Synthesis and Modification of Cordycepin-Phosphoramidate ProTide Derivatives for Antiviral Activity and Metabolic Stability
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 <b>22</b> <i>S</i> and <b>22</b> <i>R</i> showed moderate inhibitory activity against corona and influenza viruses, while these compounds and derivatives (<b>25</b> <i>S</i>, <b>27</b> <i>S</i>, and <b>27</b> <i>R</i>) demonstrated promising antiviral efficacy against dengue virus. Pharmacological screening indicated that <i>S</i>p-isomers generally exhibited slightly greater inhibitory activity than their <i>R</i>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 <i>R</i>p-isomers was observed to be slightly higher than that of the <i>S</i>p-isomers, and the addition of a fluorine group also modestly increased this rate and fluorinated <b>39</b> <i>S</i> 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.
Authors
- Amporn Suphatrakul (ORCID: https://orcid.org/0000-0003-0264-040X)
- Suppachoke Onnome (ORCID: https://orcid.org/0000-0001-5801-2088)
- Bunpote Siridechadilok (ORCID: https://orcid.org/0000-0002-1608-4283)
- Arunee Thitithanyanont (ORCID: https://orcid.org/0000-0002-9756-4763)
- Aticha Thiraporn
- Ratthiya Thiabma
- Suradej Hongeng (ORCID: https://orcid.org/0000-0002-7376-9393)
- Thanat Tiyasakulchai (ORCID: https://orcid.org/0009-0008-5677-8643)
- Peera Jaru-Ampornpan (ORCID: https://orcid.org/0000-0002-4610-2235)
- Suwimon Manopwisedjaroen (ORCID: https://orcid.org/0000-0002-7571-8733)
- Marie Hoarau (ORCID: https://orcid.org/0000-0002-5758-3556)
- Jaraspim Narkpuk
- Thitiphong Khamkhenshorngphanuch
- Chanya Srisaowakarn (ORCID: https://orcid.org/0000-0003-3652-4757)
- Nitipol Srimongkolpithak (ORCID: https://orcid.org/0000-0003-2612-2770)
- Kitlada Srichomthong
- Sewan Theeramunkong (ORCID: https://orcid.org/0000-0003-3453-5022)
Institutions
- Thammasat University (TH)
- National Science and Technology Development Agency (TH)
- Mahidol University (TH)
- Navamindradhiraj University (TH)
- Drug Discovery Laboratory (Norway) (NO)
- Pharmaceutical Biotechnology (Czechia) (CZ)
- National Center for Genetic Engineering and Biotechnology (TH)
Publication Details
- Journal
- ACS Bio & Med Chem Au
- Published
- 2024-12-07
- DOI
- https://doi.org/10.1021/acsbiomedchemau.4c00071
- Citations
- 2
- Primary Topic
- Cholinesterase and Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.90
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