Site-Specific Synthesis of Oligonucleotides Containing Malondialdehyde Adducts of Deoxyguanosine and Deoxyadenosine via a Postsynthetic Modification Strategy

Abstract

Malondialdehyde (MDA) and its reactive equivalent, base propenal, are products of oxidative damage to lipids and DNA, respectively; they are mutagenic in bacterial and mammalian systems and MDA is carcinogenic in rats. MDA adducts of deoxyguanosine (M 1 dG), deoxyadenosine (OPdA) and deoxycytidine (OPdC) have been characterized. We have developed site-specific syntheses of M 1 dG and OPdA adducted oligonucleotides that rely on a post-synthetic modification strategy. This work provides an alternative route to the M 1 dG adducted oligonucleotide and to date, the only viable strategy for the site-specific synthesis of OPdA modified oligonucleotides. The stability of the modified oligonucleotides was examined by UV thermal melting studies (T m ). In contrast to the M 1 dG adduct, OPdA caused very little change in the T m .

Interstrand DNA Cross-Links Induced by α,β-Unsaturated Aldehydes Derived from Lipid Peroxidation and Environmental Sources

“…Removal of the O 6 protecting group under acidic conditions yielded 29, which was oxidized to oligodeoxynucleotide 30. 47 Our post-synthetic modification strategy 48 allowed preparation of various dG enal adducts from a single modified phosphoramidite. A challenge was the preparation of stereochemically-defined amino diols for the crotonaldehyde (31,32) and 4-HNE adducts (33)(34)(35)(36) (Figure 2).…”

Xeroderma pigmentosum complementation group C protein (XPC) serves as a general sensor of damaged DNA

“…8-oxo-deoxyguanisine (8-oxo-dG) modified oligonucleotide was purchased from Midland Certified Reagent Co., tetrahydrofuran (THF) modified oligonucleotide was purchased from IDT. 12-mer oligonucleotides containing the 1, N 2 -ε-guanine [31], 7-(2-oxoheptyl)-ε-guanine [32], 8-hydroxy-1, N 2 -ε-guanine [33], 1, N 2 -propano-guanine [34], M 1 G [34], and methyl-formamidopyrimidine (MeFapy) [35], and modified 11-mer oligonucleotide ( 5’ GGCAG A *TGGTG 3’ ) containing the 7,12-dimethylbenz(a)anthracene-adenine (DMBA) [36] lesions were available from previous studies. 60 base pair (bp) and 42 bp substrates were constructed by ligation as described previously [37, 38] with the exception that fluorescein was incorporated on the damaged strand which allowed use of fluorescence instead of 32 P radioactivity as the probe.…”

Alcohol consumption and digestive tract cancer

“…These ROS together with polyamines (also increased in alcoholics, especially those who smoke) lead to the generation of DNA adducts, for example, mutagene 1, N 2 -propanodeoxyguanosin [20], or etheno adducts [16], which are highly reactive and modify DNA and protein systems (membrane proteins, enyzmes) ( Fig. 3) [16,20,21]. The level of acetaldehyde can be further increased in the case of bacterial overgrowth in the oral cavity [22] -a contributing factor present in many alcoholics to the extent that toxic levels are reached [10].…”

“…The risk of esophageal cancer is correlated both to the amount and the duration of alcohol intake [31 && ]. With more than 80 g ethanol/day over more than 5 years, the RR is 18 (Table 2) [20,21] and reviewed in [16].…”