The evolution of antiviral nucleoside analogues: A review for chemists and non-chemists. Part II: Complex modifications to the nucleoside scaffold

Abstract

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.

Keywords: Anti-cancer; Antiviral; Nucleoside analogues; Prodrugs; Structural modifications.

Fig. 1

Sites for potential modifications to nucleos(t)ide analogues.

Fig. 2

Examples of early 1′-modified nucleoside analogues.

Fig. 3

Gilead's first generation 1′-substituted 4-aza-7,9-dideazaadeonosine C-nucleosides.

Fig. 4

General structure of a McGuigan ProTide.

Fig. 5

Structure of the 1′-CN parent analogue and the McGuigan ProTide GS-5734.

Fig. 6

First generation 2′-methyl nucleoside analogues for HCV therapy.

Fig. 7

Modified 7-deaza-2′-methyl analogues.

Fig. 8

Second generation 2′-methylguanosine analogues.

Fig. 9

First generation 2′-deoxy-2′-fluoro-2′-methyl analogues.

Fig. 10

Phosphoramidate prodrug of 2′-deoxy-2′-fluoro-2′-methyluridine.

Fig. 11

Structure of the parent analogue, first generation phosphoramidate prodrug, and the double prodrug GS-6620.

Fig. 12

Structure of 2′-β modified 2′-deoxycytosine analogues Ara-C, CNDAC, and the prodrug Sapacitabine.

Fig. 13

Structure of the adenosine based analogues NITD008 and NITD449.

Fig. 14

Structure of the first 4′-modified furanose nucleoside Nucleocidin.

Fig. 15

Second generation 4′-fluoro analogues.

Fig. 16

Examples of 4′-methyl nucleoside analogues.

Fig. 17

Novel 4′-azido nucleoside analogues with potent anti-HIV activity.

Fig. 18

Structure of 4′-azidocytidine and its tri-isobutyl ester prodrug balapiravir.

Fig. 19

Novel structure of 4′-azido-aracytidine and 4′-azido-2′-methylcytidine.

Fig. 20

Potent HIV inhibitor 4′-cyanothymidine.

Fig. 21

Second generation 4′-cyano nucleoside analogues.

Fig. 22

Unique structure of 4′-ethynyl-2-fluoro-2′-deoxyadenosine.

Fig. 23

Structure of one of the first 5′-truncated nucleoside analogues, 5′-deoxy-5-fluorouridine.

Fig. 24

Janus-type nucleosides that feature two pyrimidine faces.

Fig. 25

Origins of fleximer analogues from treatment of thienophene expanded nucleosides with Raney Nickel.

Fig. 26

Structures of proximal and distal fleximers.

Fig. 27

Structure of Acyclovir compared to the potent antiviral acyclic fleximer analogue HP083.