Towards Selective Binding to the GLUT5 Transporter: Synthesis, Molecular Dynamics and In Vitro Evaluation of Novel C-3-Modified 2,5-Anhydro-D-mannitol Analogs
Abstract
:1. Introduction
2. Materials and Methods
2.1. Synthesis
- 3-deoxy-3-amino-2,5-anhydro-D-mannitol (2)
- 3-deoxy-3-[N-(5-fluoro-2,4-dinitro-phenyl)amino]-2,5-anhydro-D-mannitol (3)
2.1.1. General Procedure to Synthesize 4, 5 and 6
- 3-deoxy-3-[N-(4-fluorobenzenesulfonamide)amino]-2,5-anhydro-D-mannitol (4)
- 3-deoxy-3-[N-(4-fluoro-2-(trifluoromethyl)benzenesulfonamide)amino]-2,5-anhydro-D-mannitol (5)
- 3-deoxy-3-[N-(5-(dimethylamino)naphthalene-1-sulfonamide)amino]-2,5-anhydro-D-mannitol (6)
2.1.2. General Procedure to Synthesize 7 and 8
- 3-deoxy-3-[N-(1-(4-fluorophenyl)thiourea)amino]-2,5-anhydro-D-mannitol (7)
- 3-deoxy-3-[N-(3-(fluorescein)-5-yl)thiourea)amino]-2,5-anhydro-D-mannitol (8)
- 3-deoxy-3-[N-(4-fluorobenzamide)amino]-2,5-anhydro-D-mannitol (9)
- 3-deoxy-3-[N-(tert-butyl-2-amino-2-oxoethoxycarbamate)]-2,5-anhydro-D-mannitol (I)
- 3-deoxy-3-[N-(2-(((4-fluorobenzylidene)amino)oxy)acetamide)amino]-2,5-anhydro-D-mannitol (10)
- 3-deoxy-3-[N-(7-hydroxy-2-oxo-2H-chromene-3-carboxamide)amino]-2,5-anhydro-D-mannitol (V)
- 3-deoxy-3-[N-(7-(2-fluoroethoxy)-2-oxo-2H-chromene-3-carboxamide)amino]-2,5-anhydro-D-mannitol (11)
2.2. In Vitro Cell Experiments
2.2.1. Instruments
2.2.2. Buffer Solutions
2.2.3. Radiotracer Synthesis
2.2.4. Cell Culture
2.2.5. General Procedure for In Vitro Inhibition of 6-[18F]FDF Cell Uptake
- Fructose—freely soluble in Krebs–Ringer buffer;
- 2,5-AM derivatives—all the samples were first dissolved in ≤0.1% DMSO and were further diluted using Krebs–Ringer buffer according to the desired concentration maintaining ≤0.1% DMSO;
- Blank—0.1% DMSO.
2.3. Molecular Docking
Molecular Dynamics Simulations
3. Results and Discussion
3.1. Synthesis of C-3-Modified 2,5-AM Compounds
3.2. In Vitro Cell Experiments
3.3. In Silico Studies
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound | n/x | IC50 (mM) |
---|---|---|
3 | 6/2 | 1.10 ± 0.17 |
4 | 6/2 | ~6 (estimated) |
5 | 6/2 | n.d. |
6 | 9/3 | 2.29 ± 0.18 |
7 | 6/2 | n.d. |
8 | 6/2 | ~20 (estimated) |
9 | 6/2 | n.d. |
10 | 6/2 | 2.31 ± 0.35 |
11 | 6/2 | 1.71 ± 0.08 |
6-FDF | 9/3 | 17.02 ± 0.75 |
Fructose | 12/4 | 342 ± 74 |
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Rana, N.; Aziz, M.A.; Oraby, A.K.; Wuest, M.; Dufour, J.; Abouzid, K.A.M.; Wuest, F.; West, F.G. Towards Selective Binding to the GLUT5 Transporter: Synthesis, Molecular Dynamics and In Vitro Evaluation of Novel C-3-Modified 2,5-Anhydro-D-mannitol Analogs. Pharmaceutics 2022, 14, 828. https://doi.org/10.3390/pharmaceutics14040828
Rana N, Aziz MA, Oraby AK, Wuest M, Dufour J, Abouzid KAM, Wuest F, West FG. Towards Selective Binding to the GLUT5 Transporter: Synthesis, Molecular Dynamics and In Vitro Evaluation of Novel C-3-Modified 2,5-Anhydro-D-mannitol Analogs. Pharmaceutics. 2022; 14(4):828. https://doi.org/10.3390/pharmaceutics14040828
Chicago/Turabian StyleRana, Natasha, Marwa A. Aziz, Ahmed K. Oraby, Melinda Wuest, Jennifer Dufour, Khaled A. M. Abouzid, Frank Wuest, and F. G. West. 2022. "Towards Selective Binding to the GLUT5 Transporter: Synthesis, Molecular Dynamics and In Vitro Evaluation of Novel C-3-Modified 2,5-Anhydro-D-mannitol Analogs" Pharmaceutics 14, no. 4: 828. https://doi.org/10.3390/pharmaceutics14040828
APA StyleRana, N., Aziz, M. A., Oraby, A. K., Wuest, M., Dufour, J., Abouzid, K. A. M., Wuest, F., & West, F. G. (2022). Towards Selective Binding to the GLUT5 Transporter: Synthesis, Molecular Dynamics and In Vitro Evaluation of Novel C-3-Modified 2,5-Anhydro-D-mannitol Analogs. Pharmaceutics, 14(4), 828. https://doi.org/10.3390/pharmaceutics14040828