From the chemistry of epoxy-sugar nucleosides to the discovery of anti-HIV agent 4'-ethynylstavudine-Festinavir

Abstract

Branched sugar nucleosides have attracted much attention due to their biological activities. We have demonstrated that epoxysugar nucleosides serve as versatile precursor for the stereo-defined synthesis of these nucleoside derivatives on the basis of its ring opening with organoaluminum or organosilicon reagents. In this review article, novel methods for the synthesis of nucleoside analogues branched at the 1' and 4'-position will be described. During this study, we could discover an anti-HIV agent, 4'-ethynylstavudine (Festinavir). Festinavir showed more potent anti-HIV activity than the parent compound stavudine (d4T). Other significant properties of Festinavir are as follows: 1) much less toxic to various cells and also to mitochondorial DNA synthesis than d4T, 2) better substrate for human thymidine kinase than d4T, 3) resistant not only to chemical glycosidic bond cleavage but also to catabolism by thymidine phosphorylase, 4) the activity improves in the presence of a major mutation, K103N, associated with resistance to non-nucleoside reverse transcriptase inhibitors. Detailed profile of the antiviral activities, biology and pharmacology of Festinavir are also described.

Fig. 1

Anti- HIV Drugs: Nucleoside Reverse Transcriptase Inhibitors (NRTIs).

Fig. 2

Biologically-active Branched-Sugar Nucleosides.

Fig. 3

2′-Keto and 3′-Ketonucleosides Utilizing for the Synthesis of 2′-and 3′-Branched Derivatives.

Fig. 4

Structures of Epoxy-Sugar Nucleosides.

Fig. 5

Plausible Elucidation for α-Face-Selectivity of DMDO-Epoxidation of DTBS-protected 28.

Fig. 6

Structures of Ed4T analogs 79-82.

Fig. 7

Sequence Analysis for the Thumb/Connection/RNase H Domain of HIV-1 Resistant to 4′-Ed4T.

Scheme 1

Synthesis of 1′-Branched Nucleosides 3 via 2 obtained on thde basis of Nucleophilc Substitution of 1.

Scheme 2

Synthesis of 1′-Branched Nucleosides on the basis of Electrophilic Substitution.

Scheme 3

Nucleoside Anomeric Radical based Synthesis of 1′-Branched Nucleosides.

Scheme 4

Radical Reaction of 1′-Phenylsulfanyl Nucleoside 9 under Radical Reaction leading to1′-Allyldeoxyuridine 10.

Scheme 5

Intramolecular Radical Cyclization of 11 and Subsequent Transformation of 12 to 1′-Vinyl Uridine 13.

Scheme 6

Synthetic Sequence for 4′-Branched Nucleosides by means of Aldol-Cannizzaro Reaction.

Scheme 7

Synthesis of 3′-Branched Uracil Nucleoside 19 by Means of Ring Opening of 2′,3′-Lyxo-epoxide 18 with LiC≡CH.

Scheme 8

Characteristic Behaviour of 1′,2′-Epoxynucleoside 20.

Scheme 9

Preparation of Dimethyldioxirane (DMDO).

Scheme 10

Preparation and Ring-Openig of Epoxy-Sugar Nucleosides (Pg = protecting group).

Scheme 11

Epoxidation of 1′,2′-Unsaturated Uracil Nucleosides 23 and 26: Ring Opening of 1′,2′-Epoxynucleosides with Me₃Al.

Scheme 12

DMDO-mediated Epoxidation of DTBS-protected 1′,2′-Unsaturated Uracil Nucleoside 28 and Ring Opening of 1′,2′-“Down”-Epoxynucleoside 29 leading to 30.

Scheme 13

Reaction of 1′,2′-Epoxynucleoside 29 with Organoaluminum Reagents.

Scheme 14

Plausible Mechanism for the Reaction of 1′,2′-Epoxynucleoside 29 with Organoaluminum Reagents.

Scheme 15

Reaction of N³-Protected 1′,2′-Epoxyuridine Derivatives 36 and 37 with Organoaluminum Reagents.

Scheme 16

Reaction of 1′,2′-α-Epoxyadenosine Derivative 44 with Organoaluminum Reagents and Synthesis of Protected Angustmycin C.

Scheme 17

Epoxidation of 3′,4′-Unsaturated Adenine Nucleoside 51 and Ring-Opening of the Epoxy Nucleoside 52 with Me₃Al.

Scheme 18

Epoxidation of 55 and Ring-Opening of the Sugar Epoxide 56 with Me₃Al leading to 57.

Scheme 19

Proposed Reaction Mechanism for the Ring Opening of Epoxide 52.

Scheme 20

Effect of Bulkiness of the Protecting Group for the ratio of Anti-Opened/Syn-Opened Products.

Scheme 21

Optomized Reaction Conditions leading to Anti-Opened Product 59.

Scheme 22

Epoxidation of 4′,5′-Unsaturated thymidine 64 and Ring Opening of 4′,5′-Epoxide 65 with Me₃Al.

Scheme 23

Ring Opening of 4′,5′-Epoxythymine Nucleoside 68 with Organoaluminum Reagents.

Scheme 24

Attemtps to Effect Inversion at the 3′-Position of 69 and Formation of Elimination Products 75.

Scheme 25

Synthesis of 4′-Substituted d4T 76-78.