Design, Synthesis, and Biological Evaluation of EdAP, a 4′-Ethynyl-2′-Deoxyadenosine 5′-Monophosphate Analog, as a Potent Influenza a Inhibitor
Abstract
:1. Introduction
2. Results and Discussion
2.1. Effect of Compounds 1–3 on Anti-Influenza Activities
2.2. Synthesis of EdAP (5)
2.3. Anti-Influenza Activity of EdAP (5)
3. Materials and Methods
3.1. Chemistry
3.1.1. Synthesis of ((3aR,5R,6S,6aR)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-6-((4-methoxybenzyl)oxy)-2,2-dimethyltetrahydrofuro [2,3-d][1,3]dioxol-5-yl)methanol (7)
3.1.2. Synthesis of tert-butyl(((3aR,5R,6S,6aR)-5-(2,2-dibromovinyl)-6-((4-methoxybenzyl)oxy)-2,2- dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methoxy)diphenylsilane (9)
3.1.3. Synthesis of tert-butyl(((3aR,5R,6S,6aR)-6-((4-methoxybenzyl)oxy)-2,2-dimethyl-5-((triethylsilyl) ethynyl)tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methoxy)diphenylsilane (10)
3.1.4. Synthesis of (3R,4S,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-((4-methoxybenzyl)oxy)-5- ((triethylsilyl)ethynyl)tetrahydrofuran-2,3-diyl diacetate (12)
3.1.5. Synthesis of (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4- ((4-methoxybenzyl)oxy)-5-((triethylsilyl)ethynyl)tetrahydrofuran-3-yl acetate (13)
3.1.6. Synthesis of (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-((4- methoxybenzyl)oxy)-5-((triethylsilyl)ethynyl)tetrahydrofuran-3-ol (14)
3.1.7. Synthesis of O-((2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4- ((4-methoxybenzyl)oxy)-5-((triethylsilyl)ethynyl)tetrahydrofuran-3-yl) O-phenyl carbonothioate (15)
3.1.8. Synthesis of 9-((2R,4S,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-((4-methoxybenzyl)oxy)-5-((triethylsilyl)ethynyl)tetrahydrofuran-2-yl)-9H-purin-6-amine (17)
3.1.9. Synthesis of 2-(((2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-ethynyl-3-((4-methoxybenzyl)oxy) tetrahydrofuran-2-yl)methoxy)-4H-benzo[d][1,3,2]dioxaphosphinine 2-oxide (18)
3.1.10. Synthesis of 2-(((2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methoxy)-4H-benzo[d][1,3,2]dioxaphosphinine 2-oxide (5)
3.2. Biological Assays
3.2.1. Cells
3.2.2. Virus
3.2.3. Cytotoxicity Assay
3.2.4. Influenza Growth Inhibition Assay
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Sample Availability: Samples of the compounds are available from the authors. |
H1N1 Influenza A Virus | MDCK–SIAT1 | |
---|---|---|
Compound | IC50 (μM) | CC50 1 (μM) |
1 | 63 | >1000 |
2 | 401 | >1000 |
3 | >1000 | >1000 |
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Takeuchi, T.; Sriwilaijaroen, N.; Sakuraba, A.; Hayashi, E.; Kamisuki, S.; Suzuki, Y.; Ohrui, H.; Sugawara, F. Design, Synthesis, and Biological Evaluation of EdAP, a 4′-Ethynyl-2′-Deoxyadenosine 5′-Monophosphate Analog, as a Potent Influenza a Inhibitor. Molecules 2019, 24, 2603. https://doi.org/10.3390/molecules24142603
Takeuchi T, Sriwilaijaroen N, Sakuraba A, Hayashi E, Kamisuki S, Suzuki Y, Ohrui H, Sugawara F. Design, Synthesis, and Biological Evaluation of EdAP, a 4′-Ethynyl-2′-Deoxyadenosine 5′-Monophosphate Analog, as a Potent Influenza a Inhibitor. Molecules. 2019; 24(14):2603. https://doi.org/10.3390/molecules24142603
Chicago/Turabian StyleTakeuchi, Toshifumi, Nongluk Sriwilaijaroen, Ayako Sakuraba, Ei Hayashi, Shinji Kamisuki, Yasuo Suzuki, Hiroshi Ohrui, and Fumio Sugawara. 2019. "Design, Synthesis, and Biological Evaluation of EdAP, a 4′-Ethynyl-2′-Deoxyadenosine 5′-Monophosphate Analog, as a Potent Influenza a Inhibitor" Molecules 24, no. 14: 2603. https://doi.org/10.3390/molecules24142603