Abstract
Abstract Novel attributes of Locked Nucleic Acid (LNA) makes it preferable over most of the other classes of modified nucleic acid analogues and therefore, it has been extensively explored in different synthetic oligonucleotide based therapeutics. In addition to five oligonucleotides of this class undergoing clinical trials, a healthy pipeline in pre-clinical studies validates the tenacity of LNA. Due to the increasing demand, an efficient biocatalytic methodology has recently been devised for the convergent synthesis of LNA monomers via selective enzymatic monoacetylation of diastereotopic hydroxymethyl functions of 3-O-benzyl-4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose. This commentary article provides an insight into the different synthetic strategies followed for the synthesis of LNA monomers and their triumphs in clinical biotechnology.
Highlights
Novel attributes of Locked Nucleic Acid (LNA) makes it preferable over most of the other classes of modified nucleic acid analogues and it has been extensively explored in different synthetic oligonucleotide based therapeutics
After the pioneering development in dideoxy- and acyclic- nucleos(t)ides [3], currently the most promising modification in the ribofuranose moiety has appeared through the inclusion of an extra methylene bridge between 2′-O & 4′-C atom and synthesis of oligonucleotides (ONs) involving the modified nucleosides, termed as locked nucleic acid (LNA) (Figure 1) [4,5]
No significant potency was observed against cancer or viral infections by LNA monomers or its analogues [6]; there is hardly any synthetic oligonucleotide (ON) based therapeutic strategy which has not been allured by their unique features [4,5,7,8]
Summary
MicroRNA that is required by Hepatitis C virus (HCV) for replication. The liver-expressed miR-122 protects HCV from degradation. Two general strategies have been employed for the synthesis of LNA monomers; a linear strategy using commercially available RNA nucleosides as the starting material [11,19] and a convergent strategy where a common glycosyl donor is synthesized for coupling with different nucleobases [10,20,21]. Linear strategy was disclosed by Obika et al [11] for the synthesis of LNA-U monomer 1a with uridine (2) as the starting material (Scheme 1). Despite having some advantages, such as cheap and readily available RNA nucleosides as starting material and short synthetic route to LNA monomers, the linear approach suffers from poor yields. The two key reactions in the synthetic pathway, i.e. the introduction of the additional hydroxymethyl group at the C-4′-position of the protected RNA nucleoside 4 and the regioselective tosylation of the introduced 4′-C-hydroxymethyl group, generally proceeds with very low yields (Scheme 1).
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