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

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Analytical Chemistry

Background:

• Platinum-based anticancer drugs are a cornerstone of cancer therapy, primarily targeting DNA.
• Understanding the precise interactions of novel platinum prodrugs with DNA is crucial for developing more effective treatments.
• Photoactivatable platinum(IV) prodrugs offer potential for targeted drug delivery and activation.

Purpose of the Study:

• To investigate the interaction of a photoactivatable diazido Pt(IV) anticancer prodrug, trans,trans,trans-[Pt(N3)2(OH)2(py)2], with a specific 15-mer oligodeoxynucleotide (ODN I).
• To identify the DNA binding sites and characterize the reaction products, including adducts and oxidative damage.
• To elucidate the photochemical reactivity and sequence-length-dependent behavior of the Pt(IV) prodrug.

Main Methods:

• Mass spectrometric methods, including tandem mass spectrometry (MS/MS), were employed to analyze the reaction products.
• Oligodeoxynucleotide (ODN I) was incubated with the Pt(IV) prodrug.
• Fragmentation analysis was used to determine binding sites and adduct structures.

Main Results:

• Up to penta-platinated ODN I adducts were identified, with mono- and di-platinated adducts showing the highest intensity.
• Tandem MS revealed T2, G8, T11, and T9 as primary binding sites, with no significant binding to cytosine.
• Significant oxidative damage to guanine (G8) was observed, forming 8-hydroxyguanine (8-OH-G), spiroiminodihydantoin (Sp), and FapyG.
• The study indicated substantial photo-reduction of the Pt(IV) prodrug to Pt(II) and sequence-length-dependent photochemical reactivity.

Conclusions:

• The Pt(IV) prodrug exhibits specific binding preferences within the oligodeoxynucleotide, primarily at thymine and guanine residues.
• Photodecomposition of the prodrug generates reactive oxygen species, leading to significant oxidative DNA damage.
• The findings highlight the sequence-length-dependent photochemical reactivity of this Pt(IV) prodrug, offering insights for designing targeted cancer therapies.