Emel ERGENE, Hülya SİVAS, Kadriye BENKLİ

Biological activities of Cu(II) and Hg(II) complexes of a heptadentate Schiff base ligand

Two metal complexes were synthesized as [Hg(L)](ClO4)2 and [Cu(L)](ClO4)2 by the template reaction between 2,6-bis(2 aminothiophenoxymethyl)pyridine and 2,2'-bipyridine-6,6'-dicarboxaldehyde in the presence of Hg(II) and Cu(II) perchlorate salts. The structures of the compounds were elucidated by IR, 1H-NMR, MASS, and Elemental Analyses values. Cytotoxicity of the compounds were investigated by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay in normal and cancerous rat fibroblasts. Both compounds showed cytotoxicity on 2 cell lines as a dose-dependent manner. Compound [Hg(L)](ClO4)2 was more cytotoxic than [Cu(L)](ClO4)2. Apoptotic activity of compounds was evaluated by acridine orange staining and DNA fragmentation assay. Both cell lines exposed to the compounds exhibited condensed chromatin and appearance of apoptotic bodies. The percentages of all these abnormalities were found to be very high level in ras-transformed 5RP7 fibroblasts. The effect of [Hg(L)](ClO4)2 was again more stronger than the compound [Cu(L)](ClO4)2. Although the compound [Cu(L)](ClO4)2 induced the formation of DNA fragmentation in both cell lines, [Hg(L)](ClO4)2 induced the DNA fragmentation only in cancerous 5RP7 cells, indicating specific activity. In conclusion, we suggest that both complexes, especially the one with Hg(II) according to its significant differences of apoptotic morphology and DNA fragmentation, exhibit promising potentials as anticancer compounds.

Anahtar Kelimeler:

Key words: Metal complexes, apoptosis, DNA fragmentation, cancer cells, MTT

Biological activities of Cu(II) and Hg(II) complexes of a heptadentate Schiff base ligand

Keywords:

Key words: Metal complexes, apoptosis, DNA fragmentation, cancer cells, MTT,

PDF

___

1. Mothilal KK, Karunakaran C, Rajendran A et al. Synthesis, Xray crystal structure, antimicrobial activity and photodynamic effects of some thiabendazole complexes. J Inorg Biochem 98: 322-332, 2004.
2. Agh-Atabay NM, Dulger B, Gucin F. Structural characterization and antimicrobial activity of 1,3-bis(2-benzimidazyl)-2- thiapropane ligand and its Pd(II) and Zn(II) halide complexes. Eur J Med Chem 40: 1096-1102, 2005.
3. Pectasides D, Kamposioras K, Papaxoinis G et al. Chemotherapy for recurrent cervical cancer. Cancer Treat Rev 34: 603-613, 2008.
4. Rosenberg B, VanCamp L, Trosko JE et al. Platinum compounds: A new class of potent antitumour agents. Nature 222: 385-386, 1969.
5. Pasetto LM, D’Andrea MR, Brandes AA et al. The development of platinum compounds and their possible combination. Crit Rev Oncol Hematol 60: 59-75, 2006.
6. Sorenson JRJ. Copper complexes offer a physiological approach to treatment of chronic diseases. Prog Med Chem 26: 437-568, 1989
7. Raptopoulou CP, Paschalidou S, Pantazaki AA et al. Bis(acetate)bis(1-methyl-4,5-diphenylimidazole)copper(II): Preparation, characterization, crystal structure, DNA strand breakage and cytogenetic effect. J Inorg Chem 71: 15-27, 1998.
8. Beynek N, Uluçam G, Ayaz Tuylu B et al. Synthesis, characterization of a new macro cyclic legend and its copper(II), cadmium(II) and lead (II) complexes: Genotoxic activity of these complexes in cultured human lymphocytes. Drug Chem Toxicol 30: 399-410, 2007.
9. Chen SH, Lin JK, Liang YC et al. Involvement of activating transcription factors JNK, NF-kB, and AP-1 in apoptosis induced by pyrrolidine dithiocarbamate/Cu complex. Eur J Pharmacol doi: 10.1016/j.ejphar. 2008.07.024.
10. Easmon J, Pürstinger G, Heinisch G et al. Synthesis, Cytotoxicity, and Antitumor Activity of Copper(II) and Iron(II) Complexes of 4N-Azabicyclo[3.2.2]nonane Thiosemicarbazones Derived from Acyl Diazines. J Med Chem 44: 2164-2171, 2001.
11. Anand N. Sulfonamides and sulfanos. In: Wolff ME, ed. Burger’s Medicinal Chemistry. Wiley Interscience, New York; 1980: pp. 1-40.
12. Constable EC. Complexes and aqueous solution chem. of Hg(II), complexes of Hg(I), organomercury(II) complexes, compounds with Hg-heterometal bonds, and Hg in organic synthesis. Coord Chem Rev 62: 37-83, 1985.
13. Zhao X, Peng-Foo Lee P, Yan Y–K et al. Synthesis, crystal sutructures and cytotoxicities of some transition metal complexes with N-[2-{(pyridine-2-ylmethylidene)amino} ethyl]acetamide. J Inorg Biochem 101: 321-328, 2007.
14. Shrivastav A, Singh NK, Tripathi P et al. Copper(II) and manganese(III) complexes of N’-[(2-hydroxy phenyl)carbonothioyl] pyridine-2-carbohydrazine: novel therapeutic agents for cancer. Biochimie 88: 1209-1216, 2006.
15. Gokhale N, Padhye S, Rathbone D et al. The crystal structure of first copper(II) complex of a pyridine-2-carboxamidrazone – a potential antitumor agent. Inorg Chem Comm 4: 26-29, 2001.
16. Uluçam G, Beynek N, Seller Z et al. Synthesis, characterization of some transition metal complexes of a new heptadentate N5S2 schiff base ligand and the effects of these metal complexes on U2OS cells cytotoxicity and DNA cleavage activity. Phosp Sulf Sil Rel Elem 183: 2237-2247, 2008.
17. Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods 65: 55-63,1983.
18. Evan G, Littlewood T. A Matter of life and cell death. Science 281: 1317-1322, 1998.
19. Agh-Atabay NM, Neshat A, Karabiyik T et al. Synthesis, characterization and antimicrobial activity of Fe(II), Zn(II), Cd(II) and Hg(II) complexes with 2,6-bis(benzimidazol-2-yl) pyridine ligand. Eur J Med Chem 42: 205-213, 2007.