2’-Substituted 2-Amino-3-Methylpyridine Ribonucleosides in Triplex-Forming Oligonucleotides: Triplex Stability is Determined by Chemical Environment
550-558, 2011.Med. Chem. Comm. 2,
A new synthetic route to the phosphoramidite monomer of 2-amino-3-methyl-5-(2'-O-methyl-beta-D-ribofuranosyl)pyridine (Me-MAP) and its 2'-O-methoxyethyl analogue (MOE-MAP) has been established using D-ribose and 2-amino-3-methyl-5-bromopyridine as precursors. Ultraviolet melting and DNase I footprinting studies indicate that the triplex stabilizing properties of 2'-modified MAPs are determined by the conformation of the entire oligonucleotide backbone. Me-MAP confers a higher triplex stability than 2'-deoxycytidine whereas triplex stabilization by MOE-MAP is similar to that of dC. Incorporation of Me-MAP or MOE-MAP into oligonucleotides renders them dramatically more resistant to degradation by serum nucleases than incorporation of 2-amino-3-methyl-5-(2'-deoxy-beta-D-ribofuranosyl)pyridine (dMAP) or dC.