Mechanistic Studies on RNA Strand Scission from a C2′-Radical

Rutgeerts, Paul; Greenberg, Marc M.

doi:10.1021/acs.joc.6b01760

Cited by 4 publications

(5 citation statements)

References 46 publications

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“…The method is common practice in computational chemistry and has been validated in recent studies. , Previous investigations indicate that OH attack on the C5-position of uridine, which results in formation of the C6-yl radical, accounts for ∼70% of the reactions between hydroxyl and poly(U). , In the present studies, the C6-yl radical was obtained through addition of OH radical to the C5-position of the middle uracil base of the stacked trimer. The RNA C6-yl species is known to be reactive toward C2′–H2′ bond activation under anaerobic conditions. − Under aerobic conditions, however, extrinsic O 2 molecules will preferentially react with the C6-yl radical site to produce the corresponding 5-hydroxyl-2′-uridin-6-peroxyl reactive species. The primary reaction processes and the important atomic labels of the C6-peroxyl model are shown in Scheme .…”

Section: Computational Model and Methodsmentioning

confidence: 99%

“…The RNA molecules should be more easily oxidized than DNA because the 2′-OH group of the ribose moiety greatly contributes to the increased acidity of the remaining H2′ atom. Recent experiments − have demonstrated that H2′ is the most facile position to be abstracted by uracil C6-yl in an internucleotidyl process. Our previous theoretical studies showed that the efficiency of C2′–H2′ bond activation in the C6-yl radical is quite high under anaerobic conditions, which in turn leads to C3′–O3′(P) bond breakage and direct strand scission.…”

Section: Introductionmentioning

confidence: 99%

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Theoretical Insights on the Inefficiency of RNA Oxidative Damage under Aerobic Conditions

2017

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Oxidative damage to RNA has been linked to change or loss of RNA function and development of many human age-related diseases. However, knowledge on the nature of RNA oxidative damage is relatively limited. In this study, oxidative damage to RNA is investigated under anaerobic and aerobic conditions by exploring the properties and reactions of 5-hydroxyl-2'-uridin-6-yl and its peroxyl diastereoisomers in the RNA strand, respectively. Selective addition of OH to the nucleic base from the 5'-end is studied at the molecular level for the first time, explaining the large number of the 5S-isomer available for further reactions. Our results provide clear evidence that the efficiency of C2'-H2' bond activation in the peroxyl isomers is lower than in the carbon radical species. An exception is observed for the isomer cis-(5S,6R)-A1, whose internucleotidyl H2'-abstraction barrier is far smaller than that in the corresponding C6-yl radical. However, analysis of the equilibrium species distribution reveals that the amount of cis-(5S,6R)-A1 is very small among the peroxyl diastereoisomers, and hence the resulting products from direct strand scission should be a less important component in RNA oxidative damage. The species with maximum distribution is the cis-(5S,6R)-B1 isomer, which is derived from cis-(5S,6R)-A1 and has a moderate intranucleotidyl H2'-abstraction barrier. More importantly, the reaction is mildly exothermic. These results show that the main fraction of the intranucleotidyl H2'-abstraction intermediates can be formed from the cis-(5S,6R)-B1 isomer. The absolute reduction potentials, the hydrogen atom binding energies, and the key structural parameters of the C6-peroxyl species are used to understand the diverse reactivity of the cis-(5S,6R) diastereoisomers toward the C2'-H2' bonds activation. The present study shows that in addition to the selectivity of the OH radical addition, there is a strong correlation between the conformation of the modified uracil base and its reactivity in RNA oxidative damage.

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Section: Computational Model and Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Theoretical Insights on the Inefficiency of RNA Oxidative Damage under Aerobic Conditions

2017

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“…In fact, in both cases DFT optimizations resulted in either spontaneous N-O bond cleavage ( 3 7, M06-2X/cc-pVDZ) or in a very small barrier to decarboxylation (4, M06-2X/cc-pVQZ: DU ‡ = 0.8 kcal mol À1 ). Born-Oppenheimer molecular dynamics simulations (M06-2X/cc-pVDZ) also in both cases resulted in C-C cleavage (4) or N-O cleavage followed by C-C cleavage ( 3 7), within a few femtoseconds each. Hence, an assignment of transient C to either species does not appear to represent a viable option.…”

