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.

• Authors: Evyenia Shaili, Marta Fernández-Giménez, Savina Rodríguez-Astor, Albert Gandioso, Lluís Sandín, Carlos García-Vélez, Anna Massaguer, Guy J Clarkson, Julie A Woods, Peter J Sadler, Vicente Marchán
• Journal: Chemistry (Weinheim an der Bergstrasse, Germany) (Chemistry) Vol. 21 Issue 50 Pg. 18474-86 (Dec 07 2015) ISSN: 1521-3765 [Electronic] Germany
• PMID: 26662220 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antineoplastic Agents
• Ligands
• Organoplatinum Compounds
• RNA
• Guanidine

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Cell Line, Tumor
• Guanidine (analogs & derivatives, chemistry)
• Humans
• Ligands
• Organoplatinum Compounds (chemistry, pharmacology)
• RNA (chemistry, metabolism)