A novel silver iodide metalo-drug: Experimental and computational modelling assessment of its interaction with intracellular DNA, lipoxygenase and glutathione

作者：Banti C N; Kyros L; Geromichalos G D; Kourkoumelis N; Kubicki M; Hadjikakou S K^*

来源：European Journal of Medicinal Chemistry, 2014, 77(2): 388-399.

DOI：10.1016/j.ejmech.2014.03.028

• Novel metallo-drugs
• Silver(l) complexes
• CT-DNA
• Lipoxygenase
• Glutathione
• Molecular modeling

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), H-1 NMR, UV-vis, ESI-MS spectroscopic techniques and its structure was confirmed by X-ray crystallography. Mixed ligand complexes of silver(l) 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. %26lt;br%26gt;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 (K-b) 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 I. Moreover, the influence of complex I 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.

• 出版日期2014-4