2-Acetamido-2-deoxy-d-glucono-1,5-lactone Sulfonylhydrazones: Synthesis and Evaluation as Inhibitors of Human OGA and HexB Enzymes
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis of Inhibitors
2.2. Inhibition of hOGA and hHexB by 2-Acetamido-2-deoxy-d-glucono-1,5-lactone Arenesulfonylhydrazones
2.3. Computationally Predicted Enzyme–Inhibitor Binding in hOGA
3. Materials and Methods
3.1. Synthesis
3.1.1. General Methods
3.1.2. General Procedure A for the Synthesis of 1-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-2-arenesulfonyl Hydrazines (3)
1-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-2-(p-toluenesulfonyl) Hydrazine (3a)
1-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-2-(p-trifluoromethylbenzenesulfonyl) Hydrazine (3b)
1-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-2-(p-fluorobenzenesulfonyl) Hydrazine (3c)
1-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-2-(p-chlorobenzenesulfonyl) Hydrazine (3d)
1-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-2-(2-naphthalenesulfonyl) Hydrazine (3e)
1-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-2-(1-naphthalenesulfonyl) Hydrazine (3f)
3.1.3. General Procedure B for the Synthesis of 2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-d-glucono-1,5-lactone Arenesulfonylhydrazones (4)
2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-d-glucono-1,5-lactone p-Toluenesulfonylhydrazone (4a)
2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-d-glucono-1,5-lactone p-Trifluoromethylbenzenesulfonylhydrazone (4b)
2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-d-glucono-1,5-lactone p-Fluorobenzenesulfonylhydrazone (4c)
2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-d-glucono-1,5-lactone p-Chlorobenzenesulfonylhydrazone (4d)
2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-d-glucono-1,5-lactone 2-Naphthalenesulfonylhydrazone (4e)
2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-d-glucono-1,5-lactone 1-Naphthalenesulfonylhydrazone (4f)
3.1.4. General Procedure C for the Synthesis of 2-Acetamido-2-deoxy-d-glucono-1,5-lactone Arenesulfonylhydrazones (5)
2-Acetamido-2-deoxy-d-glucono-1,5-lactone p-Toluenesulfonylhydrazone (5a)
2-Acetamido-2-deoxy-d-glucono-1,5-lactone p-Trifluoromethylbenzenesulfonylhydrazone (5b)
2-Acetamido-2-deoxy-d-glucono-1,5-lactone p-Fluorobenzenesulfonylhydrazone (5c)
2-Acetamido-2-deoxy-d-glucono-1,5-lactone p-Chlorobenzenesulfonylhydrazone (5d)
2-Acetamido-2-deoxy-d-glucono-1,5-lactone 2-Naphthalenesulfonylhydrazone (5e)
2-Acetamido-2-deoxy-d-glucono-1,5-lactone 1-Naphthalenesulfonylhydrazone (5f)
3.2. Biochemical Materials and Methods
3.2.1. Protein Expression and Purification
3.2.2. Inhibition Studies
