“…15 ). ( Guillerm et al, 1995 ) Based on the mechanism of action of SAHase, it was hypothesized that the lack of a 4′-proton on 4′-fluoroadenosine would completely inhibit further catalysis, however, when tested against SAHase it was determined that 4′-fluoroadenosine had a 100-fold lower affinity for SAHase compared to natural adenosine, thus this modification proved unsuccessful ( Guillerm et al, 1995 ). Fig.…”
This is the second of two invited articles reviewing the development of nucleoside analogue antiviral drugs, written for a target audience of virologists and other non-chemists, as well as chemists who may not be familiar with the field. As with the first paper, rather than providing a chronological account, we have chosen to examine particular examples of structural modifications made to nucleoside analogues that have proven fruitful as various antiviral, anticancer, and other therapeutics. The first review covered the more common, and in most cases, single modifications to the sugar and base moieties of the nucleoside scaffold. This paper focuses on more recent developments, especially nucleoside analogues that contain more than one modification to the nucleoside scaffold. We hope that these two articles will provide an informative historical perspective of some of the successfully designed analogues, as well as many candidate compounds that encountered obstacles.
“…15 ). ( Guillerm et al, 1995 ) Based on the mechanism of action of SAHase, it was hypothesized that the lack of a 4′-proton on 4′-fluoroadenosine would completely inhibit further catalysis, however, when tested against SAHase it was determined that 4′-fluoroadenosine had a 100-fold lower affinity for SAHase compared to natural adenosine, thus this modification proved unsuccessful ( Guillerm et al, 1995 ). Fig.…”
This is the second of two invited articles reviewing the development of nucleoside analogue antiviral drugs, written for a target audience of virologists and other non-chemists, as well as chemists who may not be familiar with the field. As with the first paper, rather than providing a chronological account, we have chosen to examine particular examples of structural modifications made to nucleoside analogues that have proven fruitful as various antiviral, anticancer, and other therapeutics. The first review covered the more common, and in most cases, single modifications to the sugar and base moieties of the nucleoside scaffold. This paper focuses on more recent developments, especially nucleoside analogues that contain more than one modification to the nucleoside scaffold. We hope that these two articles will provide an informative historical perspective of some of the successfully designed analogues, as well as many candidate compounds that encountered obstacles.
“…14 Both of these issues were later resolved by Guillerm et al who switched the protecting groups at the 2′-and 3′-hydroxyls to benzoyl (19b). 15 This change allowed protecting group cleavage to be achieved under basic conditions, and used the method developed by Prisbe et al 13 (see Scheme 8) to access the benzoate 21 by treatment of the iodide 20 with m-CPBA.…”
Section: Synthesis and Functionalisation Of A 4′-methylene Unitmentioning
Modified nucleosides have received a great deal of attention from the scientific community, either for use as therapeutic agents, diagnostic tools, or as molecular probes. Perhaps the most difficult position of a nucleoside to modify is the 4'-position. Chemists have developed innovative methods to achieve this in a stereoselective manner to allow incorporation of a variety of functional groups. This review provides a summary of the most commonly used or recently published methods for ribose, deoxy-ribose, 4'-thioribose, and carbocyclics.
“…C4'-F-modified ribonucleosides have also attracted broad interest since the natural product nucleocidin (4'-F-5'-O-sulfamoyladenosine) was found to have antibiotic activity in the 1950s. [20][21][22] However, the 4'-F modification destabilizes the glycosylic bond, which makes 4'-F-ribonucleosides not stable enough for incorporation into RNA strands by solid-supported synthesis. [23] Recently, we developed a strategy to circumvent the instability of 4'-F-ribonucleoside and prepared 4'-F-modified RNA for the first time.…”
Fluoro-substitution on the ribose moiety (e. g., 2'-Fdeoxyribonucleotide) represents a popular way to modulate the ribose conformation and, hence, the structure and function of nucleic acids. In the present study, we synthesized 4'-F-deoxythymidine ( 4'-F T) and introduced it to oligodeoxyribonucleotides (ODNs). Though scission of the glycosylic bond of 4'-F T followed by strand cleavage occurred to some extent under alkaline conditions, the 4'-F T-modified ODNs were rather stable in neutral buffers. NMR studies showed that like 2'-F-deoxyribonucleoside, 4'-F T exists predominantly in the North conformation not only in the nucleoside form but also in the context of ODN strands. Circular dichroism spectroscopy, thermal denaturing and RNase H1 footprinting studies of 4'-F T-modified ODN/cDNA and ODN/cRNA duplexes indicated that the North conformation tendency of 4'-F T is maintained in the duplexes, leading to a local structural perturbation. Collectively, 4'-F-deoxyribonucleotide structurally resembles the 2'-F-deoxyribonucleotide but imparts less structural perturbation to the duplex than the latter.
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