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Antiviral nucleoside analogs

“…34 phosphazide (74) underwent a full range of preclinical and clinical trials and in 1999 was registered in the Russian Federation as an antiviral agent used in combination antiretroviral therapy against HIV infection called nikavir. 40,42 Thus, phosphazide (74) became the first and, according to our information, the only 5'-phosphite analog of nucleosides among antiretroviral drugs and a prodrug form of zidovudine (20).…”

“…Surprisingly, despite of the many publications on the synthesis of 5'-triphosphate derivatives of nucleoside analogs, we found in the literature in the last decade only a few studies on their antiviral activity 35,36 and the ability to inhibit viral polymerases thus interrupting the synthesis of viral DNA. 37,38 However, Krayevsky's group, known for their work on the synthesis of thymidine (2) derivatives, 39,40 already in 1989 synthesized 5'-phosphite derivative of 3'-azido-3'-deoxythymidine 74 (Scheme 4) called phosphazide, which demonstrated antiHIV activity and low toxicity on MT-4 cell line. 41,42 Over the next 10 years, The first strategy is the synthesis of 5'-triphosphate derivatives of nucleoside analogs containing two terminal hydrophobic fragments readily hydrolyzed by cell hydrolases (Scheme 5).…”

The First 5′-Phosphorylated 1,2,3-Triazolyl Nucleoside Analogues with Uracil and Quinazoline-2,4-Dione Moieties: A Synthesis and Antiviral Evaluation

“…Firstly, in 1989, A. Kraevsky’s group synthesized a 5′- H -phosphonate derivative of Zidovudine, which demonstrated high anti-HIV activity [ 39 ]. In 1999, this prodrug form of Zidovudine was registered in the Russian Federation as an antiviral agent for combined antiretroviral therapy against HIV infection called Nicavir [ 39 , 40 ]. Secondly, in 2007, D. Liotta’s group reported that the 5′-triphosphate of 5-fluoro-1-[ cis -3-(hydroxymethyl)-cyclobutyl]-cytosine showed in vitro anti-HIV activity against recombinant HIV reverse transcriptases (RT) and wild-type HIV RT (IC 50 = 4.7 and 6.9 μM, respectively), whereas the parent nucleoside was inactive up to 100 μM.…”

“…Fifth, the ability of the 5′-triphosphates of four HIV RT inhibitors, Zidovudine, Lamivudine, Emtricitabine, and Abacavir ( Figure 1 ), to be incorporated by the RNA-dependent RNA polymerase (RdRp) of SARS-CoV, wherein they also terminated further polymerase extension—thereby inhibiting virus replication—was demonstrated [ 44 ]. Of all the five cases listed above, only the groups of A. Kraevsky [ 39 , 40 ] and D. Liotta [ 41 ] incubated triphosphates of nucleoside analogues in infected cells (in other cases, experiments were conducted with individual viral RdRp) and found their antiviral activity. In our opinion, this is enough to cast doubt on the statement made in the 1950s that negatively-charged 5′-triphosphate nucleoside analogues cannot penetrate into cells through lipid-rich cell membranes [ 15 ].…”

Larger laboratory scale synthesis of 5-methyluridine and formal synthesis of its L-enantiomer

“…As such it can be prepared from the L 5-methyluridine 5 via deoxygenation at its 2´-position. 3 Considering the demand for both enantiomers 1 and 5, uniform access to both of them is an attractive synthetic goal. The stereochemical characteristics of 1,2;5,6-di-O-isopropylidene-α-D-glucofuranose 7 permit its transformation into 1,2-O-isopropylidene-α-D-ribofuranose 12 4 and further to 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose 15 and finally to 5-methyluridine 1.…”