Synthesis, In Vitro and In Silico Analysis of New Oleanolic Acid and Lupeol Derivatives against Leukemia Cell Lines: Involvement of the NF-κB Pathway †
Abstract
:1. Introduction
1.1. Oleanolic Acid and Lupeol
1.2. Semi-Synthetic Derivatives of the Two Natural Triterpenoids Precursors
2. Results and Discussion
2.1. Chemistry
2.2. Cytotoxic Activity on HL60 and HL60R Cell Lines
2.3. Effects of Derivatives on NF-κB (p65 Subunit) Pathway in HL60R Cells
2.4. Molecular Docking Analysis
2.5. Effects of Derivatives on IκB-α Protein Expression
3. Materials and Methods
3.1. General
3.2. Preparation of Compound 2 from OA 1
3.3. Preparation of Compounds 3 and 4 from 1
3.4. General Procedure for the Dihydroxylation of Compounds 3, 4, 10, and 12 to Give 5–8, 13, and 14
3.5. Preparation of Compound 11 from 10
3.6. Preparation of Compound 12 from 9
3.7. Preparation of Compound 15 from 14
3.8. Cell Cultures
3.9. Cell Growth Assays
3.10. NF-κB Activation
3.11. Western Blotting
3.12. Protein-Ligands Preparation, and Docking
3.13. Statistical Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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C/H | 5 | 6 | 7 | 8 | ||||
---|---|---|---|---|---|---|---|---|
1 | 35.6 t | 1.22 m 1.34 m | 35.6 t | 0.94 m 1.34 m | 33.5 t | 1.10 m 1.35 m | 34.9 t | 1.22 m 1.40 m |
2 | 33.8 t | 1.57 m 1.76 m | 33.8 t | 1.20 m 1.73 m | 28.2 t | 1.99 m 2.05 m | 33.8 t | 1.54 m 1.76 m |
3 | 77.6 s | 76.6 s | 77.0 s (78.7) * | 77.3 s | ||||
4 | 41.8 s | 41.8 s | 42.0 s | 42.6 s | ||||
5 | 51.3 d | 1.38 m | 51.7 d | 1.40 m | 53.5 d (54.5) * | 1.08 m | 54.6 d | 1.08 m |
6 | 21.3 t | 1.41 m 1.50 m | 19.9 t | 1.41 m 1.47 m | 20.00 t | 1.27 m 1.40 m | 20.3 t | 1.45 m 1.50 m |
7 | 31.6 t | 1.30 m 1.32 m | 31.6 t | 1.29 m 1.37 m | 33.3 t | 0.83 m 0.90 m | 31.6 t | 1.20 m 1.42 m |
8 | 37.9 s | 37.8 s | 37.6 s | 38.1 s | ||||
9 | 47.6 d | 1.76 m | 47.7 d | 1.73 m | 46.8 d | 1.60 m | 47.7 d | 1.70 m |
10 | 37.9 s | 37.9 s | 37.7 s | 38.3 s | ||||
11 | 24.1 t | 1.92 m 1.93 m | 24.4 t | 1.89 m 1.91 m | 23.8 t | 1.80 m 1.96 m | 24.5 t | 1.91 m 1.95 m |
12 | 123.5 d | 5.28 t (3.15) | 123.7 d | 5.26 t (3.3) | 122.4 d | 5.39 t (3.2) | 123.6 d | 5.27 t (3.1) |
13 | 145.1 s | 145.2 s | 144.9 s | 145.2 s | ||||
14 | 40.5 s | 40.8 s | 37.8 s | 40.6 s | ||||
15 | 28.8 t | 1.10 m 1.81 m | 28.8 t | 1.10 m 1.78 m | 31.01 t | 1.24 m 1.70 m | 29.0 t | 1.08 m 1.82 m |
