A Photoactivatable Platinum(IV) Anticancer Complex Conjugated to the RNA Ligand Guanidinoneomycin |
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| Authors: | Dr Evyenia Shaili Marta Fernández‐Giménez Savina Rodríguez‐Astor Albert Gandioso Lluís Sandín Carlos García‐Vélez Dr Anna Massaguer Dr Guy J Clarkson Dr Julie A Woods Prof Peter J Sadler Dr Vicente Marchán |
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| Affiliation: | 1. Department of Chemistry, University of Warwick, Warwick, CV4 7AL, Coventry (UK);2. Departament de Química Orgànica and IBUB, Universitat de Barcelona, Martí i Franquès 1‐11, 08028, Barcelona (Spain);3. Departament de Biologia, Universitat de Girona, Campus Montilivi, 17071, Girona (Spain);4. Photobiology Unit, Department of Dermatology, Ninewells Hospital, Dundee, DD1 9SY (UK) |
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| 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. |
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| Keywords: | antitumor agents DNA photochemistry platinum structure– activity relationships |
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