Synthesis and properties of 2′-O-[R- and S-(2-amino-3-methoxy)propyl] (R-AMP and S-AMP) nucleic acids

Substitution at 2′-position by either amino- or methoxy-pendant groups of the antisense oligonucleotides (AONs) is known to enhance their therapeutic value. A simple modification is described here in which we introduce both these groups in the form of enantiospecific tethers at 2′-position. Practical synthesis of modified nucleosides using natural l-serine, en route to R-AMP- and S-AMP-AONs is presented. Such tethered ONs formed stable DNA:RNA duplexes and the stability was found to be marginally better than the methoxyethyl/methoxypropyl-substituted MOE/MOP-AONs. The stereochemistry of the tether effectively differentiated the hydrolytic cleavage of AONs and the R-AMP-AON was three times more stable than the S-AMP-AONs after 4 h. In comparison, the MOE- or MOP-AONs were almost completely digested by SVPD after 1 h.

Graphical abstractDownload full-size image