Novel metformin Schiff base complexes: Synthesis, characterization and investigation of their anti-cancer properties

Cis-platin is one of the most preferred anti-carcinogenic chemotherapy agents used since 1978 and is a well-known coordination compound. However, the disadvantages of cis-platin have led research in cancer treatment to focus on new coordination compounds. Metformin is a derivative of biguanidine and has been used against insulin resistance in type 2 diabetesfor many years. In anti-cancer studies on metformin, it has been among the topics studied in the literature for many years. In the presented thesis, it was aimed to prepare Schiff base metal compounds of metformin as new potential anti-cancer agents. New chelating multi-toothed ligands have been synthesed using different starting materials, complexed with different metal salts, characterized and determed the anti-cancer effects in breast cancer. In the first step, metformin was reacted with 4,4′-methylenebis (2-hydroxybenzaldehyde) and 3-methoxy salicylaldehyde (ortho-vanillin) respectively for preparing (E, E) -1, 1 ′ (methylenebis (2-hydroxy-) 5, 1-phenylene)) bis (methanylidene) bis (N, N- dimethylbiguanidine) [Met-Da] and (E)-2-(6- (dimethylamino)-4 ((2-hydroxy-3- methoxybenzylidene) amino)-1, 6-dihydroxy-1, 3, 5 triazin-2 -yl)-6-methoxyphenol [Met-Ov] as new type chelating polydentate Schiff base ligands . Chloride salts of Cu (II), Pd (II) and Ni (II) ions were used in the preparation of the complexes. The prepared ligands and the structure of their metal complexes were characterized molecularly using FT-IR, 1H-NMR, 13C-NMR, mass spectrometry and elemental analysis data. Anti-cancer effects of metformin-containing ligands and related complexes were determined in MCF-7 human breast cancer and HUVEC in human umbilical vein endothelial cells. In the in vitro studies, WST-1 analysis and Acridine orange staining methods were used to determine cell viability and apoptotic effect, respectively. Metformin Schiff base ligands were synthesized with high yields under mild reaction conditions. Metal-chelat complexes with d8 and d9 electronic configurations, which are prone to form a square plane structure from 1st and 2nd order transition metals, and anti-cancer properties targeted by ions, were prepared with sufficient their efficiency. Obtained experimental data showed that newly synthesized ligands and Cu, Pd, Ni complexes have cytotoxic and apoptotic effects on MCF-7 cells. In addition, it has been observed that metal complexes are more effective in MCF-7 cells than Schiff bases and cause apoptotic death by causing DNA damage.