3.3. Computational Details
3.3.1. Protein Preparation
3.3.2. Enzyme–Inhibitor Complex Predictions
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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I | II | ||||
Ar | Ki (nM) | Ar | Ki (nM) | ||
OGA | HexB | OGA | HexA/B a | ||
Ph (PUGNAc) | 46 [10] | 36 [10] | Ph | 190 [12] | 205 [12] |
4-Me-C6H4- | 28 [9] | 21 [9] | 4-Me-C6H4- | 155 [12] | 332 [12] |
4-Br-C6H4- | 56 [9] | 47 [9] | 4-Cl-C6H4- | 83 [12] | 170 [12] |
2-Naphthyl | 36 [12] | 47 [12] | |||
Target compounds | |
| |||||
Reagents and conditions: (a) ArSO2NHNH2 (2, 1.5 equiv.), p-TsOH·H2O (0.1 equiv.), CHCl3, reflux; (b) activated MnO2, abs. CH2Cl2, reflux; (c) NH3/MeOH, r.t. | |||||
Ar | Products and yields (%) | ||||
3 | 4 | 5 | Overall yield of 5 from d-glucosamine | ||
a | p-MePh | 77 | 69 | 94 | 41 |
b | p-CF3Ph | 85 | 60 | 83 | 35 |
c | p-FPh | 86 | 72 | 85 | 44 |
d | p-ClPh | 89 | 77 | 78 | 44 |
e | 2-naphthyl | 76 | 56 | 75 | 26 |
f | 1-naphthyl | 89 | 66 | 80 | 39 |
Compound | Ki (nM) | Ki(hHexB)/ Ki(hOGA)a | ||
hOGA | hHexB | |||
PUGNAc | | 46 [10] | 36 [10] | 0.8 |
2-acetamido-2-deoxy- d-glucono-1,5-lactone 4-(2-naphthyl)-semicarbazone | | 36 [12] | 47 [12] | 1.3 |
5a | | 78 ± 1 | 21 ± 2 | 0.27 |
5b | | 230 ± 17 | 48 ± 4 | 0.21 |
5c | | 95 ± 11 | 45 ± 3 | 0.43 |
5d | | 70 ± 3 | 39 ± 2 | 0.56 |
5e | | 30 ± 2 | 30 ± 3 | 1 |
5f | | 27 ± 7 | 6.8 ± 1.8 | 0.25 |
| |||||||
Inhibitor/pose | Prime Hierarchical | Prime Local | QM/MM | ||||
Prime Energy (kcal/mol) | Relative Energy (kcal/mol) | Prime Energy (kcal/mol) | Relative Energy (kcal/mol) | Absolute Energy (Hartrees) | Relative Energy (kcal/mol) | Dihedral a (°) C1′=N1-N2-H | |
PUGNAc | |||||||
Pose 1 | −34,316.1 | 0.0 | −34,320.1 | 0.6 | −1328.97031 | 1.2 | - |
Pose 2 | −34,315.9 | 0.2 | −34,320.7 | 0.0 | −1328.96987 | 1.5 | - |
Pose 3 | −34,315.8 | 0.3 | −34,320.1 | 0.6 | −1328.97033 | 1.2 | - |
Pose 4 | −34,315.6 | 0.5 | −34,319.9 | 0.8 | −1328.97226 | 0.0 | - |
Pose 5 | −34,315.6 | 0.5 | −34,320.5 | 0.2 | −1328.97227 | 0.0 | - |
5a | |||||||
Pose 1 | −34,317.1 | 0.0 | −34,320.7 | 0.9 | −1728.25188 | 8.8 | −14.9 |
Pose 2 | −34,315.8 | 1.3 | −34,318.0 | 3.6 | −1728.26592 | 0.0 | −172.2 |
Pose 3 | −34,315.2 | 1.9 | −34,320.2 | 1.4 | −1728.25192 | 8.8 | −15.1 |
Pose 4 | −34,315.1 | 2.0 | −34,318.6 | 3.0 | −1728.26597 | 0.0 | −171.8 |
Pose 5 | −34,314.8 | 2.3 | −34,321.6 | 0.0 | −1728.25203 | 8.7 | −15.1 |
5b | |||||||
Pose 1 | −34,303.5 | 0.0 | −34,310.8 | 0.0 | −2025.91547 | 13.3 | 8.1 |
Pose 2 | −34,302.4 | 1.1 | −34,304.6 | 6.2 | −2025.93662 | 0.0 | −168.0 |
Pose 3 | −34,302.0 | 1.5 | −34,305.1 | 5.7 | −2025.92286 | 8.6 | −22.0 |
Pose 4 | −34,301.5 | 2.0 | −34,305.0 | 5.8 | −2025.92249 | 8.9 | −21.4 |
