Interstrand Cross-Link and Bioconjugate Formation in RNA from a Modified Nucleotide

Sloane, Jack L.; Greenberg, Marc M.

doi:10.1021/jo501982r

Cited by 15 publications

(9 citation statements)

References 52 publications

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“…To further improve the affinity with targets, crosslink formation is a reasonable strategy that covalently traps targeting biomolecules such as DNA, RNA, and protein. Various attractive crosslinkforming oligonucleotides (CFOs) have been reported using differing methods-for example, the use of reactive substituents that boost the crosslinking reaction by response to a stimulus such as UV light (Higuchi, Kobori, Yamayoshi, & Murakami, 2009;Miller, Bi, Kipp, Fok, & DeLong, 1996;Qiu, Lu, Jian, & He, 2008), photo activation (Yoshimura & Fujimoto, 2008), oxidative activation (Op de Beeck & Madder, 2011;Sloane & Greenberg, 2014), or activation using chemical reagents (Wickramaratne, Mukherjee, Villalta, Schärer, & Tretyakova, 2013)-to promote the reaction.…”

Section: Background Informationmentioning

confidence: 99%

Synthesis of RNA Crosslinking Oligonucleotides Modified with 2‐Amino‐7‐Deaza‐7‐Propynyl‐6‐Vinylpurine

Yamada

Abe

Nagatsugi

2019

CP Nucleic Acid Chemistry

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This article describes procedures to synthesize 2′‐OMe‐RNA modified with cross‐linkable 2‐amino‐7‐deaza‐7‐propynyl‐6‐vinylpurine (ADpVP) and preparation of the RNA‐crosslinking experiment in vitro. All synthesis steps yield the desired compound in moderate or high yield without expensive chemical reagents or specific devices. The crosslink‐active form of modified RNA can also be purified by commonly used reversed‐phase HPLC, can be stored at −80°C after lyophilization for a few days, and is ready to use for crosslinking experiments. This crosslink‐active RNA can efficiently form covalent bonds with complementary RNA in a sequence‐specific manner. © 2019 by John Wiley & Sons, Inc.

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Section: Background Informationmentioning

confidence: 99%

Synthesis of RNA Crosslinking Oligonucleotides Modified with 2‐Amino‐7‐Deaza‐7‐Propynyl‐6‐Vinylpurine

Yamada

Abe

Nagatsugi

2019

CP Nucleic Acid Chemistry

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“…Greenberg et al proposed through in vitro experiments that C6‐peroxy radical preferred to cross‐link with the C8 site of the neighboring guanine base to form the C6OOC8‐containing intermediate. [ 13–17 ] The relative theoretical studies by Dumont et al elucidated the possible adducts for purine‐peroxy‐pyrimidine (purine = guanine or adenine, pyrimidine = thymine or cytosine). Their average activation barriers for the intramolecular addition between pyrimidine peroxy radical and guanine ranged from 4.4 to 20.8 kcal/mol and 12.4 to 21.0 kcal/mol between pyrimidines peroxy radical and adenine.…”

Section: Introductionmentioning

confidence: 99%

A theoretical study towards understanding the origin of DNA oxidation products

Zhao

Jiang

Wang

et al. 2020

J of Physical Organic Chem

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Reactivity of thymine peroxy radical in DNA and its fate under oxygen‐less condition are studied at DFT B3LYP and M06‐2X functionals together with 6‐31+G(d,p) and aug‐cc‐pVTZ basis sets. The irreversible reaction between OH free radical‐induced C6‐yl and O2 molecule leads to the two main conformers. The spaciously accessible H2′ on the sugar can be abstracted by C6‐peroxy with the estimated barriers of 15.7–21.0 kcal/mol, dependent on various theoretical methods and the conformers. The calculations show that C6‐peroxy has a highly more reactivity towards C (sp3)‐H abstraction reactions than its relative C6‐yl, which is a counter‐intuitive case. Based on the classical Arrhenius rate formula, we find that the vertical electron affinities and proton affinities of the H‐atom acceptors are strongly relevant to electron transfer rate and proton transfer rate, respectively, in the C‐H abstraction reactions. The formed hydroperoxide with the C6‐OaObH2′ constituent can ultrafastly transfer ObH2′ to C2′ radical of the same sugar with a very low barrier (approximately 1.6 kcal/mol) and very strong exothermicity. The results show that the formed hydroperoxide product is too unstable so that it could be quickly transformed into other species and thus is very hard to be experimentally observed. Afterwards, H2′ can be again abstracted by C6‐oxyl radical to result in formation of thymine glycol. The parallel C5‐C6 bond scission reaction leads to formation of the precursor to 5‐hydroxy‐5‐methylhydantion. The two competitive reactions have very low or even negative barriers, dependent on the used functional. Thus, the new radical reaction paths to formation of both thymine glycol and 5‐hydroxy‐5‐methylhydantion are discovered under oxygen‐less condition, which is different from the previously suggested paths under high oxygen concentration surroundings. The influences of the relevant side reactions on formation of the two oxidation damage biomarker molecules are also discussed.

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“…Nevertheless, these doubly-modified thymidine analogues have been used to demonstrate the formation of interstrand cross-linking and biocongugates in RNA and DNA via a mechanism involving exocyclic methylene-modified thymidines. 12,13,30,31 Thus there has been substantial interest in designing synthetic routes that can generate modified nucleotides, 9,32 and one modified only by transposition of the olefin to an exocyclic position (i.e. compound 2 ) would be especially valuable in studies of enzyme mechanism(s).…”

Section: Introductionmentioning

confidence: 99%

Chemo-enzymatic synthesis of the exocyclic olefin isomer of thymidine monophosphate

Mondal

Koehn

Yao

et al. 2018

Bioorganic & Medicinal Chemistry

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Exocyclic olefin variants of thymidylate (dTMP) recently have been proposed as reaction intermediates for the thymidyl biosynthesis enzymes found in many pathogenic organisms, yet synthetic reports on these materials are lacking. Here we report two strategies to prepare the exocyclic olefin isomer of dTMP, which is a putative reaction intermediate in pathogenic thymidylate biosynthesis and a novel nucleotide analog. Our most effective strategy involves preserving the existing glyosidic bond of thymidine and manipulating the base to generate the exocyclic methylene moiety. We also report a successful enzymatic deoxyribosylation of a non-aromatic nucleobase isomer of thymine, which provides an additional strategy to access nucleotide analogs with disrupted ring conjugation or with reduced heterocyclic bases. The strategies reported here are straightforward and extendable towards the synthesis of various pyrimidine nucleotide analogs, which could lead to compounds of value in studies of enzyme reaction mechanisms or serve as templates for rational drug design.

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Interstrand Cross-Link and Bioconjugate Formation in RNA from a Modified Nucleotide

Cited by 15 publications

References 52 publications

Synthesis of RNA Crosslinking Oligonucleotides Modified with 2‐Amino‐7‐Deaza‐7‐Propynyl‐6‐Vinylpurine

Synthesis of RNA Crosslinking Oligonucleotides Modified with 2‐Amino‐7‐Deaza‐7‐Propynyl‐6‐Vinylpurine

A theoretical study towards understanding the origin of DNA oxidation products

Chemo-enzymatic synthesis of the exocyclic olefin isomer of thymidine monophosphate

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