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

Abstract

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, ¹H, ¹³C and ¹¹⁹Sn NMR, ESI MS and single crystal X-ray crystallography. Complex 1 resulted from the proton transfer reaction between iminodiacetic acid (H₂IDA) 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 μM 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 (GI₅₀ 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.