A Photoactivatable Platinum(IV) Anticancer Complex Conjugated to the RNA Ligand Guanidinoneomycin

A photoactivatable platinum(IV) complex, trans,trans,trans-[Pt(N-3)(2)(OH)(succ)(py)(2) (succ = succinylate, py= pyridine), has been conjugated to guanidinoneomycin to study the effect of this guanidinum-rich compound on the photoactivation, intracellular accumulation and photo toxicity of the pro-drug. Surprisingly, trifluoroacetic acid treatment causes the replacement of an azido ligand and the axial hydroxide ligand by trifluoroacetate, as shown by NMR spectroscopy, MS and X-ray crystallography. Photoactivation of the platinum-guanidinoneomycin conjugate in the presence of 5'-guanosine monophosphate (5'-GMP) led to the formation of trans-[Pt(N)(py),(5'-GMP)]-, as does the parent platinum(IV) complex. Binding of the platinum(II) photoproduct {PtN3(py)(2)}(+) to guanine nucleobases in a short single-stranded oligonucleotide was also observed. Finally, cellular uptake studies showed that guanidinoneomycin conjugation improved the intracellular accumulation of the platinum(IV) pro-drug in two cancer cell lines, particularly in SK-MEL-28 cells. Notably, the higher phototoxicity of the conjugate in 5K-MEL-28 cells than in DU 145 cells suggests a degree of selectivity towards the malignant melanoma cell line.