Premium
Triple‐Helix Formation by Pyrimidine Oligonucleotides Containing Nonnatural Nucleosides with Extended Aromatic Nucleobases: Intercalation from the major groove as a method for recognizing C·G and T · A base pairs
Author(s) -
Lehmann Thomas E.,
Greenberg William A.,
Liberles David A.,
Wada Carol K.,
Dervan Peter B.
Publication year - 1997
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19970800618
Subject(s) - nucleobase , chemistry , stereochemistry , pyrimidine , oligonucleotide , triple helix , base pair , dna , biochemistry
The sequence‐specific recognition of double‐helical DNA by oligonucleotide‐directed triple helix formation is limited primarily to purine tracts. To identify potential lead compounds which are able to extend the sequence repertoire of triple helical complexes, we designed two carbocyclic nucleosides with nucleobases attached via amide bonds. N 5 ‐[(1 R , 2 S , 3 R , 4 R )‐3‐hydroxy‐4‐(hydroxymethyl)‐2‐methoxycyclopentyl]‐2‐{[(1 H ‐pyrrol‐2‐yl)carbonyl]‐amino}thiazole‐5‐carboxamide ( L1 ) and 2‐benzamido‐ N 5 ‐[(1 R , 2 S , 3 R , 4 R )‐3‐hydroxy‐4‐(hydroxymethyl)‐2‐methoxycyclopentyl]thiazole‐5‐carboxamide ( L2 ) were synthesized and incorporated into pyrimidine oligonucleotides. The 2‐(trimethylsilyl)ethoxymethyl (SEM) protecting group for the 1 H ‐pyrrole NH was found to be compatible with DNA solid‐phase synthesis of pyrimidine Oligonucleotides. By quantitative DNase I footprinting analysis, both nonnatural nucleosides L1 and L2 showed preferential binding of pyrimidine over purine bases: L1 / 2 ·(C·G) ≈ L1 / 2 ·(T · A) > L1 / 2 ·(G·C) ≈ L1 / 2 ·(A · T). Comparison with the previously reported nonnatural nucleosides with extended aromatic nucleobases 1‐(2‐deoxy‐β‐ D ‐ribofuranosyl)‐4‐(3‐benzamidophenyl)‐imidazole ( D3 ) and N 4 ‐[6‐(benzamido)pyridin‐2‐yl]‐2′‐deoxycytidine ( bz M ) suggests that the observed binding selectivity C · G ≈ T · A > G · C ≈ A · T for the nucleoside analogs L1 , L2 , D3 , and bz M is derived from sequence‐specific intercalation with preferential stacking of their nucleobases over pyrimidine · purine Watson ‐ Crick base pairs.