Pose 5 | −34,301.5 | 2.0 | −34,305.2 | 5.6 | −2025.92290 | 8.6 | −22.0 |
5c | |||||||
Pose 1 | −34,318.0 | 0.0 | −34,322.8 | 0.3 | −1788.16899 | 8.7 | −17.9 |
Pose 2 | −34,317.5 | 0.5 | −34,323.1 | 0.0 | −1788.16894 | 8.8 | −17.5 |
Pose 3 | −34,317.4 | 0.6 | −34,322.3 | 0.8 | −1788.18292 | 0.0 | −170.7 |
Pose 4 | −34,317.3 | 0.7 | −34,321.8 | 1.3 | −1788.18290 | 0.0 | −170.6 |
Pose 5 | −34,316.8 | 1.2 | −34,319.1 | 4.0 | −1788.18236 | 0.4 | −149.3 |
5d | |||||||
Pose 1 | −34,318.3 | 0.0 | −34,320.1 | 0.2 | −2148.53075 | 9.0 | −19.6 |
Pose 2 | −34,316.6 | 1.7 | −34,320.3 | 0.0 | −2148.53084 | 8.9 | −19.7 |
Pose 3 | −34,315.9 | 2.4 | −34,319.4 | 0.9 | −2148.53121 | 8.7 | −20.5 |
Pose 4 | −34,315.8 | 2.5 | −34,319.1 | 1.2 | −2148.53073 | 9.0 | −19.3 |
Pose 5 | −34,315.1 | 3.2 | −34,319.5 | 0.8 | −2148.54505 | 0.0 | −169.2 |
5e | |||||||
Pose 1 | −34,303.0 | 0.0 | −34,308.7 | 0.0 | −1842.54825 | 8.6 | −11.8 |
Pose 2 | −34,302.9 | 0.1 | −34,306.0 | 2.7 | −1842.56165 | 0.2 | −169.3 |
Pose 3 | −34,300.8 | 2.2 | −34,306.6 | 2.1 | −1842.56197 | 0.0 | −169.6 |
Pose 4 | −34,300.6 | 2.4 | −34,306.9 | 1.8 | −1842.56199 | 0.0 | −169.5 |
Pose 5 | −34,300.3 | 2.7 | −34,306.7 | 2.0 | −1842.56189 | 0.1 | −169.7 |
5f | |||||||
Pose 1 | −34,308.4 | 0.0 | −34,311.4 | 1.5 | −1842.54544 | 4.7 | −0.8 |
Pose 2 | −34,304.6 | 3.8 | −34,309.9 | 3.0 | −1842.54384 | 5.7 | 3.6 |
Pose 3 | −34,303.2 | 5.2 | −34,312.9 | 0.0 | −1842.53822 | 9.2 | −2.1 |
Pose 4 | −34,302.0 | 6.4 | −34,305.5 | 7.4 | −1842.54411 | 5.6 | −169.9 |
Pose 5 | −34,301.4 | 7.0 | −34,308.7 | 4.2 | −1842.55296 | 0.0 | −154.1 |
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Kiss, M.; Timári, I.; Barna, T.; Mészáros, Z.; Slámová, K.; Bojarová, P.; Křen, V.; Hayes, J.M.; Somsák, L. 2-Acetamido-2-deoxy-d-glucono-1,5-lactone Sulfonylhydrazones: Synthesis and Evaluation as Inhibitors of Human OGA and HexB Enzymes. Int. J. Mol. Sci. 2022, 23, 1037. https://doi.org/10.3390/ijms23031037
Kiss M, Timári I, Barna T, Mészáros Z, Slámová K, Bojarová P, Křen V, Hayes JM, Somsák L. 2-Acetamido-2-deoxy-d-glucono-1,5-lactone Sulfonylhydrazones: Synthesis and Evaluation as Inhibitors of Human OGA and HexB Enzymes. International Journal of Molecular Sciences. 2022; 23(3):1037. https://doi.org/10.3390/ijms23031037
Chicago/Turabian StyleKiss, Mariann, István Timári, Teréz Barna, Zuzana Mészáros, Kristýna Slámová, Pavla Bojarová, Vladimír Křen, Joseph M. Hayes, and László Somsák. 2022. "2-Acetamido-2-deoxy-d-glucono-1,5-lactone Sulfonylhydrazones: Synthesis and Evaluation as Inhibitors of Human OGA and HexB Enzymes" International Journal of Molecular Sciences 23, no. 3: 1037. https://doi.org/10.3390/ijms23031037