Synthesis and Modification of Cordycepin-Phosphoramidate ProTide Derivatives for Antiviral Activity and Metabolic Stability
Year: 2024
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide 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 22 S and 22 R showed moderate inhibitory activity against corona and influenza viruses, while these compounds and derivatives ( 25 S, 27 S, and 27 R ) demonstrated promising antiviral efficacy against dengue virus. Pharmacological screening indicated that S p-isomers generally exhibited slightly greater inhibitory activity than their R p-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 R p-isomers was observed to be slightly higher than that of the S p-isomers, and the addition of a fluorine group also modestly increased this rate and fluorinated 39 S 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.
Source: ACS Bio & Med Chem Au
Authors: Aticha Thiraporn, Thanat Tiyasakulchai, Thitiphong Khamkhenshorngphanuch, Marie Hoarau, Ratthiya Thiabma, Suppachoke Onnome, Amporn Suphatrakul, Jaraspim Narkpuk, Chanya Srisaowakarn, Suwimon Manopwisedjaroen, Kitlada Srichomthong, Suradej Hongeng, Arunee Thitithanyanont, Peera Jaru-ampornpan, Sewan Theeramunkong, Bunpote Siridechadilok, Nitipol Srimongkolpithak
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $3,500
Funders: Mahidol University, National Science and Technology Development Agency, National Research Council of Thailand, Thammasat University, National Center for Genetic Engineering and Biotechnology, Thailand Science Research and Innovation, Faculty of Science, Mahidol University, Department of Microbiology, Faculty of Science, Chulalongkorn University
Awards: G4622575007, G918482472, G944952031
OpenAlex ID: W4405141875