Influence of 2'-fluoro versus 2'-O-methyl substituent on the sugar puckering of 4'-C-aminomethyluridine

Abstract

Herein, we report the synthesis of 4'-C-aminomethyl-2'-deoxy-2'-fluorouridine, a therapeutically appealing RNA modification. Conformational analysis by DFT calculations and molecular dynamics simulations using trinucleotide model systems revealed that modified sugar adopts C3'-endo conformation. In this conformer, a weak intramolecular C-H···F H-bond between the hydrogen atom of the 4'-C-CH2 group and the F atom at the 2' position is observed. Comparative studies with unmodified, 2'-fluoro-, 2'-O-methyl-, and 4'-C-aminomethyl-2'-O-methyluridine showed the chemical nature of 2'-substituent dictates the sugar puckering of 2',4'-modified nucleotides.