Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemistry
2.1.1. General Experimental Details
2.1.2. General Procedure for the Synthesis of 2-Pyrrolin-5-one derivatives 1
2.1.3. Synthesis of Compounds 2
2.1.4. Prediction of Physicochemical, ADME and CNS Permeability Properties
2.1.5. Antioxidant Capacity by the ORAC Assay
2.1.6. Anti-Oxidant Capacity by the 1,1-Diphenyl-2-picryl-hydrazyl (DPPH) Reduction Assay
2.1.7. Computational Study of PHF6 Hexapeptide Aggregation
2.2. Biological Studies
2.2.1. Culture of HEK293-Tau3R Cells
2.2.2. Culture of SH-SY5Y Neuroblastoma Cells
2.2.3. Culture of AREc32 Cells
2.2.4. Culture of BV2 Cells
2.2.5. Cell Viability Studies in HEK293-Tau3R and SH-SY5Y Cells
2.2.6. Reactive Oxygen Species (ROS) Measurement in HEK293-Tau3R Cells
2.2.7. PHF6 Peptide Aggregation
2.2.8. Thioflavin T Assay
2.2.9. Nrf2 Induction Capacity
2.2.10. Neuroprotection Assays in SH-SY5Y Cells
2.2.11. Nitrite Production Reduction Assay
2.3. Statistical Analyses
3. Results and Discussion
3.1. Prediction of Physicochemical, ADME and CNS Permeability Properties of Compounds 2
3.2. Synthesis of Compounds 2
3.3. In Vitro Characterization of the Antioxidant Capacity of Compounds 2
3.4. Biological Evaluation of Curcumin Derivatives
3.4.1. Cytotoxicity Evaluation in the HEK293-Tau3R and SH-SY5Y Cell Lines
3.4.2. ROS Scavenger Activity in HEK293-Tau3R Cells
3.4.3. Nrf2 Induction
3.4.4. Inhibition of PHF6 Aggregation
3.4.5. Anti-Inflammatory Properties
3.4.6. Neuroprotection against Oxidative Stress
3.4.7. Neuroprotection against Tau Hyperphosphorylation Induced by Okadaic Acid
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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Cmpd. | MW (g/mol) | TPSA (Å2) | Heavy Atoms | HBA | HBD | RotB | Log P | QPP Caco (nm/s) | QPP MDCK (nm/s) | %Human Oral Absorption | Rule of Five |
---|---|---|---|---|---|---|---|---|---|---|---|
Curcumin | 368.38 | 96.22 | 27 | 6 | 3 | 12 | 3.17 | 141.2 | 59.6 | 81.8 | 0 |
2a | 497.51 | 94.53 | 36 | 8 | 1 | 12 | 4.09 | 903.3 | 799.9 | 100 | 1 |
2b | 431.48 | 94.53 | 31 | 7 | 1 | 12 | 3.13 | 864.1 | 422.5 | 96.5 | 1 |
2c | 483.49 | 94.53 | 35 | 8 | 1 | 11 | 3.71 | 428.8 | 357.5 | 95.8 | 1 |
2d | 445.51 | 94.53 | 32 | 7 | 1 | 13 | 3.47 | 1044.3 | 518.4 | 100 | 1 |
2e | 387.43 | 96.3 | 28 | 6 | 2 | 11 | 2.69 | 314.4 | 141.6 | 100 | 0 |
2f | 465.50 | 94.53 | 34 | 7 | 1 | 11 | 3.36 | 980.3 | 484.2 | 100 | 1 |
Entry | Compound | CNS MPO.v2 [0–6] |
---|---|---|
1 | Curcumin | 3.97 |
2 | 2a | 4.03 |
3 | 2b | 4.93 |
4 | 2c | 4.23 |
5 | 2d | 4.63 |
6 | 2e | 4.60 |
7 | 2f | 4.53 |
Entry | Compound | ORAC | DPPH |
---|---|---|---|
Trolox Eqs. | SC50, μM | ||
1 | Curcumin | 3.88 ± 0.18 | 18.2 ± 0.63 |
2 | Ascorbic acid | -- | 17.2 ± 1.14 |
3 | 2a | 0.50 ± 0.23 *** | 20.6 ± 2.17 |
4 | 2b | 0.52 ± 0.22 *** | 10.8 ± 0.06 ***/### |
5 | 2c | 0.35 ± 0.13 *** | 56.9 ± 1.18 **/## |
6 | 2d | 1.63 ± 0.06 *** | 14.2 ± 2.15 |
7 | 2e | 1.73 ± 0.68 *** | 8.87 ± 0.45 ***/### |
8 | 2f | 0.65 ± 0.11 *** | 36.6 ± 1.02 |
Parameter | Apo-System | With Curcumin | With Compound 2d |
---|---|---|---|
RMSD (Å) | 1.16 ± 0.33 | 1.85 ± 0.35 | 2.47 ± 0.80 |
Rg | 1.94 ± 0.19 | 2.33 ± 0.24 | 3.00 ± 0.60 |
Hbond | 122.18 ± 6.13 | 118.23 ± 5.55 | 112.02 ± 4.70 |
Entry | Compound | IC50 (μM) BV2 |
---|---|---|
1 | Curcumin | 0.64 ± 0.17 |
2 | 2a | 0.30 ± 0.04 * |
3 | 2b | 0.42 ± 0.08 |
4 | 2c | 0.56 ± 0.03 |
5 | 2d | 0.55 ± 0.08 |
6 | 2e | 0.37 ± 0.05 |
7 | 2f | 0.76 ± 0.13 |
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Cores, Á.; Carmona-Zafra, N.; Martín-Cámara, O.; Sánchez, J.D.; Duarte, P.; Villacampa, M.; Bermejo-Bescós, P.; Martín-Aragón, S.; León, R.; Menéndez, J.C. Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation. Antioxidants 2022, 11, 28. https://doi.org/10.3390/antiox11010028
Cores Á, Carmona-Zafra N, Martín-Cámara O, Sánchez JD, Duarte P, Villacampa M, Bermejo-Bescós P, Martín-Aragón S, León R, Menéndez JC. Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation. Antioxidants. 2022; 11(1):28. https://doi.org/10.3390/antiox11010028
Chicago/Turabian StyleCores, Ángel, Noelia Carmona-Zafra, Olmo Martín-Cámara, Juan Domingo Sánchez, Pablo Duarte, Mercedes Villacampa, Paloma Bermejo-Bescós, Sagrario Martín-Aragón, Rafael León, and J. Carlos Menéndez. 2022. "Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation" Antioxidants 11, no. 1: 28. https://doi.org/10.3390/antiox11010028
APA StyleCores, Á., Carmona-Zafra, N., Martín-Cámara, O., Sánchez, J. D., Duarte, P., Villacampa, M., Bermejo-Bescós, P., Martín-Aragón, S., León, R., & Menéndez, J. C. (2022). Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation. Antioxidants, 11(1), 28. https://doi.org/10.3390/antiox11010028