Journal:JBIC:25

Synthesis, characterization and binding properties towards CT-DNA and Lipoxygenase, of mixed ligand silver(I) complexes with 2-mercapto-thiazole and its derivatives and triphenylphosphine.

L. Kyros, C.N. Banti, N. Kourkoumelis, M. Kubicki, I. Sainis and S.K. Hadjikakou ^[1]

Molecular Tour
Silver has been recognized as an effective antimicrobial agent, specifically in the form of silver nitrate since 17th and 18th centuries. It has also been used in the treatment of chronic skin ulcers, open wounds, and suppurating wounds. Nowadays, silver sulfadiazine remains one of the most effective and widely used topical burn treatments. The astringent properties of silver against a wide range of bacteria were recognized and although the cytotoxic effects of silver against Gram-positive and Gram-negative bacteria have long been established, the exact mechanisms of action are not completely understood. It has been reported that silver-treated bacterial cells exhibited a region in their cytoplasm with condensed DNA molecules. Condensed DNA molecules lose their ability to replicate. Another mechanism was proposed, suggesting that the silver moiety in silver sulfadiazine is dissociated from sulfadiazine and bounds to components within the cell. The subsequent inhibition of bacterial growth would be due to the amount of silver bound to bacterial DNA. Recently, the antitumor activity of silver(I) ions has been attributed to their interaction with nucleic acids, preferentially with the bases in DNA rather than with the phosphate groups. is an enzyme that takes part in the metabolism of arachidonic acid. LOX catalyzes the oxidation of arachidonic acid to leukotrienes, in an essential mechanism for the cell life. Prostaglandines the final products formed from the metabolism of arachidonic acid contribute to tumorigenesis as angiogenetic factors. Studies have shown that LOX inhibitors induce the release of cytochrome c from mitochondria into the cytosol causing apoptosis through the mitochondrial pathway both in vivo and in vitro. The literature data on bacterial lipoxygenases are extremely limited, since these enzymes have only recently been found in prokaryotes (e.g. Pseudomonas aeruginosa). No bacterial lipoxygenases are detected in Escherichia coli. A possible biological role of lipoxygenases is to facilitate the dynamic plasticity of membranes in bacteria. We are interested in the development of new metallotherapeutics which would be able to overcome the cell resistance while still interacting with intracellular components and leading to cell death. In this study, we have synthesized and evaluated three novel silver(I) chloride complexes with triphenylphosphine and the heterocyclic thioamides: 2-mercapto-thiazolidine, 2-mercapto-benzothiazole and 5-chloro-2-mercapto-benzothiazole.

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• . Intramolecular hydrogen bonds is shown as a dashed line. For clarity, other components of the crystal structure (free ligand and solvent molecules) are not shown.

DNA binding tests indicate the ability of the complexes to modify the activity of the cells. The binding constants towards calf-thymus DNA indicate strong interaction while changes in fluorescent emission light of Ethidium bromide (EtBr) in the presence of DNA suggest intercalation or electrostatic interactions with DNA. . Complexes probably act through interaction with DNA rather than interfering with LOX enzyme.