Synthesis and Modification of Cordycepin-Phosphoramidate ProTide Derivatives for Antiviral Activity and Metabolic Stability
6
Issued Date
2024-01-01
Resource Type
eISSN
26942437
Scopus ID
2-s2.0-85211448485
Journal Title
ACS Bio and Med Chem Au
Rights Holder(s)
SCOPUS
Bibliographic Citation
ACS Bio and Med Chem Au (2024)
Suggested Citation
Thiraporn A., Tiyasakulchai T., Khamkhenshorngphanuch T., Hoarau M., Thiabma R., Onnome S., Suphatrakul A., Narkpuk J., Srisaowakarn C., Manopwisedjaroen S., Srichomthong K., Hongeng S., Thitithanyanont A., Jaru-Ampornpan P., Theeramunkong S., Siridechadilok B., Srimongkolpithak N. Synthesis and Modification of Cordycepin-Phosphoramidate ProTide Derivatives for Antiviral Activity and Metabolic Stability. ACS Bio and Med Chem Au (2024). doi:10.1021/acsbiomedchemau.4c00071 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/102424
Title
Synthesis and Modification of Cordycepin-Phosphoramidate ProTide Derivatives for Antiviral Activity and Metabolic Stability
Corresponding Author(s)
Other Contributor(s)
Abstract
In our study, Prodrug nucleoTide (ProTide) technology was applied to cordycepin to enhance its antiviral activities and metabolic stability. Using cordycepin as starting material, we developed a synthetic method to access a series of stereospecific-phosphoramidate derivatives with various ester groups. We also successfully synthesized halogenated cordycepin derivatives via stannylation. Our 17 ProTide-cordycepin derivatives were pharmacologically evaluated for their antiviral activities. Phosphorus diastereomers 22S and 22R showed moderate inhibitory activity against corona and influenza viruses, while these compounds and derivatives (25S, 27S, and 27R) demonstrated promising antiviral efficacy against dengue virus. Pharmacological screening indicated that Sp-isomers generally exhibited slightly greater inhibitory activity than their Rp-isomer counterparts against the dengue virus. The selected ProTides were assessed for their metabolic mechanism and stability via carboxypeptidase and microsomes. The hydrolysis rate of the Rp-isomers was observed to be slightly higher than that of the Sp-isomers, and the addition of a fluorine group also modestly increased this rate and fluorinated 39S extended its half-life compared to nonfluorinated counterparts. These findings suggested not only structure-activity relationships of cordycepin ProTide but also the comprehensive synthetic route to access cordycepin derivatives for further antiviral development.