Synthesis, characterization, and toxicity studies of a (4,0) diruthenium(III,II) complex.

摘要

Cisplatin, a successful transition metal based drug used in chemotherapy for more than three decades. However, development of resistance in some solid tumor cells, and adverse side effects provoked researchers to look for alternative to cisplatin, based on other transition metals. Ruthenium emerged as a very promising candidate, due to its intrinsic properties. Based on these inherent properties, we aimed to synthesize a diruthenium complex coordinated with N,N' bidentate ligand. In the current study, 4-amino-2-anilinopyridine (Aap) was synthesized and used as an equatorial ligand in the preparation of Ru2(Aap)4Cl complex. Both the ligand and the diruthenium complex were characterized by their thermal analysis, elemental analysis, spectroscopic (MALDI, NMR, & FT-IR) and structural properties. Spectroscopic and thermal data were consistent with the proposed structures. Single X-ray crystallography of the ligand and the complex further revealed that: i) the 4-amino group on the pyridine ring was not involved in complex formation; ii) the new diruthenium complex was a (4, 0) isomer; and iii) interesting conformational changes were also observed in the Aap ligand after the complex formation. The newly synthesized diruthenium complex was tested in vitro against cisplatin resistant cancerous lung epithelial cells (A549) and a normal smooth muscle cells (SMC) for its inhibitory and anti-proliferative effects. Using a modified MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, IC50 values were determined as 39 +/- 1.3 microM, 5.8 +/- 0.4 microM, and 3.86 +/- 0.8 microM for proliferation assay; 6.8 +/- 0.4 microM, 5.8 +/- 0.3 microM, and 3.6 +/- 0.3 microM for toxicity assay at 24, 48, and 72 hours of treatment on A549 cell line. Where as SMC had 58.05 +/- 2.5 microM and 27.9 +/- 1.95 microM for toxicity assay after 48 and 72 hours of treatment. Morphological changes observed during the treatment were also reported in the current work. The effect of diruthenium complex was also evaluated on both cell lines in the presence of PTK (protein tyrosine kinase) inhibitor like tyrphostin-25 and mitogen like PGF2a, and reported. These findings suggest that the new diruthenium complex may serve as a potential chemo-preventive agent in cisplatin resistant lung cancer cells.