The evolution of nucleoside analogue antivirals: A review for chemists and non-chemists. Part 1: Early structural modifications to the nucleoside scaffold

Abstract

This is the first 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. Rather than providing a simple chronological account, we have examined and attempted to explain the thought processes, advances in synthetic chemistry and lessons learned from antiviral testing that led to a few molecules being moved forward to eventual approval for human therapies, while others were discarded. The present paper focuses on early, relatively simplistic changes made to the nucleoside scaffold, beginning with modifications of the nucleoside sugars of Ara-C and other arabinose-derived nucleoside analogues in the 1960's. A future paper will review more recent developments, focusing especially on more complex modifications, particularly those involving multiple changes to the nucleoside scaffold. We hope that these articles will help virologists and others outside the field of medicinal chemistry to understand why certain drugs were successfully developed, while the majority of candidate compounds encountered barriers due to low-yielding synthetic routes, toxicity or other problems that led to their abandonment.

Keywords: Analogue; Anticancer; Antiviral; History; Modification; Nucleoside.

Fig. 1

Natural occurring DNA and RNA nucleoside building blocks.

Fig. 2

Sites for potential modifications in nucleoside/tide drug design including changes to the heterocyclic base, the glycosidic bond, the sugar moiety, and the phosphate group.

Fig. 3

Examples of “Ara” nucleosides where the 2′-OH is in the “up” configuration found in arabinose sugars rather than the “down” configuration typical of ribose nucleosides.

Fig. 4

Standard furanose ring puckering found in ribose and 2′-deoxyribose nucleosides.

Fig. 5

Examples of 2′-F nucleoside analogues where the fluorine can be in the “down” or “up” configuration, or in both the “up” and “down” configuration as in Gemcitabine.

Fig. 6

Examples of 3′-methyl nucleoside analogues where the methyl at the 3′ carbon of the sugar ring is in the “up” configuration and the 3′-OH is in the “down” configuration.

Fig. 7

Examples of 2′,3′-dideoxy nucleosides that act as obligate chain terminators due to the lack of a 3′-OH for the incoming nucleotide to couple to, thus chain elongation is terminated.

Fig. 8

Examples of second generation 2′,3′-dideoxy obligate nucleoside chain terminators.

Fig. 9

Early carbocyclic nucleosides that feature a C-C-N glycosidic bond that is more stable compared to the corresponding hemiacetal bond found in the natural sugar nucleosides.

Fig. 10

Examples of second generation carbocyclic nucleosides with the 5′-OH or 4′-substituent removed to generate "truncated" nucleosides.

Fig. 11

Structure of the 2′,3′-dideoxy obligate chain terminator Carbovir, a nucleoside that features unsaturation in the sugar ring.

Fig. 12

Structure of the 2′-deoxy non-obligate chain terminator Entecavir that features a unique exocyclic double bond which leads to unfavorable steric interactions resulting in chain termination despite the presence of a 3′-OH.

Fig. 13

The spatial and structural similarities between Lobucavir and Entecavir that provided the rationale for Entecavir's unique design.

Fig. 14

Examples of nucleosides with four-membered rings including the corresponding carbocyclic (“carba”) analogues.

Fig. 15

Examples of cyclopropyl nucleoside analogues that feature three-membered sugar rings.

Fig. 16

Examples of nucleoside analogues that feature a six-membered ring instead of the typical five-membered ring found in natural nucleosides.

Fig. 17

Examples of non-furanose sugars where the oxygen is replaced with either an isosteric sulfur atom or a selenium atom.

Fig. 18

Structure of the imino sugar modified nucleoside Immucillin-H, where the furanose oxygen is replaced with a nitrogen.

Fig. 19

Comparison of the structure of guanosine with the acyclic nucleosides Ganciclovir, which is missing a 2′ carbon and corresponding 2′-OH, Acyclovir, which is missing both the 2′ and 3′ hydroxyl groups, and Penciclovir, the analogous carbocyclic version of Ganciclovir.

Fig. 20

Examples of the prodrug analogues of Acyclovir, Ganciclovir, and Pencyclovir that increase lipophillicity and subsequent bioavailability.

Fig. 21

Examples of acyclic nucleoside phosphonates such as Cidofovir, Adefovir, and Tenofovir, where the phosphate group is replaced by the more stable phosphonate group.

Fig. 22

Structure of the acyclic nucleoside phosphonate Tenofovir and its prodrug analogues Tenofovir disoproxyl fumarate and Tenofovir alafenamide.

Fig. 23

Examples of typical heterocyclic modifications at the 5-position of the pyrimidine moiety.

Fig. 24

Example of a homologous series of modifications that increase lipophillicity up to a certain threshold.

Fig. 25

Examples of bicyclic pyrimidine nucleoside analogues (BCNAs) with potent anti-VZV activity.

Fig. 26

Examples of “deaza” modifications to the heterobase scaffold where a nitrogen is removed from either the purine or the pyrimidine ring.

Fig. 27

Examples of “aza” modifications to the heterobase scaffold where a nitrogen is added to either the purine or pyrimidine ring.

Fig. 28

Structures of the “benzene-expanded” purine nucleosides originally developed by Leonard, in which there is a benzene spacer ring separating the imidazole and the pyrimidine components of the purine nucleobase scaffold.

Fig. 29

Structures of the “thieno-expanded” purine nucleosides developed by Seley-Radtke based on Leonard's original benzyl-expanded derivatives, where a 5 membered thiophene ring separates the imidazole and pyrimidine components of the nucleobase scaffold.

Fig. 30

Comparison of the structure of adenosine and the corresponding C-adenosine analogue where the glycosidic bond is removed due to removal of the N1 nitrogen in the purine ring.

Fig. 31

Examples of early naturally occurring C-nucleosides Pseudouridine and Showdomycin.

Fig. 32

Structure of C-nucleosides with an imino sugar.

Fig. 33

Examples of Iso-adenosine analogues where the sugar moiety is now attached to the N3 instead of the N7 as in natural nucleosides. Iso-analogues can also be formed with attachment of the nucleobase at the 2′-carbon instead of the 1′-carbon.

Fig. 34

Examples of the l-enantiomer of nucleoside analogues that were assumed to be inactive since naturally occurring nucleosides are the D-enantiomers. Later it was shown that the L-nucleosides exhibit potent biological activity against a variety of pathogens.