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

Abstract 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 phototoxicity 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 3 )(py) 2 (5′‐GMP)] + , as does the parent platinum(IV) complex. Binding of the platinum(II) photoproduct {PtN 3 (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 SK‐MEL‐28 cells than in DU‐145 cells suggests a degree of selectivity towards the malignant melanoma cell line.