16 | 24.4 t | 1.61 m 2.03 m | 24.5 t | 1.59 m 2.02 m | 26.1 t | 0.99 m 1.00 m | 24.1 t | 1.64 m 2.04 m |
17 | 43.0 s | 43.0 s | 42.2 s | 42.9 s | ||||
18 | 42.7 d | 2.88 dd (13.9, 4.4) | 42.7 d | 2.86 dd (14.0, 4.5) | 39.8 d | 3.20 dd (13.6, 4.5) | 42.8 d | 2.87 dd (13.7, 4.7) |
19 | 47.2 t | 1.14 m 1.70 m | 47.3 t | 1.12 m 1.67 m | 46.7 t | 1.21 m 1.69 m | 47.3 t | 1.16 m 1.71 m |
20 | 29.5 s | 29.9 s | 28.7 s | 30.8 s | ||||
21 | 34.9 t | 1.22 m 1.34 m | 34.9 t | 0.95 m 1.33 m | 34.9 t | 1.08 m 1.33 m | 34.7 t | 1.22 m 1.35 m |
22 | 34.1 t | 1.56 m 1.77 m | 34.1 t | 1.55 m 1.75 m | 34.8 t | 1.03 m 1.24 m | 34.2 t | 1.55 m 1.77 m |
23 | 17.7 q | 0.84 s | 17.7 q | 0.83 s | 23.8 q | 1.01 s | 24.6 q | 0.90 s |
24 | 19.9 q | 0.82 | 24.0 q | 0.91 s | 19.4 q | 1.05 s | 20.0 q | 0.92 s |
25 | 15.0 q | 0.97 s | 15.5 q | 0.92 s | 16.1 q | 0.85 s | 16.2 q | 1.02 s |
26 | 17.8 q | 0.96 s | 17.8 q | 0.83 s | 17.5 q | 0.92 s | 17.9 q | 0.86 s |
27 | 26.5 q | 1.22 s | 26.4 q | 1.19 s | 24.7 q | 1.10 s | 26.1 q | 1.22 s |
28 | 181.8 s | 181.9 s | nd | 181.8 s | ||||
29 | 33.5 q | 0.94 s | 33.6 q | 0.95 s | 31.0 q | 0.85 s | 33.2 q | 0.95 s |
30 | 24.0 q | 0.97 s | 24.0 q | 0.95 s | 23.8 q | 0.92 s | 24.0 q | 0.98 s |
1′ | 38.0 t | 1.47 m 1.78 m | 40.5 t | 1.42 m 1.84 m | 34.8 t | 1.93 m 2.29 m | 37.8 t | 1.62 m 1.92 m |
2′ | 70.3 d | 4.04 d quint. (1.8, 5.4) | 69.6 d | 3.94 m | 70.8 d | 4.42 quint. (5.3) | 70.3 d | 3.92 quint. (5.7) |
3′ | 67.8 t | 3.49 dd (5.7, 10.6) 3.44 dd (5.6, 10.6) | 68.6 t | 3.48 dd (5.1, 10.9) 3.44 dd (6.4, 10.8) | 68.2 t | 3.93 dd (5.8, 10.6) 3.83 dd (5.11, 10.7) | 68.6 t | 3.49 dd (11.7, 6.8) 3.58 dd (11.6, 6.8) |
C/H | 13 | 14 | ||
---|---|---|---|---|
1 | 39.5 t | 1.91 m 1.41 m | 38.4 t | 1.70 m 1.00 m |
2 | 34.1 t | 2.40 ddd (7.8, 4.6, 4.6) 2.50 ddd (7.8, 5.0, 5.1) | 24.8 t | 1.60 m 1.63 m |
3 | 218.4 s | - | 81.0 d | 4.48 dd |
4 | 47.2 s | - | 37.6 s | - |
5 | 54.7 d | 1.32 m | 55.3 d | 0.78 m |
6 | 19.6 t | 1.45 m 0.80 m | 18.9 t | 1.45 m 1.50 m |
7 | 33.8 t | 1.43 m 1.44 m | 34.5 t | 1.48 m 1.39 m |
8 | 41.2 s | - | 41.4 s | - |
9 | 49.6 d | 1.34 m | 50.2 d | 1.28 m |
10 | 36.7 s | - | 37.8 s | - |
11 | 21.9 t | 1.33 m 1.46 m | 21.4 t | 1.48 m 1.34 m |
12 | 27.5 t | 1.02 m 1.89 m | 27.5 t | 1.00 m 1.51 m |
13 | 40.3 d | 1.42 m | 37.0 t | 0.99 m 1.68 m |
14 | 43.5 s | - | 43.5 s | - |
15 | 27.5 t | 1.51 m 1.74 m | 27.5 t | 1.70 m 1.51 m |
16 | 35.4 t | 1.48 m 1.34 m | 35.5 t | 1.39 m 1.40 m |
