Abstract
Limitations exist among the commonly used cyclic nitrone spin traps for biological free radical detection using electron paramagnetic resonance (EPR) spectroscopy. The design of new spin traps for biological free radical detection and identification using EPR spectroscopy has been a major challenge due to the lack of systematic and rational approaches to their design. In this work, density functional theory (DFT) calculations and stopped-flow kinetics were employed to predict the reactivity of functionalized spin traps with superoxide radical anion (O2 •-). Functional groups provide versatility and can potentially improve spin-trap reactivity, adduct stability, and target specificity. The effect of functional group substitution at the C-5 position of pyrroline N-oxides on spin-trap reactivity toward O2 •- was computationally rationalized at the PCM/B3LYP/6-31+G(d,p) //B3LYP/6-31G(d) and PCM/mPW1K/6-31+G(d,p) levels of theory. Calculated free energies and rate constants for the reactivity of O2 •- with model nitrones were found to correlate with the experimentally obtained rate constants using stopped-flow and EPR spectroscopic methods. New insights into the nucleophilic nature of O2 •- addition to nitrones as well as the role of intramolecular hydrogen bonding of O2 •- in facilitating this reaction are discussed. This study shows that using an N-monoalkylsubstituted amide or an ester as attached groups on the nitrone can be ideal in molecular tethering for improved spin-trapping properties and could pave the way for improved in vivo radical detection at the site of superoxide formation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 8177-8191 |
| Number of pages | 15 |
| Journal | Journal of the American Chemical Society |
| Volume | 129 |
| Issue number | 26 |
| DOIs | |
| State | Published - Jul 4 2007 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Chemistry(all)
Cite this
Reactivity of superoxide radical anion with cyclic nitrones : Role of intramolecular H-Bond and electrostatic effects. / Villamena, Frederick A.; Xia, Shijing; Merle, John K.; Lauricella, Robert; Tuccio, Beatrice; Hadad, Christopher M.; Zweier, Jay L.
In: Journal of the American Chemical Society, Vol. 129, No. 26, 04.07.2007, p. 8177-8191.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Reactivity of superoxide radical anion with cyclic nitrones
T2 - Role of intramolecular H-Bond and electrostatic effects
AU - Villamena, Frederick A.
AU - Xia, Shijing
AU - Merle, John K.
AU - Lauricella, Robert
AU - Tuccio, Beatrice
AU - Hadad, Christopher M.
AU - Zweier, Jay L.
PY - 2007/7/4
Y1 - 2007/7/4
N2 - Limitations exist among the commonly used cyclic nitrone spin traps for biological free radical detection using electron paramagnetic resonance (EPR) spectroscopy. The design of new spin traps for biological free radical detection and identification using EPR spectroscopy has been a major challenge due to the lack of systematic and rational approaches to their design. In this work, density functional theory (DFT) calculations and stopped-flow kinetics were employed to predict the reactivity of functionalized spin traps with superoxide radical anion (O2 •-). Functional groups provide versatility and can potentially improve spin-trap reactivity, adduct stability, and target specificity. The effect of functional group substitution at the C-5 position of pyrroline N-oxides on spin-trap reactivity toward O2 •- was computationally rationalized at the PCM/B3LYP/6-31+G(d,p) //B3LYP/6-31G(d) and PCM/mPW1K/6-31+G(d,p) levels of theory. Calculated free energies and rate constants for the reactivity of O2 •- with model nitrones were found to correlate with the experimentally obtained rate constants using stopped-flow and EPR spectroscopic methods. New insights into the nucleophilic nature of O2 •- addition to nitrones as well as the role of intramolecular hydrogen bonding of O2 •- in facilitating this reaction are discussed. This study shows that using an N-monoalkylsubstituted amide or an ester as attached groups on the nitrone can be ideal in molecular tethering for improved spin-trapping properties and could pave the way for improved in vivo radical detection at the site of superoxide formation.
AB - Limitations exist among the commonly used cyclic nitrone spin traps for biological free radical detection using electron paramagnetic resonance (EPR) spectroscopy. The design of new spin traps for biological free radical detection and identification using EPR spectroscopy has been a major challenge due to the lack of systematic and rational approaches to their design. In this work, density functional theory (DFT) calculations and stopped-flow kinetics were employed to predict the reactivity of functionalized spin traps with superoxide radical anion (O2 •-). Functional groups provide versatility and can potentially improve spin-trap reactivity, adduct stability, and target specificity. The effect of functional group substitution at the C-5 position of pyrroline N-oxides on spin-trap reactivity toward O2 •- was computationally rationalized at the PCM/B3LYP/6-31+G(d,p) //B3LYP/6-31G(d) and PCM/mPW1K/6-31+G(d,p) levels of theory. Calculated free energies and rate constants for the reactivity of O2 •- with model nitrones were found to correlate with the experimentally obtained rate constants using stopped-flow and EPR spectroscopic methods. New insights into the nucleophilic nature of O2 •- addition to nitrones as well as the role of intramolecular hydrogen bonding of O2 •- in facilitating this reaction are discussed. This study shows that using an N-monoalkylsubstituted amide or an ester as attached groups on the nitrone can be ideal in molecular tethering for improved spin-trapping properties and could pave the way for improved in vivo radical detection at the site of superoxide formation.
UR - http://www.scopus.com/inward/record.url?scp=34447116491&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34447116491&partnerID=8YFLogxK
U2 - 10.1021/ja0702622
DO - 10.1021/ja0702622
M3 - Article
C2 - 17564447
AN - SCOPUS:34447116491
VL - 129
SP - 8177
EP - 8191
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 26
ER -