Synthesis, speciation, DNA binding, electrochemical and antiproliferative properties of pd(ii) complexes designed to improve the Interaction with DNA

Abstract

With the success of cisplatin, further extensive research activities resulted in the discovery of carboplatin (a second-generation drug), where the chloride is replaced by 1,1-cyclobutanedicarboxylate as a new leaving group. In the current study, we continue our previous work on the binding behavior of [Pd(byp)(H2O)2]2+ with structural features that enhance the interaction with DNA. The coordination properties of 2,2-bipyridine ligand have been changed such that a versatile ligand can be formed. [Pd(byp)(gly)]+ (1) and [Pd(byp)(CBDCA)] (2), where byp is 2,2-bipyridine, gly is glycine, and CBDCA is cyclobutane-1,1-dicarboxylic acid, were synthesized and characterized. The stability constants and stoichiometries of the complexes formed between various DNA unit constituents and [Pd(byp)(H2O)2]2+ were investigated. The binding properties of the complexes (1) and (2) with CT-DNA were analyzed by UV-vis spectroscopy, viscosity measurements, and cyclic voltammmetry. The determined binding constants for both complexes show strong binding to CT-DNA. The (Kb) values of both complexes are found to be greater than that reported in our previous finding for [Pd(byp)(H2O)2]2+. The determined (Kb) value for complex (1) (Kb= 4.36x103 M?1 ) as a cationic intercalator, suggests an electrostatic binding mode of the positively charged complex (1) together with hydrogen bonding with the negative sites of the bound DNA. The comparatively higher (Kb) value measured for complex (2) (Kb= 2.11x104 M?1) indicates an intercalation mode of binding whereby a ring-opening reaction of CBDCA occurs, followed by the reaction with guanosine 5'-monophosphate to form [(Pdbyp)(CBDCA-O)(5'-GMP)]. The small change in the measured δTm following binding of complex (1) supports strong electrostatic binding, while the significant change in δTm obtained for complex (2) supports the intercalation mode of binding. The two complexes in the absence and in the presence of CT-DNA show quasi-reversible oxidation-reduction redox CV wave . The variation in the values of E1/2, ?Ep and Ipc/Ipa also supports the electrostatic binding of the complex (1) and the intercalation mode for complex (2). The antitumor effects of the two complexes were tested against two different types of cancer cell lines, breast cancer (MCF-7) and colon cancer (HCT-116), as well as one normal cell line; the human normal melanocytes (HFB4). The two complexes display dose-dependent anti-proliferation activity. Complex (2) was shown to have more efficient apoptosis than Complex (1) and may be considered a model for carboplatin with a prediction of improved efficacy against cancer.