Assignment of absolute configurations of the enantiomeric spiroiminodihydantoin nucleobases by experimental and computational optical rotatory dispersion methods

Alexander Durandin, Lei Jia, Conor Crean, Alexander Kolbanovskiy, Shuang Ding, Vladimir Shafirovich, Suse Broyde, Nicholas E. Geacintov

Research output: Contribution to journalArticle

Abstract

The diastereomeric spiroiminodihydantoin (Sp) lesions are oxidation products of guanine and 8-oxo-7,8-dihydroguanine (8-oxoG) and have generated considerable interest because of their stereochemistry-dependent mutagenic properties in vivo (Henderson, P. T., et al. (2003) Biochemistry 42, 9257-9262). However, the absolute configurations of the two diastereomers have not yet been elucidated, and such information may prove valuable for understanding relationships between biological function and structure at the DNA level (Jia, L., Shafirovich, V., Shapiro, R., Geacintov, N. E., and Broyde, S. (2005) Biochemistry 44, 13342-13353). We have synthesized the two chiral Sp nucleobases by hydrolysis of the nucleosides denoted by dSp1 and dSp2 according to their elution order in HPLC experiments using a Hypercarb column, and determined their absolute configurations using a combination of experimentally measured optical rotatory dispersion (ORD) spectra in aqueous solutions and computed ORD specific rotations using density functional theory (DFT). Recent developments have shown that DFT methods are now sufficiently robust for predicting ORD values of chiral molecules (Polavarapu, P. L. (2002) Chirality 14, 768-781). The nucleobases Sp1 and Sp2 exhibit experimentally measured CD and ORD spectra that are very close to those of the respective precursor nucleosides dSp1 and dSp2 in shape and sign. The first nucleoside stereoisomer (dSp1) to elute from a typical Hypercarb HPLC column has (-)-S, while the second (dSp2) has (+)-R absolute configuration. The R and S assignments are applicable to the amino tautomeric forms in each case.

Original languageEnglish (US)
Pages (from-to)908-913
Number of pages6
JournalChemical Research in Toxicology
Volume19
Issue number7
DOIs
StatePublished - Jul 2006

Fingerprint

Optical Rotatory Dispersion
Nucleosides
Biochemistry
Density functional theory
High Pressure Liquid Chromatography
Stereochemistry
Stereoisomerism
Chirality
Guanine
Hydrolysis
Oxidation
Molecules
spiroiminodihydantoin
DNA
Experiments

ASJC Scopus subject areas

  • Chemistry(all)
  • Organic Chemistry
  • Health, Toxicology and Mutagenesis
  • Drug Discovery
  • Toxicology

Cite this

Assignment of absolute configurations of the enantiomeric spiroiminodihydantoin nucleobases by experimental and computational optical rotatory dispersion methods. / Durandin, Alexander; Jia, Lei; Crean, Conor; Kolbanovskiy, Alexander; Ding, Shuang; Shafirovich, Vladimir; Broyde, Suse; Geacintov, Nicholas E.

In: Chemical Research in Toxicology, Vol. 19, No. 7, 07.2006, p. 908-913.

Research output: Contribution to journalArticle

Durandin, Alexander ; Jia, Lei ; Crean, Conor ; Kolbanovskiy, Alexander ; Ding, Shuang ; Shafirovich, Vladimir ; Broyde, Suse ; Geacintov, Nicholas E. / Assignment of absolute configurations of the enantiomeric spiroiminodihydantoin nucleobases by experimental and computational optical rotatory dispersion methods. In: Chemical Research in Toxicology. 2006 ; Vol. 19, No. 7. pp. 908-913.
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abstract = "The diastereomeric spiroiminodihydantoin (Sp) lesions are oxidation products of guanine and 8-oxo-7,8-dihydroguanine (8-oxoG) and have generated considerable interest because of their stereochemistry-dependent mutagenic properties in vivo (Henderson, P. T., et al. (2003) Biochemistry 42, 9257-9262). However, the absolute configurations of the two diastereomers have not yet been elucidated, and such information may prove valuable for understanding relationships between biological function and structure at the DNA level (Jia, L., Shafirovich, V., Shapiro, R., Geacintov, N. E., and Broyde, S. (2005) Biochemistry 44, 13342-13353). We have synthesized the two chiral Sp nucleobases by hydrolysis of the nucleosides denoted by dSp1 and dSp2 according to their elution order in HPLC experiments using a Hypercarb column, and determined their absolute configurations using a combination of experimentally measured optical rotatory dispersion (ORD) spectra in aqueous solutions and computed ORD specific rotations using density functional theory (DFT). Recent developments have shown that DFT methods are now sufficiently robust for predicting ORD values of chiral molecules (Polavarapu, P. L. (2002) Chirality 14, 768-781). The nucleobases Sp1 and Sp2 exhibit experimentally measured CD and ORD spectra that are very close to those of the respective precursor nucleosides dSp1 and dSp2 in shape and sign. The first nucleoside stereoisomer (dSp1) to elute from a typical Hypercarb HPLC column has (-)-S, while the second (dSp2) has (+)-R absolute configuration. The R and S assignments are applicable to the amino tautomeric forms in each case.",
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AU - Durandin, Alexander

AU - Jia, Lei

AU - Crean, Conor

AU - Kolbanovskiy, Alexander

AU - Ding, Shuang

AU - Shafirovich, Vladimir

AU - Broyde, Suse

AU - Geacintov, Nicholas E.

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AB - The diastereomeric spiroiminodihydantoin (Sp) lesions are oxidation products of guanine and 8-oxo-7,8-dihydroguanine (8-oxoG) and have generated considerable interest because of their stereochemistry-dependent mutagenic properties in vivo (Henderson, P. T., et al. (2003) Biochemistry 42, 9257-9262). However, the absolute configurations of the two diastereomers have not yet been elucidated, and such information may prove valuable for understanding relationships between biological function and structure at the DNA level (Jia, L., Shafirovich, V., Shapiro, R., Geacintov, N. E., and Broyde, S. (2005) Biochemistry 44, 13342-13353). We have synthesized the two chiral Sp nucleobases by hydrolysis of the nucleosides denoted by dSp1 and dSp2 according to their elution order in HPLC experiments using a Hypercarb column, and determined their absolute configurations using a combination of experimentally measured optical rotatory dispersion (ORD) spectra in aqueous solutions and computed ORD specific rotations using density functional theory (DFT). Recent developments have shown that DFT methods are now sufficiently robust for predicting ORD values of chiral molecules (Polavarapu, P. L. (2002) Chirality 14, 768-781). The nucleobases Sp1 and Sp2 exhibit experimentally measured CD and ORD spectra that are very close to those of the respective precursor nucleosides dSp1 and dSp2 in shape and sign. The first nucleoside stereoisomer (dSp1) to elute from a typical Hypercarb HPLC column has (-)-S, while the second (dSp2) has (+)-R absolute configuration. The R and S assignments are applicable to the amino tautomeric forms in each case.

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