Design and synthesis of enantiomeric (R)- and (S)-copper(II) and diorganotin(IV)-based antitumor agents: Their in vitro DNA binding profile, cleavage efficiency and cytotoxicity studies

Abstract

New chiral reduced Schiff base ligands (R)/(S)-2-(2-hydroxy-1- phenylethylaminomethyl)phenol (L), (R)/(S)-2-(benzylamino)-2-phenylethanol (L′) and their Cu(II)/organotin(IV) complexes (1-4) were synthesized and thoroughly characterized. Preliminary in vitro DNA binding studies of (R)- and (S)-enantiomeric pairs of ligands L, L′ and complexes 1-4 were carried out employing UV-vis, fluorescence and circular dichroic techniques to evaluate their enantioselective DNA binding potential, thereby to act as antitumor chemotherapeutic drug entities. The observations demonstrated that S-enantiomer of Cu(II) complex, 1 binds more avidly to DNA in comparison to its R-enantiomeric form and organotin(IV) complex 2. This was further established by Kb and Ksv values of ligands L and L′ and (S)-/(R)-1-4 complexes, which demonstrated multifold increase in case of S-enantiomer of copper complex 1 in comparison to its R-enantiomeric form. This clearly demonstrates the chiral preference of S-enantiomer over R-enantiomer and its potency to act as a chemotherapeutic agent. Cleavage studies of 1-4 with pBR322 plasmid DNA were carried out, noticeably, S-enantiomer of complex 1 exhibited effective DNA cleavage efficiency in absence of external agents. The cytotoxicity of ligands L and L′ and (S)-/(R)-1-4 complexes was examined on a panel of 19 human tumor cell lines of different histological origins by SRB assay. In the both the cases, the S-enantiomer of complex 1 and 3 revealed remarkably good cytotoxic activity (GI50 values <10) against T24 (Urinary Bladder), DU145 (Prostate), U373MG (Astrocytoma) and HCT15, SW620 (Colon) clearly underlining the influence of enantiomeric discrimination. Interestingly, ligands L, L′ and rest of the complexes demonstrated moderate cytotoxic activity (GI50 values <40). © 2014 Elsevier B.V. All rights reserved.