An Overview of Diazine Nucleoside Analogues

Abstract

Early work on antiviral agents focused on traditional nucleoside analogues in which the base was linked to one or other of the naturally occurring sugars. Some of these were indeed shown to possess anti-metabolic properties, but it became apparent that their usefulness was severely limited by instability and poor selectivity. Since the discovery of the first successful anti-viral drug, acyclovir, in 1974 by Gertrude "Trudy" Elion, interest has diversified towards compounds in which the heterocycle and sugar components of the nucleoside differ significantly from the natural form. These novel types of nucleosides act as anticancer, antiviral or antibacterial drugs. The intense search for clinically useful nucleoside derivatives has resulted in a wealth of new approaches for their synthesis. In this review, we will give an overview of the synthesis of some pyrimidine nucleosides according to their structural types (e.g., acyclics, carbocyclics, and C5-substituted pyrimidine nucleosides), including compounds having "unnatural" L-stereochemistry, along with the synthetic routes of some selected examples. The article also refers to other relevant review articles that have covered particular areas of investigation or have dealt in depth with a single compound.

Synthesis and Antiviral Evaluation of 3′-Fluoro-5′-norcarbocyclic Nucleoside Phosphonates Bearing Uracil and Cytosine as Potential Antiviral Agents

“…From azido derivative (±)-4, the required amine (±)-5 was obtained after reduction with LiAlH4 in 84% yield. Finally, introduction of the uracil moiety of the common precursor (±)-7 was achieved through a two steps procedure [8] with 76% yield by treatment of (±)-5 with (E)-3-ethoxyacryloyl chloride followed by a cyclization reaction under acidic conditions. Synthesis of 3′-fluoro-5′-norcarbocyclic nucleoside phosphonates bearing uracil was carried out in four steps from compound (±)-7 (Scheme 2).…”

C6‐substituted purine derivatives: an experimental and theoretical 1H, 13C and 15N NMR study

“…Modified nucleosides and nucleotides are very important classes of compounds used in the therapy of a wide variety of diseases because they can act as antiviral, antitumor or antimicrobial agents. Nucleosides in which the furanose‐ring oxygen is replaced with a methylene, ethylene or vinylene group are called carbocyclic nucleosides, and these compounds typically excel in enzymatic as well as chemical stability, which makes them an attractive research target …”

Alkyne-Azide Click Chemistry Mediated Carbanucleosides Synthesis

“…[1] Particularly, analogues of nucleosides structurally related to ribavirin have focused much interest as potent inhibitors of the inosine monophosphate dehydrogenase (IMPDH), which SCHEME 1 is a requirement for cell replication as this enzyme is involved in de novo guanine synthesis. [2] Thus, as part of our drug discovery group, we demonstrate herein the efficient microwave assisted synthesis of hitherto unknown 1,2,3-triazolo-carbocyclic nucleosides, an important pharmaceutical class, through a unique "click" approach.…”