Differentiated oxidation modes of guanine between CpG and ^5mCpG by a photoactivatable Pt(iv) anticancer prodrug

Abstract

CpG and its cytosine-methylated counterpart (5mCpG) are unique reversible pair of sequences in regulating the expression of genes epigenetically. As DNA is the potential target of Pt-based anticancer metallodrugs, herein,...

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

“…Moreover, it should be noted that the two mono-platinated I adducts ( 2 and 3 ) attached by [Pt II (N 3 )(py) 2 ] + and [Pt II (py) 2 ] 2+ were almost in equal intensity. This is significantly different from the results obtained in the photo-interactions of complex 1 or its analogue with other ODNs, 16,20–22,26 where the intensity ratio of the [Pt II (py) 2 ] 2+ modified adducts vs. [Pt II (N 3 )(py) 2 ] + modified adducts were ca. one quarter or even lower.…”

“…2 and Table S1 †). Similar to those observed in the photo-interactions of complex 1 with other ODNs, 16,[19][20][21][22] most of the minor platinated I adducts were accompanied by base oxidation. The most probable oxidized base was guanine as there are three guanines in such a short hexamer sequence of ODN I, and guanine is the most sensitive DNA base to the oxidation of ROS.…”

“…20 The guanine oxidation adducts by complex 1 were significantly affected by its neighboring base. 21 Moreover, for 15-mer longer single strand, a comparable amount of platinated ODN adducts by fragments [Pt(Py) 2 ] 2+ and [Pt(N 3 )(Py) 2 ] + were unambiguously observed in the mass spectrum. 22 While the latter platinated adducts were usually the only major adducts for short ODNs.…”

“…Pt(IV) complex (trans,trans,trans-[Pt (N 3 ) 2 (OH) 2 ( py) 2 ], 1) (Chart 1) was synthesized as previously reported, 13 and its purity was verified by HPLC, 1 H NMR, and ESI-MS. 21 Acetonitrile (HPLC grade) was purchased from Merck (Germany). The HPLC-purified hexamer oligodeoxynucleotide (ODN), 5′-T 1 TAGGG 6 -3′ (I) (Chart 1) was obtained from Sangon Biotech.…”

“…16,17,19 These results suggest that DNA is the possible potential target of such prodrugs. Our recent results by introducing electrospray ionization mass spectrometry (ESI-MS) to characterize the photo-reaction products further revealed a unique interaction mode of complex 1 with different oligodeoxynucleotides (ODNs) from mononucleosides/tides, 16 dinucleotides 20,21 to 15-mer single-G containing oligodeoxynucleotide (ODN) 5′-C 1 TCTCTTGTCTTCTC 15 -3′. 22 For example, for guanine and thymine, only two guanine oxidation adducts as 8-hydroxyguanine (8-OH-G) and N-formylamidoiminohydantoin (RedSp) and one thymine oxidation adduct as 5-hydroxymethyl-2′-deoxyuridine (HMdUrd) were identified for 5′-GMP/guanosine and thymidine, respectively, in the photoreactions with complex 1 or its analogue.…”