Synthesis and anti-HIV activity of 4'-azido- and 4'-methoxynucleosides.

doi:10.1021/JM00086A013

Paper

Synthesis and anti-HIV activity of 4'-azido- and 4'-methoxynucleosides.

Published Apr 17, 1992 · H. Maag, R. Rydzewski, M. J. Mcroberts

Journal of medicinal chemistry

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141

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2

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Abstract

A series of nucleosides were synthesized in which the 4'-hydrogen was substituted with either an azido or a methoxy group. The key steps in the syntheses of the 4'-azido analogues were the stereo- and regioselective addition of iodine azide to a 4'-unsaturated nucleoside precursor followed by an oxidatively assisted displacement of the 5'-iodo group. The 4'-methoxynucleosides were made via epoxidation of 4'-unsaturated nucleosides with in suit epoxide opening by methanol. Reaction-mechanism considerations, empirical conformation rules, NMR-based conformational calculations, and NOE experiments suggest that the 4'-azidonucleosides prefer a 3'-endo (N-type) conformation of the furanose moiety. When evaluated for their inhibitory effect on HIV in A3.01 cell culture, all the 4'-azido-2'-deoxy-beta-D-nucleosides exhibited potent activity. IC50's ranged from 0.80 microM for 4'-azido-2'-deoxyuridine (6c) to 0.003 microM for 4'-azido-2'-deoxyguanosine (6e). Cytotoxicity was detected at 50-1500 times the IC50's in this series. The 4'-methoxy-2'-deoxy-beta-D-nucleosides were 2-3 orders of magnitude less active and less toxic than their azido counterparts. Modifications at the 2'- or 3'-position of the 4'-substituted-2'-deoxynucleosides tended to diminish activity. Further evaluation of 4'-azidothymidine (6a) in H9, PBL, and MT-2 cells infected with HIV demonstrated a similar inhibitory profile to that of AZT. However, 4'-azidothymidine (6a) retained its activity against HIV mutants which were resistant to AZT.

In Vitro Study

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Study Snapshot

4'-azido-2'-deoxy-beta-D-nucleosides show potent anti-HIV activity, with 4'-azidothymidine (6a) maintaining activity against resistant HIV mutants.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Synthesis and anti-HIV activity of 4'-azido- and 4'-methoxynucleosides.

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References

Citations

Synthesis and Resolution of 4'-Substituted Nucleosides with Potential Antiviral and Antisense Strategies.

This study successfully synthesized and resolved 4'-substituted nucleosides, yielding both d- and l-isomers with high optical purity, for potential antiviral and antisense strategies.

Protecting Group Control of Hydroxyketone-Hemiketal Tautomeric Equilibrium Enables the Stereoselective Synthesis of a 1'-Azido C-Nucleoside.

The synthesis of 1'-azido C-nucleosides enables bioorthogonal applications and potential antiviral drugs by preventing ring-chain tautomerism and enabling efficient -diastereoselectivity.

Access to Reverse Glycosyl Azides and Rare Sugar-Based Glycosyl Azides via Radical Decarboxylative Azidation: Divergent Synthesis of 4'-C-Azidonucleosides as Potential Antiviral Agents.

Radical decarboxylative azidation efficiently synthesizes 4'-C-azidonucleosides, which show potential as antiviral agents by inhibiting covalently closed circular DNA.

4'-Ethynyl-2'-deoxy-2'-β-fluoro-2-fluoroadenosine: A Highly Potent and Orally Available Clinical Candidate for the Treatment of HIV-1 Infection.

The 4'-ethynyl-2'-deoxy-2'--fluoro-2'-fluoroadenosine analog 1c (CL-197) is a highly potent and orally bioavailable clinical candidate for treating HIV-1 infection with low cytotoxicity and favorable pharmacokinetics profiles

Design, synthesis and biological evaluation of Nucleosidic CD99 inhibitors that selectively reduce Ewing sarcoma viability.

BK50164 and BK60106 selectively reduce Ewing sarcoma cell viability by inhibiting CD99, providing a roadmap for developing targeted CD99 inhibitors for targeted treatment of the cancer.