17 | 44.6 s | - | 44.7 s | - |
18 | 47.9 d | 1.40 m | 48.0 d | 1.40 m |
19 | 47.3 d | 1.93 m | 47.3 d | 1.91 m |
20 | 75.2 s | - | 75.2 s | - |
21 | 28.6 t | 1.05 m 1.52 m | 27.9 t | 1.51 m 1.04 m |
22 | 37.7 t | 1.73 m 1.75 m | 40.4 t | 1.10 m 1.32 m |
23 | 26.6 q | 1.06 s | 28.6 q | 0.85 s |
24 | 21.0 q | 1.02 s | 16.5 q | 0.84 s |
25 | 16.0 q | 0.94 s | 16.2 q | 0.87 s |
26 | 16.0 q | 1.08 s | 16.2 q | 1.05 s |
27 | 14.7 q | 0.92 s | 14.8 q | 0.94 s |
28 | 18.9 q | 0.80 s | 18.2 q | 0.80 s |
29 | 67.2 t | 3.44 d (10.3) 3.65 d (10.3) | 67.3 t | 3.44 d (10.3) 3.63 d (10.3) |
30 | 24.8 q | 1.20 s | 23.7 q | 1.20 s |
-COCH3 | - | - | 171.0 s | - |
-COCH3 | - | - | 21.3 q | 2.03 s |
HL60 IC50 (Mean ± SE) | HL60R IC50 (Mean ± SE) | |
---|---|---|
1 | 44.0 ± 0.7 | 43.5 ± 10.3 |
2 | 4.5 ± 3.3 | 11.2 ± 3.9 |
3 | 20.2 ± 0.5 | 19.0 ± 0.3 |
4 | 12.7 ± 0.9 | 16.0 ± 0.7 |
5 | 35.7 ± 0.9 | 32.2 ± 1.2 |
6 | 72.2 ± 2.3 | 72.7 ± 3.4 |
7 | 33.0 ± 3.5 | 39.5 ± 3.2 |
8 | 32.0 ± 1.8 | 32.0 ± 1.1 |
9 | >100 | >100 |
10 | >100 | >100 |
11 | 18.2 ± 2.3 | 22.5 ± 8.1 |
12 | 25.5 ± 5.3 | 24.2 ± 5 8 |
13 | 36.7 ± 1.9 | 44.7 ± 0.9 |
14 | 21.2 ± 4.1 | 43.2 ± 3.4 |
15 | 9.6 ± 0.1 | 14.5 ± 4.9 |
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Fontana, G.; Badalamenti, N.; Bruno, M.; Castiglione, D.; Notarbartolo, M.; Poma, P.; Spinella, A.; Tutone, M.; Labbozzetta, M. Synthesis, In Vitro and In Silico Analysis of New Oleanolic Acid and Lupeol Derivatives against Leukemia Cell Lines: Involvement of the NF-κB Pathway. Int. J. Mol. Sci. 2022, 23, 6594. https://doi.org/10.3390/ijms23126594
Fontana G, Badalamenti N, Bruno M, Castiglione D, Notarbartolo M, Poma P, Spinella A, Tutone M, Labbozzetta M. Synthesis, In Vitro and In Silico Analysis of New Oleanolic Acid and Lupeol Derivatives against Leukemia Cell Lines: Involvement of the NF-κB Pathway. International Journal of Molecular Sciences. 2022; 23(12):6594. https://doi.org/10.3390/ijms23126594
Chicago/Turabian StyleFontana, Gianfranco, Natale Badalamenti, Maurizio Bruno, Davide Castiglione, Monica Notarbartolo, Paola Poma, Alberto Spinella, Marco Tutone, and Manuela Labbozzetta. 2022. "Synthesis, In Vitro and In Silico Analysis of New Oleanolic Acid and Lupeol Derivatives against Leukemia Cell Lines: Involvement of the NF-κB Pathway" International Journal of Molecular Sciences 23, no. 12: 6594. https://doi.org/10.3390/ijms23126594