Novel platinum(II)-based anticancer complexes and molecular hosts as their drug delivery vehicles.
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 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 (1)H and (195)Pt NMR, ESI-MS and elemental analysis, the first dinuclear platinum(II) DNA sequence selective agent. Finally, using (1)H 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.
Wheate
Nial J
NJ
Nanoscale Organisation and Dynamics Group, School of Biomedical and Health Sciences, University of Western Sydney, Locked Bag 1797, Penrith South DC, NSW, 1797, Australia.
Taleb
Robin I
RI
Krause-Heuer
Anwen M
AM
Cook
Rebekah L
RL
Wang
Shaoyu
S
Higgins
Vincent J
VJ
Aldrich-Wright
Janice R
JR
D000970:Antineoplastic Agents / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry; D004337:Drug Carriers; D007364:Intercalating Agents / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D017671:Platinum Compounds / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization
D000970:Antineoplastic Agents; D018736:DNA Adducts; D004337:Drug Carriers; D007364:Intercalating Agents; D017671:Platinum Compounds