Assignment of absolute configurations of the enantiomeric spiroiminodihydantoin nucleobases by experimental and computational optical rotatory dispersion methods.
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.
Durandin
Alexander
A
Department of Chemistry, New York University, New York 10003-5180, USA.
Jia
Lei
L
Crean
Conor
C
Kolbanovskiy
Alexander
A
Ding
Shuang
S
Shafirovich
Vladimir
V
Broyde
Suse
S
Geacintov
Nicholas E
NE
D002467:Cell Nucleus / Q000737:chemistry*; D003198:Computer Simulation; D006151:Guanosine / Q000031:analogs & derivatives* / Q000737:chemistry; D008968:Molecular Conformation; D015394:Molecular Structure; D009696:Nucleic Acids / Q000737:chemistry*; D009905:Optical Rotatory Dispersion; D010084:Oxidation-Reduction; D013141:Spiro Compounds / Q000737:chemistry*; D013237:Stereoisomerism
D009696:Nucleic Acids; D013141:Spiro Compounds; C408822:spiroiminodihydantoin; D006151:Guanosine