Novel Heme Oxygenase-1 (HO-1) Inducers Based on Dimethyl Fumarate Structure
Abstract
:1. Introduction
2. Results and Discussions
2.1. Chemistry
2.2. Rational Design and Biological Evalution
2.3. Computational Studies
3. Materials and Methods
3.1. Chemistry
3.2. General Procedure for the Synthesis of (2E)-2-Butenedioic Acid Derivatives (1a–k)
3.2.1. (2E)-2-Butenedioic acid, 1,4-diphenyl ester (1a)
3.2.2. (2E)-2-Butenedioic acid, 1,4-bis(4-chlorophenyl) ester (1b)
3.2.3. (2E)-2-Butenedioic acid, 1,4-bis(4-iodophenyl) ester (1c)
3.2.4. (2E)-2-Butenedioic acid, 1,4-bis(4-trifluoromethyphenyl) ester (1d)
3.2.5. (2E)-2-Butenedioic acid, 1,4-bis(4-cyanophenyl) ester (1e)
3.2.6. (2E)-2-Butenedioic acid, 1,4-bis 4-methylphenyl) ester (1f)
3.2.7. (2E)-2-Butenedioic acid, 1,4-bis(4-methoxyphenyl) ester (1g)
3.2.8. (2E)-2-Butenedioic acid, 1,4-bis(2-carboxyphenyl) ester (1h)
3.2.9. (2E)-2-Butenedioic acid, 1,4-bis(phenylmethyl) ester (1i)
3.2.10. (2E)-2-Butenedioic acid, 1,4-bis(phenylethyl) ester (1j)
3.2.11. (2E)-2-Butenedioic acid, 1,4-bis(phenylpropyl) ester (1k)
3.3. General Procedure for the Synthesis of (E)-N, N’-Diphenylalkyl-Butenediamide Derivatives (1l–o)
3.3.1. (E)-N, N’-Diphenyl-2-butenediamide (1l)
3.3.2. (E)-N, N’-Diphenylmethyl-2-butenediamide (1m)
3.3.3. (E)-N, N’-Diphenylethyl-2-butenediamide (1n)
3.3.4. (E)-N, N’-Diphenylpropyl-2-butenediamide (1o)
3.4. Synthesis of (2E)-2-Butenedioic Acid, Methyl Phenyl Ester (2a)
3.5. General Procedure for the Synthesis of (2E)-2-Butenedioic Acid Derivatives 2b and 2c
3.5.1. (2E)-2-Butenedioic acid, methyl phenylmethyl ester (2b)
3.5.2. (2E)-2-Butenedioic acid, methyl phenylethyl ester (2c)
3.6. Biology
3.6.1. Cell Culture of LX2 Cells
3.6.2. ELISA Heme Oxygenase Inducer (HO-1) Measurements
3.6.3. MTT Assay
3.6.4. Reactive Oxygen Species (ROS) Assay
3.7. Computational Study
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Compound | Fold Induction 1 (ELISA) | MTT IC50 (μM) | ||
---|---|---|---|---|
1 μM | 5 μM | 10 μM | ||
1a | 6.65 ± 0.15 | 7.93 ± 0.18 | 8.16 ± 0.32 | >50 |
1b | 8.81 ± 0.20 | 8.19 ± 0.21 | 11.74 ± 0.41 | >50 |
1c | 6.02 ± 0.13 | 7.70 ± 0.19 | 8.13 ± 0.23 | 20.8 ± 1.5 |
1d | (−0.95) ± 0.02 | 1.40 ± 0.03 | 0.68 ± 0.02 | >50 |
1e | 3.68 ± 0.21 | 5.22 ± 0.11 | 6.50 ± 0.17 | >50 |
1f | 1.82 ± 0.09 | 3.94 ± 0.13 | 3.76 ± 0.15 | >50 |
1g | 0.30 ± 0.01 | 0.76 ± 0.02 | 0.90 ± 0.06 | 22.3 ± 1.8 |
1h | 6.37 ± 0.22 | 7.45 ± 0.21 | 9.95 ± 0.19 | >50 |
1i | 3.40 ± 0.18 | 5.86 ± 0.19 | 7.34 ± 0.28 | 17.7 ± 1.3 |
1j | 2.29 ± 0.10 | 5.91 ± 0.17 | 8.47 ± 0.33 | >50 |
1k | 2.26 ± 0.09 | 5.98 ± 0.16 | 9.55 ± 0.27 | >50 |
1l | 6.90 ± 0.14 | 9.74 ± 0.25 | 10.19 ± 0.29 | >50 |
1m | 7.46 ± 0.16 | 14.15 ± 0.34 | 13.76 ± 0.35 | 18.6 ± 1.4 |
1n | 5.82 ± 0.12 | 7.52 ± 0.21 | 8.40 ± 0.38 | >50 |
1o | 4.85 ± 0.13 | 6.93 ± 0.23 | 6.30 ± 0.21 | >50 |
2a | (−2.26) ± 0.08 | (−2.15) ± 0.04 | (−2.25) ± 0.02 | >50 |
2b | (−1.61) ± 0.06 | (−0007) ± 0.001 | (0.28) ± 0.01 | >50 |
2c | (−0.88) ± 0.02 | (−0.60) ± 0.01 | (−0.11) ± 0.01 | >50 |
DMF | 2.78 ± 0.09 | 7.63 ± 0.31 | 8.3 ± 0.23 | >50 |
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Sorrenti, V.; Vanella, L.; Platania, C.B.M.; Greish, K.; Bucolo, C.; Pittalà, V.; Salerno, L. Novel Heme Oxygenase-1 (HO-1) Inducers Based on Dimethyl Fumarate Structure. Int. J. Mol. Sci. 2020, 21, 9541. https://doi.org/10.3390/ijms21249541
Sorrenti V, Vanella L, Platania CBM, Greish K, Bucolo C, Pittalà V, Salerno L. Novel Heme Oxygenase-1 (HO-1) Inducers Based on Dimethyl Fumarate Structure. International Journal of Molecular Sciences. 2020; 21(24):9541. https://doi.org/10.3390/ijms21249541
Chicago/Turabian StyleSorrenti, Valeria, Luca Vanella, Chiara Bianca Maria Platania, Khaled Greish, Claudio Bucolo, Valeria Pittalà, and Loredana Salerno. 2020. "Novel Heme Oxygenase-1 (HO-1) Inducers Based on Dimethyl Fumarate Structure" International Journal of Molecular Sciences 21, no. 24: 9541. https://doi.org/10.3390/ijms21249541