Novel Uridine Glycoconjugates, Derivatives of 4-Aminophenyl 1-Thioglycosides, as Potential Antiviral Compounds
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Evaluation
2.2.1. Antiviral Activity against Classical Swine Fever Virus
2.2.2. Antiviral Activity against Hepatitis C Virus
2.2.3. Time-of-Drug Addition Studies
2.2.4. The Inhibitory Effect of Compounds 9 and 12 on HCV Replication
2.2.5. Inhibitory Activity against β-1,4GalT
3. Materials and Methods
3.1. General Experimental Procedures
3.1.1. Synthesis of Succinic Acid Mono-2′,3′-di-O-tert-butyldimethylsilyl-uridin-5′-yl Ester (2)
3.1.2. Synthesis of Glycoconjugates 7–13
Glycoconjugate 7
Glycoconjugate 8
Glycoconjugate 9
Glycoconjugate 10
Glycoconjugate 11
Glycoconjugate 12
Glycoconjugate 13
3.1.3. Synthesis of Glycoconjugates 14,15
Glycoconjugate 14
Glycoconjugate 15
3.2. Antiviral Activity
3.2.1. Antiviral Compounds
3.2.2. Cells and Viruses
3.2.3. Cell Viability Assays
3.2.4. CSFV Pseudo-Plaque Reduction Assay
3.2.5. The HCVcc Pseudo-Plaque Reduction Assay
3.2.6. SEAP Reporter Assay
3.2.7. Antiviral Screening Using Replicon Huh7-J17 Cell Line
3.2.8. RNA Inhibition (RT-PCR)
3.2.9. Bovine Milk β-1,4GalT I Assay
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Sample Availability: Samples of the compounds 7–15 are available from the authors. |
Entry | Substrate 1 Amine | Substrate 2 Uridine Deriv. | Product | Procedure | Reaction Time (h) | Yield (%) |
---|---|---|---|---|---|---|
1 | 5 | 1 | 7 | A | 48 | 30 |
2 | 5 | 1 | 7 | B | 2 | 34 |
3 | 5 | 2 | 8 | A | 48 | 28 |
4 | 5 | 2 | 8 | B | 2 | 32 |
5 | 6 | 2 | 9 | A | 48 | 38 |
6 | 6 | 2 | 9 | B | 2 | 40 |
7 | 5 | 3 | 10 | A | 72 | 48 |
8 | 5 | 3 | 10 | B | 2 | 57 |
9 | 6 | 3 | 11 | A | 72 | 43 |
10 | 6 | 3 | 11 | B | 2 | 51 |
11 | 5 | 4 | 12 | A | 72 | 28 |
12 | 5 | 4 | 12 | B | 2 | 31 |
13 | 6 | 4 | 13 | A | 72 | 35 |
14 | 6 | 4 | 13 | B | 2 | 41 |
Compound | CSFV (SK6 Cells) | HCV (Huh-7.5 Cells) | ||||
---|---|---|---|---|---|---|
CC50 (μM) a | IC50 (μM) b | SI c | CC50 (μM) a | IC50 (μM) b | SI c | |
7 | 103 ± 5.9 | 97 ± 2 | 1.1 | 399 ± 11.4 | 281 ± 4.7 | 1.4 |
8 | 42 ± 1.9 | 4.5 ± 0.3 | 9.3 | 16 ± 1.1 | 4 ± 0.2 | 4.0 |
9 | 124 ± 6.8 | 4.2 ± 0.5 | 29.5 | 257 ± 5.7 | 4.9 ± 0.3 | 52.4 |
10 | 326 ± 11.2 | 149 ± 6.1 | 2.2 | 258 ± 6.2 | 154 ± 2.8 | 1.7 |
11 | 340 ± 9.1 | 217 ± 3.9 | 1.6 | 272 ± 4.5 | 167 ± 3.1 | 1.6 |
12 | 56 ± 4.3 | 4 ± 0.1 | 14.0 | 270 ± 2.9 | 13.5 ± 0.7 | 20.0 |
13 | 49 ± 3.5 | 25 ± 0.9 | 2.0 | 14 ± 0.9 | 7.4 ± 0.2 | 1.9 |
14 | 265 ± 8.6 | 241 ± 9.2 | 1.1 | >475 ± 12.5 | 444 ± 12.4 | >1.1 |
15 | 278 ± 4.3 | 257 ± 6.9 | 1.1 | 460 ± 9.3 | 454 ± 9.8 | 1.0 |
I | 86 ± 2.4 | 3 ± 0.1 | 28.7 | 135 ± 2.4 | 7 ± 0.7 | 19.3 |
II | 151 ± 3.1 | 6 ± 0.4 | 25.2 | 173 ± 3.2 | 7 ± 0.4 | 24.7 |
SOFOSBUVIR | ND | ND | ND | 31 ± 1.2 | 0.26 ± 0.02 | 119.2 |
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Krol, E.; Pastuch-Gawolek, G.; Chaubey, B.; Brzuska, G.; Erfurt, K.; Szewczyk, B. Novel Uridine Glycoconjugates, Derivatives of 4-Aminophenyl 1-Thioglycosides, as Potential Antiviral Compounds. Molecules 2018, 23, 1435. https://doi.org/10.3390/molecules23061435
Krol E, Pastuch-Gawolek G, Chaubey B, Brzuska G, Erfurt K, Szewczyk B. Novel Uridine Glycoconjugates, Derivatives of 4-Aminophenyl 1-Thioglycosides, as Potential Antiviral Compounds. Molecules. 2018; 23(6):1435. https://doi.org/10.3390/molecules23061435
Chicago/Turabian StyleKrol, Ewelina, Gabriela Pastuch-Gawolek, Binay Chaubey, Gabriela Brzuska, Karol Erfurt, and Boguslaw Szewczyk. 2018. "Novel Uridine Glycoconjugates, Derivatives of 4-Aminophenyl 1-Thioglycosides, as Potential Antiviral Compounds" Molecules 23, no. 6: 1435. https://doi.org/10.3390/molecules23061435
APA StyleKrol, E., Pastuch-Gawolek, G., Chaubey, B., Brzuska, G., Erfurt, K., & Szewczyk, B. (2018). Novel Uridine Glycoconjugates, Derivatives of 4-Aminophenyl 1-Thioglycosides, as Potential Antiviral Compounds. Molecules, 23(6), 1435. https://doi.org/10.3390/molecules23061435