Reaction of human telomeric unit TTAGGG and a photoactivatable Pt(iv) anticancer prodrug

Abstract

The interaction of a photoactivatable diazidodihydroxido Pt(IV) prodrug, trans,trans,trans-[Pt(N3)2(OH)2(py)2] (py = pyridine; 1), with a hexamer straight human telomeric DNA unit sequence (5′-T1T2A3G4G5G6-3′, I) upon light irradiation was investigated by...

Adenine–adenine, adenine–cytosine and cytosine–cytosine intrastrand crosslinks induced by a photoactivatable Pt(iv) anticancer prodrug

“…5,14–16,18 Usually, there are two pathways proposed during the photodecomposition of complex 1 : two single-electron donations from either of the two azides to produce trans -[Pt II (py) 2 ] 2+ , or one azide and one hydroxide ligand to produce trans -[Pt II (N 3 )(py) 2 ] + . 4,19 Our previous reports have shown a sequence-dependent photodecomposition mechanism of complex 1 when incubating with DNA, 9,15–17 and the results obtained herein further confirmed such a photo-interaction mode of complex 1 . Moreover, the mono-functional trans -[Pt II (N 3 )(py) 2 ] + and bi-functional trans -[Pt II (py) 2 ] 2+ will produce distinct DNA adducts, e.g.…”

“…9,15,18 Our recent research has shown that a 1,3-intrastrand crosslink at G4 and G6 might be formed by trans -[Pt(py) 2 ] 2+ in the photo-interactions of complex 1 with the 6-mer human telomeric unit, 5′-T 1 T 2 A 3 G 4 G 5 G 6 . 17 However, for adenine and cytosine, no explorations have been performed to investigate their potential to form crosslinks by complex 1 so far.…”

“…The bifunctional adduct with trans -[Pt II (py) 2 ] 2+ was identified as a 1,3-intrastrand crosslinked adduct with binding sites at G 4 and G 6 . 17 This result implies that the 1,3-GNG- trans -[Pt II (py) 2 ] 2+ crosslinking might play an indispensable role in the action of the photoactivable Pt( iv ) complex, which inspired us to further explore the formation of 1,3-ANA-/ANC-/CNA-/CNC- crosslinks induced by the reduced species of complex 1 because both adenine and cytosine bases also showed high affinity to the reduced species of complex 1 . 9,18 To achieve this goal, in this work, we designed four trinucleotides, i.e.…”