## 3 Fluorocarbon OligoNucleotide Amphiphiles (FONs) and Fluorinated Oligonucleotide Analogues
### Application of Fluorinated Oligonucleotide Analogues  
Various groups have been interested in the synthesis and application of fluorinated oligonucleotide analogues. There are different possible sites for the modification of an oligonucleotide with one or more fluorine atoms for various biological and therapeutical applications. Fluorine atoms have a strong  
Figure 5: Conjugation of fluorocarbon chain to the oligonucleotide (FONs) allows the delivery of highly polyanionic oligonucleotides into human cells. influence on both the electronic and the conformational properties of the nucleic acids' furanose ring. The 2'-position in the ribose moiety of RNA is prime target for chemical modifications. Extensive research work is going on towards the study of structural properties, biological applications and delivery strategies of oligonucleotides-incorporated with 2'-deoxy-2'fluoronucleotide in combination with other structural modifications [67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84]. Oligonucleotides containing 2'-deoxy-2'fluoronucleosides have been synthesized for regiospecific cleavage of RNA by RNase H [67]. Incorporation of 2'-deoxy-2'-fluoronucleotide into oligonucleotides induces substantial enhancement in their binding affinities to RNA targets [68]. [PERSON] _et al._ have shown that fluorine-induced sugar pucker in 2'-deoxy-2'fluoro-\(\beta\)-D-ribonucleacid (2'-F RNA; C3'-_endo_) and 2'-deoxy-2'fluoro-\(\beta\)-D-arabinonucleacid (2'-F ANA; C2'/O4'-_endo_) can improve the activity of siRNA (Figure 6) and enhance its serum stability. They have also provided the evidences for an important role of a pseudohydrogen bond between the \(F^{2}\)' and \(H^{8}\) of the nucleobase for 2'-F ANA:RNA duplex stability [72, 73, 74, 75, 76, 77, 78, 79, 80, 82, 83, 84]. On the other side, very interesting and novel studies have been carried out by [PERSON] _et al._ using 3'-deoxy-3'ribofluoro/xylofluoro uridine incorporated oligonucleotides (2'-5'-strand) [85]. They have shown the effect of incorporation of one or more unit of 3'-deoxy-3'-fluoronucleosides (having either locked or frozen S-type/Ntype sugar conformations) on the stability of _iso_DNA:RNA duplexes. For the first time, evidences were given that the DNA strand prefers S-type geometry in stable _iso_DNA:RNA duplexes (Figure 7) [85]. Figure 6: Structure and sugar puckering equilibrium for (**a**) 2’-deoxy-2’-fluororibonucle acid (2’-F RNA); C3’-endo is the most stable conformation for 2’-F RNA. (**b**) 2’-deoxy-2’-fluororarabonucleic acid (2’-F ANA); C2’-endo is the most stable conformation for 2’-F ANA. To investigate the forces (hydrogen bonding, base stacking and solvation) which are responsible for stability of the secondary structure of nucleic acids, [PERSON] _et al._ have synthesized novel nucleic acid analogues in which nucleobases are replaced by their steric mimics, containing one or more fluorine atom. They have utilized fluorobenzene and fluorobenzimidazole derivatives (Figure 8) [86, 87]. They have discussed how C-F\(\cdots\)H-C hydrogen bonds affect the stability of the secondary structure of nucleic acids in details. Owing to the favorable NMR properties of fluorine atom (\({}^{19}\)F), fluorinated oligonucleotide derivatives provide a sensitive probe for structural study of nucleic acids in the solution state and their interactions with other biological moieties [71, 88, 89, 90, 91, 92, 93, 94, 95]. [PERSON] et _al._ have synthesized nucleosides with perfluorinated _tert_-butyl group and successfully incorporated it into the oligonucleotide at different positions and demonstrated as a sensitive \({}^{19}\)F NMR probe of nucleic acid conformation [95]. Oligonucleotides, labeled with radioactive isotopes, are new imaging tools to study gene expression at the nucleic acid and protein levels. Due to its positron-emission properties, fluorine-18 (radioactive isotope of fluorine) is widely used for oligonucleotide labeling for _in vivo_ PET (Positron Emission Tomography) imaging. [PERSON] _et al._[96, 97, 98, 99, 100].