Section: Laser Flash Photolysismentioning

confidence: 95%

“…Enol and enol ether radical cations 1 are of considerable significance both to chemical 2,3 and biological [4][5][6][7] systems. Due to their relevance, several studies directed at elucidating the reactivity of enol ether radical cations via direct kinetic methods such as laser flash photolysis (LFP) have been published.…”

Section: Introductionmentioning

confidence: 99%

Fragmentation of a dioxolanyl radical via nonstatistical reaction dynamics: characterization of the vinyloxy radical by ns time-resolved laser flash photolysis

Bucher

Lal

Rana

et al. 2018

Phys. Chem. Chem. Phys.

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The photochemistry of two Barton esters, one derived from a dioxolane carboxylic acid and the other from pivalic acid, was investigated by product analysis and nanosecond laser flash photolysis (LFP). As expected, photolysis of the pivalate ester resulted in formation of the pyridine-2-thiyl and the t-butyl radical. Photolysis of the Barton ester of 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid, on the other hand, revealed a complex multi-step fragmentation. In addition to the pyridine-2-thiyl and dioxolanyl radical, we gained evidence for the formation of the vinyloxy radical, CH2[double bond, length as m-dash]CHO˙. The latter was identified in the LFP by its π-complexes with benzene and diphenylether, its rapid quenching by electron-rich arenes and tri-n-butyl tin hydride, and its oxidative power in presence of trifluoroacetic acid as demonstrated by the oxidation of ferrocene to ferrocenium. Formation of CH2[double bond, length as m-dash]CHO˙ can be rationalized via fragmentation of the dioxolanyl radical. As the calculated barriers are too high for the reaction sequence to occur on the LFP time scale, we investigated the fragmentation of the photoexcited Barton ester via Born-Oppenheimer molecular dynamics simulations. In one trajectory, we could observe all reaction steps including ring opening of the dioxolanyl radical, suggesting that the excess energy gained in the ester cleavage and decarboxylation may lead to fragmentation of the hot dioxolanyl radical.

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“…Extensive theoretical[3a, 6] and experimental research on model systems indicates that hydrogen bonding profoundly alters the reactivity of enols (including phenols) and their one‐electron oxidized species. Enol and enol ether radical cations have also been investigated for their role in DNA and RNA damage.…”

Section: Introductionmentioning

confidence: 99%

Detection and follow‐up reactions of distonic β,β‐dimesityl enol radical cations containing nitrogen heterocyclic bases

Çınar

Lal

Deiseroth

et al. 2018

J of Physical Organic Chem

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β,β-Dimesityl enols E2-E4 containing various nitrogen heterocyclic bases in the α-position were investigated by laser flash photolytic oxidation and density functional theory in order to identify distonic enol radical cations in solution and characterize their immediate follow-up reactions. Enol E1 with a tert-butyl group in the α-position served as a reference. Experimental and computational efforts reveal that one-electron oxidation of enol E1 furnishes the enol radical cation, whereas oxidation of E2-E4 provides distonic radical cations in solution. While the distonic radical cations of E2-E3 undergo intermolecular acid-base reactions, the distonic radical cation of E4 experiences an intramolecular hydrogen abstraction followed by subsequent ring closure and ring-opening steps. As a final product on the laser flash photolysis time scale, the rearranged radical cation E4d-R is generated that is characterized by a dimesitylmethyl radical subunit. KEYWORDS cyclic voltammetry (CV), density functional theory (DFT), distonic radical cation, laser flash photolysis (LFP), enol radical cation

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Mechanistic Studies on RNA Strand Scission from a C2′-Radical

Cited by 4 publications

References 46 publications

Theoretical Insights on the Inefficiency of RNA Oxidative Damage under Aerobic Conditions

Theoretical Insights on the Inefficiency of RNA Oxidative Damage under Aerobic Conditions

Fragmentation of a dioxolanyl radical via nonstatistical reaction dynamics: characterization of the vinyloxy radical by ns time-resolved laser flash photolysis

Detection and follow‐up reactions of distonic β,β‐dimesityl enol radical cations containing nitrogen heterocyclic bases

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