Reactions of a photoactivatable diazido Pt(iv) anticancer complex with a single-stranded oligodeoxynucleotide

Abstract

Platinum based anticancer agents are widely applied in clinic and their major target is believed to be DNA. Herein, the interaction of a photoactivatable diazido Pt(IV) anticancer prodrug trans,trans,trans-[Pt(N₃)₂(OH)₂(py)₂] (py = pyridine; 1) with a 15-mer single-G-containing oligodeoxynucleotide (ODN I: 5′-CT₂CTCTTG₈T₉CT₁₁TCTC-3′) was investigated by mass spectrometric methods. Up to penta-platinated ODN I adducts were identified from primary mass spectra while the mono- and di-platinated adducts had the highest intensity. Fragmentation of mono-, di- and tri-platinated I adducts in tandem MS revealed that T₂, G₈, T₁₁ and T₉ are binding sites. No cytosine sites were identified which may be due to the facile loss of Pt adducts from cytosine during CID. The intensity of {Pt(py)₂}-bound adducts was comparable to that of {Pt(N₃)(py)₂}-bound adducts, indicating that the photo-reduction pathway of complex 1 from Pt(IV) to Pt(II) through two one-electron donations from two azides was substantial. Moreover, no transformation of N₃ to NH₃ on the {Pt(N₃)(py)₂}-bound adducts was observed, whereas it is very popular during the reactions of complexes with short ODNs or mono-nucleotides. The oxidation on I induced by the reactive oxygen species (ROS) formed by the photodecomposition of complex 1 was significant, and the oxidation of G₈ to 8-hydroxyguanine (8-OH-G), spiroiminodihydantoin (Sp) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) was discovered. These results unambiguously revealed a sequence-length-dependent photochemical reactivity of complex 1 when it interacted with different ODNs, providing deeper understanding in the reactivity of photoactivatable diazido anticancer Pt(IV) prodrugs to DNA.