New dinuclear palladium(II) complexes: Studies of the nucleophilic substitution reactions, DNA/BSA interactions and cytotoxic activity.

Six new dinuclear Pd(II) complexes, [{Pd(2,2'-bipy)Cl}2(μ-pz)](ClO4)2 (Pd1), [{Pd(dach)Cl}2(μ-pz)](ClO4)2 (Pd2), [{Pd(en)Cl}2(μ-pz)](ClO4)2 (Pd3), [{Pd(2,2'-bipy)Cl}2(μ-4,4'-bipy)](ClO4)2 (Pd4), [{Pd(dach)Cl}2(μ-4,4'-bipy)](ClO4)2 (Pd5) and [{Pd(en)Cl}2(μ-4,4'-bipy)](ClO4)2 (Pd6) (where 2,2'-bipy=2,2'-bipyridyl, pz=pyrazine, dach=trans-(±)-1,2-diaminocyclohexane, en=ethylenediamine, 4,4'-bipy=4,4'-bipyridyl) have been synthesized and characterized by elemental microanalysis, IR, 1H NMR and MALDI-TOF mass spectrometry. The pKa values of corresponding diaqua complexes were determined by spectrophotometric pH titration. Substitution reactions with thiourea (Tu), l-methionine (l-Met), l-cysteine (l-Cys), l-histidine (l-His) and guanosine-5'-monophosphate (5'-GMP) were studied under the pseudo-first order conditions at pH7.2. Reactions of Pd1 with Tu, l-Met and l-Cys were followed by decomposition of complexes, while structures of dinuclear complexes were preserved during the substitution with nitrogen donors. Interactions with calf-thymus DNA (CT-DNA) were followed by absorption spectroscopy and fluorescence quenching measurements. All complexes can bind to CT-DNA exhibiting high intrinsic binding constants (Kb=104-105M-1). Competitive studies with ethidium bromide (EB) have shown that complexes can displace DNA-bound EB. High values of binding constants towards bovine serum albumin protein (BSA) indicate good binding affinity. Finally, all complexes showed moderate to high cytotoxic activity against HeLa (human cervical epithelial carcinoma cell lines) and MDA-MB-231 (human breast epithelial carcinoma cell lines) tumor cell lines inducing apoptotic type cell death, whereas normal fibroblasts were significantly less sensitive. The impact on cell cycle of these cells was distinctive, where Pd4, Pd5 and Pd6 showed the most prominent effect arresting MDA-MB-231 (human lung fibroblast cell lines) cell in G1/S phase of cell cycle.