Facile Photocyclization Chemistry of 5-Phenylthio-2‘-deoxyuridine in Duplex DNA

Abstract

We report here the synthesis of 5-phenylthio-2'-deoxyuridine (d PhS U), its incorporation into oligodeoxynucleotides (ODNs), and its photocyclization chemistry. Irradiation of dinucleoside monophosphate d( PhS UG) and d PhS U-bearing duplex ODNs with 254 nm light results in the facile formation of a cyclic product where the C6 of uracil is covalently bonded to the C2 of the phenyl Yinsheng.Wang@ucr.edu. Supporting Information Available. NMR spectra of synthetic compounds, LC traces, MS data, and LC-MS/MS results. This material is available free of charge via Internet at http://pubs.acs.org. ring. The chemistry reported here may serve as the basis for the efficient preparation of a new class of duplex DNA with an extended π system. NIH Public AccessPhenylthio-substituted nucleosides have been successfully employed as photolabile precursors for the generation of carbon-centered radicals to mimic the deleterious effects of ionizing radiation 1-6 . In addition, it has been shown that the photoirradiation of pyrimidine nucleosides with a halogen atom being substituted at the C5 position may result in the formation of C5-centered radicals 7-10 . It remains unclear what the photochemistry is for pyrimidine nucleosides bearing a 5-thiophenyl moiety.In this study, we set out to explore this chemistry by first synthesizing 5-phenylthio-2'-deoxyuridine (d PhS U). The incorporation of a phenylthio group to the C5 of uracil was inspired from the previous procedures for the preparation of 8-benzyloxy-2'-deoxyguanosine 11 . In this regard, treatment of the commercially available 5-bromo-2'-deoxyuridine with thiophenol and sodium in DMSO renders the desired 5-phenylthio-2'-deoxyuridine in ∼47% yield (Scheme 1). We then synthesized the phosphoramidite building block of d PhS U following standard procedures 12 and inserted it into dinucleoside monophosphate and ODNs by automated solidphase synthesis (Scheme 1).We next examined the photochemistry of d( PhS UG) and d PhS U-bearing ODNs. Here we began our discussion with the major product isolated from the irradiation mixture of d( PhS UG) (The HPLC trace for the separation of the 254 nm irradiation mixture is shown in Figure 1a). Negative-ion ESI-MS of the major fraction eluting at 51.3-min gave an ion of m/z 661.8 ( Figure 1a, inset), and we designate the product as d ( To further elucidate the structure of the major product, we recorded its 1 H-NMR spectrum, which showed the presence of four aromatic protons ( Figure S5). These protons can be assigned to the protons of the phenyl group, which is supported by 2-D NOESY measurement ( Figure S6). The losses of the H6 proton of uracil and an aromatic proton from the phenyl ring support the proposed structure of the major photoproduct (Scheme 2). It is worth noting that the NMR spectra are also consistent with an alternative cyclic structure where the sulfur is bonded to the C6 of the uracil component. This possibility, however, can be excluded for two reasons. First, the formation of the latter product would necessitate th...

yDNA versus yyDNA pyrimidines: computational analysis of the effects of unidirectional ring expansion on the preferred sugar–base orientation, hydrogen-bonding interactions and stacking abilities

“…42 Of particular interest is base expansion, which has been attempted using several different ring spacers. Specifically, bases with heterocyclic ring spacers including thiophene, [43][44][45] benzo[b]thiophene, 46,47 furan 45 and pyrrole, 45 as well as other heteroring expanded purines 43,48,49 and pyrimidines, 50 have been synthesized. Such modifications bring additional hydrogen-bonding capabilities, and increase stacking interactions by increasing the polarizability of the canonical nucleobases.…”

yDNA versus xDNA Pyrimidine Nucleobases: Computational Evidence for Dependence of Duplex Stability on Spacer Location

“…Due to the widespread applications of Kool’s xDNA helices, several other types of expanded DNA nucleobases have been synthesized. For example, other ring spacers have been considered including thiophene, , benzo[ b ]thiophene, , and naphthalene, − and a variety of heteroring expanded versions of guanine have also been studied . Furthermore, spacers that extend the nucleobases in other ways have been developed.…”

Synthesis, structure and imaging of oligodeoxyribonucleotides with tellurium-nucleobase derivatization

“…Aryl-chalcogenides (S and Se), such as phenyl sulfenyl and phenyl selenyl moieties, have been tethered to the 5-position of pyrimidine nucleosides and been incorporated into DNA ( 38–41 ). Methods, which are available in the literature for the introduction of the alkyl or aryl chalcogenides (S and Se) at the 5-position of pyrimidines, include the electrophillic addition–elimination on the C5–C6 double bond ( 42 ), the palladium-catalyzed nucleophillic substitution of 5-mercururio derivatives ( 39 , 43 ), and the lithiation of 5-halo derivatives in the presence of the electrophilic species ( 44 ).…”