ISSN:
0018-019X
Keywords:
Chemistry
;
Organic Chemistry
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
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. N5-[(1R, 2S, 3R, 4R)-3-hydroxy-4-(hydroxymethyl)-2-methoxycyclopentyl]-2-{[(1H-pyrrol-2-yl)carbonyl]-amino}thiazole-5-carboxamide (L1) and 2-benzamido-N5-[(1R, 2S, 3R, 4R)-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 1H-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 N4-[6-(benzamido)pyridin-2-yl]-2′-deoxycytidine (bzM) suggests that the observed binding selectivity C · G ≈ T · A 〉 G · C ≈ A · T for the nucleoside analogs L1, L2, D3, and bzM is derived from sequence-specific intercalation with preferential stacking of their nucleobases over pyrimidine · purine Watson-Crick base pairs.
Additional Material:
6 Ill.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/hlca.19970800618
Permalink
