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

Abstract

A photoactivatable platinum(IV) complex, trans,trans,trans-[Pt(N3 )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(N3 )(py)2 (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 SK-MEL-28 cells than in DU-145 cells suggests a degree of selectivity towards the malignant melanoma cell line.

Keywords: DNA; antitumor agents; photochemistry; platinum; structure-activity relationships.