Synthesis of nucleotide analogues, EFdA, EdA and EdAP, and the effect of EdAP on hepatitis B virus replication

Abstract

4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) and 4′-ethynyl-2′-deoxyadenosine (EdA) are nucleoside analogues which inhibit human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. EdAP, a cyclosaligenyl (cycloSal) phosphate derivative of EdA, inhibits the replication of the influenza A virus. The common structural feature of these compounds is the ethynyl group at the 4′-position. In this study, these nucleoside analogues were prepared by a common synthetic strategy starting from the known 1,2-di-O-acetyl-D-ribofuranose. Biological evaluation of EdAP revealed that this compound reduced hepatitis B virus (HBV) replication dose-dependently without cytotoxicity against host cells tested in this study.

Antiviral nucleoside analogs

“…5 Substitution of 1,2,4-triazole ring in ribavirin (15) to imidazole led to 1-(β-D-ribofuranosyl)-5-ethynylimidazole-4-carboxamide (EICAR) (17) which demonstrates a wide spectrum of activity against DNA and RNA viruses and significantly exceeds the activity of ribavirin (15). 6 Replacement of the carboxamide group in ribavirin (15) with an ethynyl group resulted in 1-(β-D-ribofuranosyl)-3-ethynyl-1,2,4-triazole (ETAR) (18) which showed a high level of antiviral activity against hantaviruses and flaviviruses. 7 Advances in the synthesis of antiviral agents based on the scaffold of ribavirin (15) led chemists to employ the 1,2,3-triazole ring as a bridge between the nucleic base and the D-ribofuranosyl fragment.…”

“…17 Substitution of the azido group and cyano groups at the C-4' position by the ethynyl group does not affect the antiviral activity. Thus, thymidine (2) analog festinavir (30) 16 and adenosine (4) analog islatravir (31) 14,18 inhibit HIV reverse transcriptase (Table 1). Moreover, replication of hepatitis B virus and HIV is inhibited by 2-amino-2'-deoxyadenosine analogs 32-34 and 2'-deoxyguanosine analogs 35-37 containing at the position C-4' the vinyl (compounds 32, 35), trifluoromethyl (compounds 33, 36), and even ethyl (compounds 34, 37) groups.…”

Nine-Step Stereoselective Synthesis of Islatravir from Deoxyribose

“… , It is the first NRTTI reported to date and has shown great promise in preclinical studies, including remarkable potency and a long intracellular half-life. As befits its promise as a drug candidate, several total syntheses of 1 have been reported in the literature thus far …”