Design, synthesis, characterization and DNA-binding studies of a triphenyltin(iv) complex of N-glycoside (GATPT), a sugar based apoptosis inducer: in vitro and in vivo assessment of induction of apoptosis by GATPT

Abstract

The novel organotin complex 1-{(2-hydroxyethyl)amino}-2-amino-1,2-dideoxy-D-glucose triphenyltin(IV) (GATPT) was synthesized by the reaction of N-glycoside ligand and triphenyltin(IV) chloride. GATPT was characterized by elemental analyses, polarimetry, IR, CD, UV and multinuclear (¹H, ¹³C, ¹¹⁹Sn) 1D and 2D NMR. The interaction of GATPT with calf thymus DNA was studied by using viscometry, absorption, emission and circular dichoric spectral methods. The DNA binding results suggested the intercalative mode of binding for GATPT with DNA along with simultaneous electrostatic interaction between the Sn(IV) center and the phosphate backbone of the DNA helix. GATPT was tested for its cytotoxic properties against SY5Y, PC-12 and N2A neuronal tumor cell lines. GATPT induced significant apoptosis in the PC-12 cell line characterized by DNA fragmentation and chromosome condensation. Treatment of PC-12 cells with GATPT resulted in a dramatic up-regulation of Bax and Bak and down-regulation of the anti-apoptotic factor Bcl-2. Apoptotic induction by GATPT was shown to be mediated in a p53-dependent manner and loss of p53 impaired the release of cytochrome c from mitochondria to cytosol. Caspase-3 was found to be indispensable for the GATPT triggered apoptosis signaling pathway. Furthermore, in vivo studies using a nude mice model revealed that GATPT exhibits significant antiproliferative activity against tumor development with minimal cytotoxicity. These findings warrant further clinical investigations of GATPT as a therapeutic agent for cancer chemotherapy.