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

Abstract

Introducing a 4′-C-trifluoromethyl (4′-CF3) modification into oligodeoxynucleotides (ODNs) leads to improved nuclease resistance and increased cell permeability.

C4’‐Fluorinated Oligodeoxynucleotides: Synthesis, Stability, Structural Studies

“…Taking into account that 4'-F-uridine [24] and 4'-CF 3deoxythymidine [6] modifications also decrease the thermal stability of duplexes, we can conclude that in general, 4'-fluoromodifications are detrimental to the thermal stability of duplexes. The 4' modification is in close proximity to the phosphate linkage and is located in the minor groove and may disturb the "spine of hydration", which is known to be very important for the formation and stability of duplexes.…”

“…C4'-modified nucleos(t)ides have found a wide range of biomedical applications, either as probes of nucleic acid structure and function and antiviral agents [1][2][3][4] or for use in oligonucleotide-based therapeutics. [5][6][7][8][9][10] The obvious advantage of C4'-modification on nucleos(t)ides is that it is located at the backbone edge, thus rendering a stereoelectronic effect to the ribose conformation without introducing notable steric clash to the nucleic acid duplexes. [11,12] This feature makes C4'-modification an attractive approach to modulate the structure of nucleic acids, which in turn dictates their functions.…”

4′‐SCF3‐Labeling Constitutes a Sensitive 19F NMR Probe for Characterization of Interactions in the Minor Groove of DNA

“…Second, because C4' is located on the edge of the sugarphosphate backbone, modification at C4' has minimal effect on the tertiary structure of nucleic acids. Although numerous C4'-modified nucleotides have been synthesized and have found a wide variety of applications, [23][24][25][26][27][28][29][30] there have been only a few reports of the synthesis of C4'-fluorinated nucleotides as probes for 19 F NMR studies of nucleic acid structure and function. [31] Recently, we synthesized 4'-F-RNA and 4'-F-DNA.…”

4′-Fluorinated RNA: Synthesis, Structure, and Applications as a Sensitive 19F NMR Probe of RNA Structure and Function

“…Fluorinated nucleic acids have attracted considerable interest in recent decades . Owing to the unique physical properties of the fluorine atom (e.g., its small atomic radius and high electronegativity), , introducing a fluorine atom into nucleic acid molecules markedly affects their structure, , lipophilicity, , nuclease resistance, and interactions with other molecules. − Thus, fluorination has become a popular strategy for improving the pharmacokinetics and pharmacodynamics of nucleic acid based drugs. , In addition to pegaptaniba fluorinated RNA aptamer that has been approved by the FDA for the treatment of ocular vascular diseasemany fluorinated antisense oligonucleotides, , small-interfering RNAs, ,, RNA aptamers, , and ribozymes , exhibit striking properties, and some of these compounds are in clinical trials.…”

“…Fluorinated nucleic acids have attracted considerable interest in recent decades. 1 Owing to the unique physical properties of the fluorine atom (e.g., its small atomic radius and high electronegativity), 2,3 introducing a fluorine atom into nucleic acid molecules markedly affects their structure, 4,5 lipophilicity, 6,7 nuclease resistance, and interactions with other molecules. 8−11 Thus, fluorination has become a popular strategy for improving the pharmacokinetics and pharmacodynamics of nucleic acid based drugs.…”