cell line MRC-5 (normal human fetal lung fibroblast cells) and normal immortalized human mammary gland epithelial cell line (MTSV17) with SRB assay. The results showed that 1 mediates a strong cytotoxic response to the tested normal and cancer cell lines. It exhibits equal activity against MDA-MB-231 cells where estrogen receptors (ERs) are devoid with the one against MCF-7 where ERs are present. Molecular docking studies have shown that 1 is docked in the different pocket than that of the ERs modulators. The binding affinity of 1 towards the intracellular molecules DNA and lipoxygenase (LOX) was studied for the evaluation of the mechanism of its cytostasis. The binding constant (Kb) of 1 towards CT-DNA was calculated by UV-Vis and fluorescent spectra suggesting intercalation or electrostatic interactions of 1 into DNA. Docking studies on DNA-complex interactions confirm the binding of 1. Moreover, the influence of complex 1 on the catalytic peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX) was kinetically and theoretically studied. In addition, since the deactivation of cisplatin caused by glutathione, seems to be an important determinant of its cytotoxic effects, the reaction of 1 with glutathione (GSH) was investigated by UV-absorption spectroscopy.
authors.affiliation: Section of Inorganic and Analytical Chemistry, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece.
authors.forename: C N
authors.initials: CN
authors.lastname: Banti
authors.affiliation: Section of Inorganic and Analytical Chemistry, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece.
authors.forename: L
authors.initials: L
authors.lastname: Kyros
authors.affiliation: Cell Culture, Molecular Modeling and Drug Design Lab., Symeonidion Research Center, Theagenion Cancer Hospital, Thessaloniki, Greece.
authors.forename: G D
authors.initials: GD
authors.lastname: Geromichalos
authors.affiliation: Medical Physics Laboratory, Medical School, University of Ioannina, Greece.
authors.forename: N
authors.initials: N
authors.lastname: Kourkoumelis
authors.affiliation: Department of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznań, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Kubicki
authors.affiliation: Section of Inorganic and Analytical Chemistry, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece. Electronic address: shadjika@uoi.gr.
authors.forename: S K
authors.initials: SK
authors.lastname: Hadjikakou
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000737:chemistry* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007454:Iodides / Q000737:chemistry*; D019787:Linoleic Acid / Q000737:chemistry / Q000378:metabolism; D008084:Lipoxygenase / Q000737:chemistry* / Q000378:metabolism; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018030:Silver Compounds / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014466:Ultraviolet Rays
chemical_list: D000970:Antineoplastic Agents; D007454:Iodides; D009942:Organometallic Compounds; D018030:Silver Compounds; C030584:silver iodide; D004247:DNA; D019787:Linoleic Acid; D008084:Lipoxygenase; D005978:Glutathione
keywords: CT-DNA; Glutathione; Lipoxygenase; Molecular modeling; Novel metallo-drugs; Silver(I) complexes