4′-C-Trifluoromethyl modified oligodeoxynucleotides: synthesis, biochemical studies, and cellular uptake properties

Herein, we report the synthesis of 4 '-C-trifluoromethyl (4 '-CF3) thymidine (T4 '-CF3) and its incorporation into oligodeoxynucleotides (ODNs) through solid-supported DNA synthesis. The 4 '-CF3 modification leads to a marginal effect on the deoxyribose conformation and a local helical structure perturbation for ODN/RNA duplexes. This type of modification slightly decreases the thermal stability of ODN/RNA duplexes (-1 degrees C/modification) and leads to improved nuclease resistance. Like the well-known phosphorothioate (PS) modification, heavy 4 '-CF3 modifications enable direct cellular uptake of the modified ODNs without any delivery reagents. This work highlights that 4 '-CF3 modified ODNs are promising candidates for antisense-based therapeutics, which will, in turn, inspire us to develop more potent modifications for antisense ODNs and siRNAs.