SYNTHESIS OF LPHA-D-ERYTHRO-PENTOFURANOSYL)(THYMIN-1-YL)ALKANES AND BETA-D-ERYTHRO-PENTOFURANOSYL)(THYMIN-1-YL)ALKANES AND THEIR INCORPORATION INTO OLIGODEOXYRIBONUCLEOTIDES - EFFECT OF NUCLEOBASE-SUGAR LINKERFLEXIBILITY ON THE FORMATION OF DNA-DNA AND DNA-RNA HYBRIDS

On the basis of modeling studies, the (2-deoxy-alpha- and beta-D-eryth ro-pentofuranosyl) (thymin-1-yl) alkanes 1a,b and 2a,b were selected a s potential conformational probes for altDNA oligonucleotides. A strai ghtforward approach to the synthesis of 1a,b and 2a,b from commercial 2-deoxy-D-ribose (3) and 2-deoxy-3,5-di-O-p-toluoyl-D-erythro-pentofur anose (13), respectively, was developed. These nucleoside analogues we re converted to the phosphoramidite derivatives 27a,b-30a,b and incorp orated into oligonucleotide 31 at predetermined sites and defined inte rnucleotidic motifs. The insertion of 1a,b according to either a (3' - -> 5')- or a (3' --> 3')-internucleotidic polarity produced oligonucle otides exhibiting a slightly higher affinity for their complementary u nmodified DNA sequence than for the corresponding RNA sequence (Table 3). Conversely, the incorporation of 2a into 31 according to a (3' --> 3')-orientation generated, for the first time, an altDNA oligonucleot ide displaying a greater affinity for its complementary unmodified RNA sequence (Delta T-m = 6 degrees C) than for the corresponding DNA seq uence (Delta T-m = 10 degrees C). thermodynamically less stable than t he duplex having unmodified alpha-2'-deoxythymidine similarly incorpor ated into 31 (Delta Delta T-m = 3 degrees C).