Cationic Pd(II)/Pt(II) 5,5-Diethylbarbiturate Complexes with Bis(2-Pyridylmethyl)amine and Terpyridine: Synthesis, Structures, DNA/BSA Interactions, Intracellular Distribution, Cytotoxic Activity and Induction of Apoptosis

Abstract

Four new cationic Pd(II) and Pt(II) 5,5-diethylbarbiturate (barb) complexes, [M(barb)(bpma)]X·H<inf>2</inf>O [M=PdII, X = Cl (1); M = PtII, X = NO<inf>3</inf> - (2)] and [M(barb)(terpy)]NO<inf>3</inf>·0.5H<inf>2</inf>O [M=PdII (3); M = PtII (4)], where bpma=bis(2-pyridylmethyl)amine and terpy=terpyridine, were synthesized and characterized by elemental analysis, IR, UVvis, NMR, ESI-MS and X-ray crystallography. The DNA binding properties of the cationic complexes were investigated by spectroscopic titrations, displacement experiments, viscosity, DNA melting and electrophoresis measurements. The results revealed that the complexes effectively bind to FS-DNA (fish sperm DNA) via intercalative/minor groove binding modes with intrinsic binding constants (K<inf>b</inf>) in the range of 0.50 × 10<inf>4</inf> - 1.67 × 10<inf>5</inf> M-1. Absorption, emission and synchronous fluorescence measurements showed strong association of the complexes with protein (BSA) through a static mechanism. The mode of interaction of complexes towards DNA and proteinwas also supported bymolecular docking. Complexes 1 and 3 showed significant nuclear uptake in HT-29 cells. In addition, 1 and 3 showed higher inhibition than cisplatin on the growth of MCF-7 and HT-29 cells and induced apoptosis on these cells much more effectively than the rest of the complexes as evidenced by pyknotic nuclearmorphology. The levels of caspase-cleaved cytokeratin 18 (M30 antigen) in HT-29 cells treated with 1 and 3 increased in a dose-dependent manner, suggesting apoptosis. Moreover, qRT-PCR experiments showed that 1 and 3 caused significant increases in the expression of TNFRSF10B in HT-29 cells, indicating the initiation of apoptosis via cell surface death receptors. © 2015 Elsevier Inc. All rights reserved.