Synthesis, Structure Elucidation and Reactivity of Palladium(Ii) and Platinum(Ii) Complexes for Anticancer Applications

Abstract

The objective of the work was to come up with stable metal complexes with bulky ligands coordinated to the metal center and test them in anticancer studies. Literature reports that bulky ligands and trans geometry for palladium and platinum complexes may produce compounds with enhanced anticancer activity but this has not yet been studied. Palladium and platinum metal centers were chosen for this work due to their prominence and indepth literature reports on their use in similar anticancer studies. The similarities in the bonding profiles of the +2 oxidation states for these d8 ions produces 16-electron low spin complexes with similar square planar geometry to the well-known commercially available anticancer drugs which allows their anticancer activity to be compared. However, the differences in their d-orbital energies, ligand substitution kinetics and effective nuclear charge affords interesting contrasts in the resulting compounds. In this regard, a series of eleven new Palladium(II) and Platinum(II) complexes from four pyrrolebased ligands and four thiosemicarbazide-based ligands; have been synthesized, characterized, and their electronic properties, DNA binding modes and anti-cancer properties studied. The synthesis for all the compounds was performed under mild conditions; reflux in absolute methanol for the ligands and room temperature for the complexes. Inert procedures were employed in the synthesis and isolation followed by characterization by FTIR, 1H and 13C NMR, UV–vis, cyclic voltammetry and elemental analysis in addition to x-ray crystallography for 4 ligands and 1 platinum complex. The complexes were found to be of square planar geometry. Yields for the pyrrole-based ligands ranged from 80%- 95% while the thiosemicarbazide ligands yields ranged from 54%-68%. The yields for the complexes ranged from 42%- 98%. These yields were on average lower compared to those of the ligands and were attributed to the steric shielding of the bulky ligands to the metal center making coordination to the metal challenging. The cyclic voltammograms for the palladium complexes showed irreversible reduction peaks at - 0.57V, -1.47 V and -1.7V vs Ag/AgCl which corresponded to the Pd(II)→Pd(I) and Pd(I)→Pd(0) reduction processes. The platinum complexes showed peaks around – 0.5 V corresponding to H+ reduction to H2 occurring at -0.41V at pH 7 vs Ag/AgCl. The molar conductivities ranged from 4.0- 8.8μS/cm suggesting neutrality. Solubility studies were carried out by studying their partition coefficients. This gave a range of logP values ranging between 0.6- 1.9927 indicating a more than 20times partitioning for most of the compounds in oil layer compared to the water layer. This indicated the lipophilic nature for these complexes. Stability study measurements were performed using 1H NMR in DMSO-d6 after adding 200μl of D2O over a 72h period. Proton scans were conducted at 6h intervals to monitor any changes in peaks. The lack of shift in peaks or any other change in spectra over the test period indicted that the compounds were stable in solution, and therefore could be analysed for bioassay DNA-binding kinetics were studied by spectroscopy using calf thymus DNA. The complexes were found to bind to DNA through intercalative mode and to induce apoptosis, where one of the platinum complexes showed the highest binding constant of 8.049 x 104 M-1. The compounds showed comparable DNA-binding profiles to some of the available well-known intercalators indicating they can be important candidates in the line of potential DNA intercalators for further work.

The anti-cancer cytotoxicity and apoptosis for the complexes was performed in vitro, using human colon, Human Cervical, Human Hepatocellular Carcinoma, breast cancer, human prostate and noncancer...........