Abstract
The formation of interstrand cross-links in nucleic acids can have a strong impact on biological function of nucleic acids; therefore, many cross-linking agents have been developed for biological applications. Despite numerous studies, there remains a need for cross-linking agents that exhibit both efficiency and selectivity. In this study, a 4-vinyl-substituted analog of thymidine (T-vinyl derivative) was designed as a new cross-linking agent, in which the vinyl group is oriented towards the Watson–Crick face to react with the amino group of an adenine base. The interstrand cross-link formed rapidly and selectively with a uridine on the RNA substrate at the site opposite to the T-vinyl derivative. A detailed analysis of cross-link formation while varying the flanking bases of the RNA substrates indicated that interstrand cross-link formation is preferential for the adenine base on the 5′-side of the opposing uridine. In the absence of a 5′-adenine, a uridine at the opposite position underwent cross-linking. The oligodeoxynucleotides probe incorporating the T-vinyl derivative efficiently formed interstrand cross-links in parallel-type triplex DNA with high selectivity for dA in the homopurine strand. The efficiency and selectivity of the T-vinyl derivative illustrate its potential use as a unique tool in biological and materials research.
Highlights
Many chemical entities, of either exogenous or endogenous origins, cause the alkylation of or damage to DNA and RNA; they have a strong impact on biological functions of nucleic acids [1,2,3]
The octylsulfide group was oxidized with magnesium metaperoxyphthalate (MMPP) in carbonate buffer, and the resulting sulfoxide derivatives were treated with 0.5 M NaOH solution to generate the vinyl group, providing the cross-linking ODNs (3,4 and 5) in good yields
This interpretation is supported by molecular orbital calculations (B3LYP/6-31G*); a syn-conformation [15], in which the vinyl group is directed towards the Watson–Crick face, is 2.57 kcal/mol more stable than the anti-conformation [16] of T-vinyl (R = CH3), whereas this conformation is only 0.52 kcal/mol more stable in the U-vinyl (R = H) (Figure 3 and Supplementary Figure S6C and D)
Summary
Of either exogenous or endogenous origins, cause the alkylation of or damage to DNA and RNA; they have a strong impact on biological functions of nucleic acids [1,2,3]. Chemotherapeutic agents, such as mitomycin C, exert their effects by the alkylation of DNA [4]. A variety of functional groups have been developed to enable interstrand cross-linking, including disulfide bonds [12], benzophenone derivatives [13], carbazoles [14], quinone methides [15,16], phenylselenyl derivatives of pyrimidines [17] and furan derivatives [18]. To further advance these studies, an efficient cross-linking method is still desired
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