Novel platinum(II)-based anticancer complexes and molecular hosts as their drug delivery vehicles

摘要

Platinum( II)-based DNA intercalators where the intercalating ligand is 1,10-phenanthroline or a phenanthroline derivative and where the ancillary ligand is either achiral ( e. g. ethylenediamine) or chiral ( e. g. diaminocyclohexane) show a range of cytotoxicities with a defined structure-activity relationship. The most cytotoxic are those that contain methylated-phenanthroline ligands and 1S, 2S-diaminocyclohexane ( S, S-dach) as the ancillary ligand. We have developed a new purification method using Sep-Pak (R) C-18 reverse phase columns, which means these metal complexes can be made faster and cheaper compared to published methods. Platinum( II)-based complexes containing imidazole, pyrrole and beta-alanine subunits, that are capable of recognising specific DNA base-pair sequences have also been synthesised. These include linear or hairpin polyamide ligands that can recognise DNA sequences up to seven base-pairs in length and contain single platinum centres capable of forming monofunctional adducts with DNA. We have now synthesised and characterised, by H-1 and Pt-195 NMR, ESI-MS and elemental analysis, the first dinuclear platinum( II) DNA sequence selective agent. Finally, using 1H NMR we have examined the encapsulation of our platinum( II)-based DNA intercalators by cucurbit[6]uril ( CB[ 6]). Encapsulation by CB[ 6] was found to not significantly change the cytotoxicity of five platinum( II)-based DNA intercalators, indicating it may have utility as a molecular carrier for improved drug delivery.