A highly effective nonpolar isostere of deoxyguanosine: synthesis, structure, stacking, and base pairing.
We describe the preparation and structure of the deoxyribonucleoside of 4-fluoro-6-methylbenzimidazole, abbreviated dH (8), which acts as a close shape mimic of the nucleoside deoxyguanosine. The nucleoside is prepared from 2-fluoro-4-methylaniline in seven steps. The X-ray crystal structure reveals a (-sc) glycosidic orientation, an S conformation for the deoxyribose moiety, and quite close shape mimicry of guanine by the substituted benzimidazole. Conformational studies by (1)H NMR and (1)H-(1)H ROESY experiments reveal an S-type conformation and an anti glycosidic orientation in solution (D(2)O), essentially the same as that of deoxyguanosine. Base-stacking studies in a "dangling end" context reveal that the benzimidazole base mimic stacks more strongly than all four natural bases, and more strongly than its counterpart guanine by 1.1 kcal/mol. Base-pairing studies in a 12mer DNA duplex show that, like other nonpolar nucleoside isosteres, H is destabilizing and nonselective when paired opposite natural bases. However, when paired opposite another nonpolar isostere, difluorotoluene (F), a mimic of thymine, the pair exhibits stability approaching that of its natural analogue, a G-T (wobble) base pair. The nucleoside analogue dH will be useful in studies of protein-DNA interactions, and the H-F base pair will serve as a structurally and thermodynamically close mimic of G-T in studies of DNA mismatch repair enzymes.
Department of Chemistry, University of San Diego, 5998 Alcala Park, San Diego, California 92110, USA.
Bryan M
BM
O'Neill
Jessica E
JE
Ratto
Kristi L
KL
Good
Deborah C
DC
Tahmassebi
Sandra A
SA
Helquist
Juan C
JC
Morales
Eric T
ET
Kool
D000814:Aniline Compounds / Q000737:chemistry; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry*; D002625:Chemistry, Organic / Q000379:methods*; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D018716:Molecular Mimicry; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D013237:Stereoisomerism
C470897:2-fluoro-4-methylaniline; C470896:4-fluoro-6-methylbenzimidazole; D000814:Aniline Compounds; D001562:Benzimidazoles; D004247:DNA; D003849:Deoxyguanosine