Synthesis of Oligonucleotides Containing Interchain Cross-Links of Bifunctional Pyrroles

Tsarouhtsis, Dimitrios; Kuchimanchi, Satya; DeCorte, Bart L.; Harris, Constance M.; Harris, Thomas M.

doi:10.1021/ja00149a027

Cited by 25 publications

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“…Cross-linked Oligonucleotides 3a and 3b-The oligonucleotides utilized in these studies were synthesized by a novel application of the postoligomerization strategy developed by Harris et al (15,22,23) (Fig. 1).…”

Section: Synthesis and Characterization Of Butadiene Diepoxidementioning

confidence: 99%

Butadiene-induced Intrastrand DNA Cross-links: A Possible Role in Deletion Mutagenesis

Carmical¹,

Kowalczyk²,

Zou³

et al. 2000

Journal of Biological Chemistry

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To initiate studies designed to identify the mutagenic spectrum associated with butadiene diepoxide-induced N 2 -N 2 guanine intrastrand cross-links, site specifically adducted oligodeoxynucleotides were synthesized in which the adducted bases were centrally located within the context of the human ras 12 codon. The two stereospecifically modified DNAs and the corresponding unmodified DNA were ligated into a single-stranded M13mp7L2 vector and transfected into Escherichia coli. Both stereoisomeric forms (R,R and S,S) of the DNA cross-links resulted in very severely decreased plaqueforming ability, along with an increased mutagenic frequency for both single base substitutions and deletions compared with unadducted DNAs, with the S,S stereoisomer being the most mutagenic. Consistent with decreased plaque formation, in vitro replication of DNA templates containing the cross-links by the three major E. coli polymerases revealed replication blockage by both stereoisomeric forms of the cross-links. The same DNAs that were used for replication studies were also assembled into duplex DNAs and tested as substrates for the initiation of nucleotide excision repair by the E. coli UvrABC complex. UvrABC incised linear substrates containing these intrastrand cross-links with low efficiency, suggesting that these lesions may be inefficiently repaired by the nucleotide excision repair system.Metabolic bioactivation of 1,3-butadiene results in a diepoxide. As a bifunctional electrophile, butadiene diepoxide is theoretically capable of producing inter-and intrastrand DNA-DNA cross-links. Cross-linked adducts are thought to be responsible for the observation that the diepoxide is considerably more mutagenic in mice than the monoepoxide under identical exposure conditions (1) and for the fact that butadiene is more genotoxic to mice than rats. The latter observation is attributed to the greater effectiveness of mice at metabolizing butadiene to the diepoxide (2). Both species appear to be equally susceptible to cytogenetic damage inflicted by butadiene diepoxide when the epoxide is introduced directly into isolated rat or mouse lymphocytes (splenic or peripheral blood) (3).There are a number of studies supporting the existence of butadiene diepoxide-induced interstrand cross-links (4 -9). Evidence for such cross-links is based largely on denaturation/ renaturation experiments in which interstrand-cross-linked DNA renatures more rapidly than noncross-linked. The only cross-linked species thus far identified, a guanine N7-guanine N7 cross-link, was isolated from salmon sperm DNA by Lawley and Brookes (8). In 1993, Millard and White (10) reported that synthetic oligonucleotide duplexes of varying sequences reacted rather diffusely with butadiene diepoxide but showed preference for interstrand cross-linking at 5Ј-GNC sites. As expected for guanine N7 cross-links most of the bands that migrated in denaturing gels in the region expected for dimeric structures were cleavable by piperidine at 90°C. However, some cross-linked material persis...

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Section: Synthesis and Characterization Of Butadiene Diepoxidementioning

confidence: 99%

Butadiene-induced Intrastrand DNA Cross-links: A Possible Role in Deletion Mutagenesis

Carmical¹,

Kowalczyk²,

Zou³

et al. 2000

Journal of Biological Chemistry

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“…There is risk of losing the NPE group by β-elimination if sodium methoxide is used for this step. The trimethylsilylethyl group is also very useful for O6-protection (Tsarouhtsis et al, 1995;DeCorte et al, 1996). Both groups can be used for preparation of O6-protected 2-fluoro-2′-deoxyinosine phosphoramidites and for oligonucleotide synthesis.…”

Section: Synthesis Of Modified Nucleosidesmentioning

confidence: 99%

Synthesis of N2‐Substituted Deoxyguanosine Nucleosides from 2‐Fluoro‐6‐O‐(Trimethylsilylethyl)‐2′‐Deoxyinosine

Harris

2000

CP Nucleic Acid Chemistry

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Syntheses of N2-substituted nucleosides have been studied for many years, primarily with ribonucleosides. However, the primary route to these compounds requires acidic conditions that are too vigorous for the acid-labile deoxyribonucleosides. The current strategy takes advantage of methods for low-temperature, nonaqueous diazotization of ribosides in organic solvents using t-butyl nitrate as the diazotizing agent and HF/pyridine as the fluoride source for the preparation of a 2-fluoro-2-deoxyinosine derivative that can be used to synthesize N2-substituted deoxyguanosine.

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“…The total synthesis of crosslinked DNA is depicted in Scheme 19 and rests on the incorporation of fluoro-nucleosides into DNA. 171 DNA-single strands like 150, which contain such a fluorocontaining base, feature an electrophilic center, which can react with amine-analogs like 151 and 152 of the natural mutagens 148 and 149. The synthesis of fluoronucleosidecontaining DNA strands like 150 is a challenging task, bacause deprotection of the oligonucleotides with conc.…”

Section: Building Blocks For Dna Crosslinks 162mentioning

confidence: 99%

Synthesis of DNA Lesions and DNA-Lesion-Containing Oligonucleotides for DNA-Repair Studies

Butenandt¹,

Burgdorf²,

Carell³

1999

Synthesis

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DNA and RNA are the molecules which store the genetic information in every organism. Both macromolecules are severely damaged by a variety of exogenous and endogenous events. This leads to a loss of genetic information. Main lesions are strand breaks, apurinic and apyrimidinic sites and a variety of DNA bases with an altered structure. The result of these DNA modifications are cell death, mutations and in the worst scenario carcinogenous growth. In order to study the effect of DNA lesions on the structure of the DNA double helix, a variety of lesion building blocks were recently synthesized and incorporated into oligonucleotides. In addition, oligonucleotides which contain DNA lesions at specific sites are the basis for a detailed investigation of repair mechanisms that were developed by organisms in order to counteract the lethal effect of DNA damage. This review article describes the recent synthetic progress that has enabled the preparation of DNA lesion phosphoramidite building blocks. The synthetic procedures employed for their preparation and the methods used to incorporate these building blocks into oligonucleotides are described. The biological effect of each particular lesion is briefly recapitulated.

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Synthesis of Oligonucleotides Containing Interchain Cross-Links of Bifunctional Pyrroles

Cited by 25 publications

References 0 publications

Butadiene-induced Intrastrand DNA Cross-links: A Possible Role in Deletion Mutagenesis

Butadiene-induced Intrastrand DNA Cross-links: A Possible Role in Deletion Mutagenesis

Synthesis of N2‐Substituted Deoxyguanosine Nucleosides from 2‐Fluoro‐6‐O‐(Trimethylsilylethyl)‐2′‐Deoxyinosine

Synthesis of DNA Lesions and DNA-Lesion-Containing Oligonucleotides for DNA-Repair Studies

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