Crystal structure determination, spectroscopic characterization and biological profile of a tailored ionic molecular entity, Sn(IV) iminodiacetic acid-piperazinediium conjugate: in vitro DNA/RNA binding studies, Topo I inhibition activity, cytotoxic and systemic toxicity studies

A novel ionic tin(IV) iminodiacetic acid-piperazinediium conjugate (1) was designed and synthesized as a potential antitumor chemotherapeutic molecular entity and was thoroughly characterized by elemental analysis, FT-IR, H-1, C-13 and Sn-119 NMR, ESI MS and single crystal X-ray crystallography. Complex 1 resulted from the proton transfer reaction between iminodiacetic acid (H(2)IDA) and piperazine (pipz), and its subsequent complexation with tin(IV) chloride salt. 1 crystallized in orthorhombic space group Ima2 and comprises of an anionic metallic unit, a piperazinediium cation and a chloride ion. In continuity of our previous strategy in search of robust metal-based antitumor drug entities exhibiting reduced systemic toxicity, we have carried out in vitro interaction studies of 1 with ct-DNA, tRNA and Topo I targets, to validate its chemotherapeutic potential. Complex 1 exhibited more avid binding propensity with RNA which was reflected by its higher K-b and K values with RNA as compared to DNA. Topoisomerase inhibition activity of 1 was performed by gel electrophoresis which revealed significant inhibitory effect on the catalytic activity of the enzyme at 30 mu M concentration. Molecular docking studies of the complex were carried out with DNA (PDB ID: 1BNA), RNA (PDB ID: 6TNA) and Topo I (PDB ID: ISC7) targets to ascertain the specific binding mode thereby substantiated the spectroscopic results. Cytotoxic studies were carried out on a panel of eight human cancer cell lines; U373MG, PC3, Hop62, HL60, HCT15, SK-OV-3, HeLa and MCF-7 by SRB assay which revealed significant regression specifically for HCT15, HOP62, MCF-7 and SK-OV-3 human cancer cell lines (GI(50) value < 10) as compared to the standard drug Adriamycin. Systemic toxicity of 1 was carried out by the estimation of oxidative stress biomarkers such as lipid peroxides (expressed as malondialdehyde; MDA) and reduced glutathione (GSH) levels in kidney and liver homogenates and the study was supported by the histopathologic examination of kidney and liver of female Wistar rats.