Synthesis and Antiviral Activity of C-5 Substituted β-D- and β-L-D4T Analogues

Abstract

A series of beta-D-2',3'-didehydro-2',3'-dideoxy-nucleosides bearing a tether attached at the C-5 position and their beta-L-counterparts was synthesized. Their inhibitory activities against human immunodeficiency virus (HIV) were investigated and compared to establish relationship(s) between compound structure and their antiviral activity. No significant activity was observed for beta-D- and beta-L-modified nucleosides respectively 7a-c and 14a-c, but 7d and 14d exhibited a weak activity against HIV-1.

Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy

“…Therefore, the present study focused on utilizing d4T-4PEG-TMC as our bifunctional prototype. Previous studies on C-5-substituted d4T derivatives yielded mixed results but mostly resulted in inactive analogues. ,,− Moreover, earlier attempts to show efficient HIV replication inhibition of bifunctional compounds all failed. , We hypothesized that one of the possible reasons for these unsuccessful attempts could be impaired phosphorylation of the nucleoside end of bifunctional analogues catalyzed by cellular kinases. Consequently, the synthesis of a metabolically active triphosphate form of our d4T-4PEG-TMC bifunctional nucleoside was conducted to directly address the phosphorylation requirement for in vitro incorporation assays catalyzed by HIV-1 RT.…”

Novel Antiviral Activity of l-Dideoxy Bicyclic Nucleoside Analogues versus Vaccinia and Measles Viruses in Vitro

“…First, reaction of the carbohydrate 1 with cyanamide, according to the methodology reported by Ladureé et al, 27 afforded the corresponding bicyclic oxazoline 2. Treatment with methyl propiolate in methanol yielded the 2,2′-anhydronucleoside 3 which via a bromoacetylation reaction 28 with acetyl bromide in acetonitrile gave the nucleoside 4 in good yield.…”