2’-Substituted 2-Amino-3-Methylpyridine Ribonucleosides in Triplex-Forming Oligonucleotides: Triplex Stability is Determined by Chemical Environment

C. Lou, Q. Xiao, R. R. Tailor, N. Ben Gaied, N. Gale, M. E. Light, K. R. Fox and T. Brown. Med. Chem. Comm. 2, 550-558, 2011.


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.