Biological Activity and In Silico Study of 3-Modified Derivatives of Betulin and Betulinic Aldehyde
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Antiproliferative Activity
2.3. In Silico Study
3. Materials and Methods
3.1. General Techniques
3.2. Synthesis of 3-Acetylbetulin 2 and 3-Acetylbetulinic Aldehyde 3
3.3. Synthesis of 28-Tetrahydropyranylbetulin 4
3.4. General Procedure for the Synthesis of Betulin Derivatives 5–9
3.5. General Procedure for the Synthesis of Betulin Derivatives 10–14
3.6. General Procedure for the Synthesis of Betulinic Aldehyde Derivatives 15–24
3.7. Antiproliferative Activity—MTT and SRB Assays
3.7.1. Human Cell Lines
3.7.2. Antiproliferative Assays
3.8. In Silico Study
4. Conclusions
Supplementary Materials
Author Contributions
Acknowledgments
Conflicts of Interest
Abbreviations
Akt | serine/threonine protein kinase |
ADME | absorption, distribution, metabolism and excretion |
PPARγ | peroxisome proliferator-activated receptor |
EGFR | epidermal growth factor receptor |
DHFR | dihydrofolate reductase |
VEGFR | vascular endothelial growth factor |
NF-κβ | transcription factor |
HER-2/neu | epidermal growth factor receptor EGFR family |
hCA-IX | human carbonic anhydrase IX |
CDK6 | cyclin-dependent kinase 6 |
LOX | lipoxygenase |
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Compound | MV-4-11 IC50 (μM) | Compound | MV-4-11 IC50 (μM) |
---|---|---|---|
5 | 38.9 ± 11.8 | 15 | 71.8 ± 22.9 |
6 | 4.2 ± 1.2 | 16 | 5.8 ± 1.8 |
7 | 62.4 ± 9.9 | 17 | 86.7 ± 42.8 |
8 | Neg | 18 | Neg |
9 | 4.5 ± 1.7 | 19 | 35.9 ± 4.9 |
10 | 20.0 ± 1.5 | 20 | 25.1 ± 7.2 |
11 | 30.8 ± 1.5 | 21 | 80.2 ± 14.4 |
12 | 20.1 ± 4.7 | 22 | 38.3 ± 4.6 |
13 | 7.4 ± 1.7 | 23 | 30.0 ± 6.1 |
14 | 8.9±0.9 | 24 | 28.3 ± 7.4 |
Betulin 1 | 8.1 ± 2.9 | ||
2 | 27.2 ± 5.9 | ||
3 | 35.0 ± 12.8 | ||
Cisplatin | 1.0 ± 0.27 |
Compound | Antiproliferative Activity IC50 (μM) | ||||
---|---|---|---|---|---|
A549 | Du-145 | Hs294T | MCF-7 | MCF-10A | |
6 | 23.3 ± 1.8 | 84.5 ± 39.4 | 69.0 ± 3,4 | 45.9 ± 3.8 | 119.8 ± 15.3 |
9 | 83.5 ± 25.3 | 7.3 ± 0.8 | 10.6 ± 4.3 | 10.4 ± 5.7 | 71.7 ± 8.6 |
13 | 14.9 ± 2.5 | 95.1 ± 16.8 | 82.7 ± 8.4 | 28.9 ± 4.6 | Neg |
14 | 33.8 ± 2.8 | 126.1 ± 13.2 | 164.0 ± 15.8 | 39.2 ± 6.9 | Neg |
16 | 15.1 ± 5.0 | 67.1 ± 4.6 | 74.4 ± 7.3 | 60.4 ± 4.4 | 112.6 ± 11.7 |
Betulin 1 | 8.6 ± 0.7 | 44.0 ± 19.4 | 44.1 ± 7.2 | 26.2 ± 6.5 | 124.2 ± 41.6 |
Cisplatin | 4.3 ± 1.3 | 1.6 ± 0.3 | 6.3 ± 1.3 | 7.7 ± 0.3 | 14.7 ± 1.0 |
Compounds | LogBB a | cLogP b | HBA c | HBD d | TPSA e |
---|---|---|---|---|---|
5 | 0.3 | 8.42 | 3 | 1 | 46.53 |
6 | 0 | 8.23 | 3 | 1 | 46.53 |
7 | −0.42 | 8.85 | 3 | 1 | 46.53 |
8 | −0.79 | 9.72 | 3 | 1 | 46.53 |
9 | −0.3 | 8.31 | 3 | 1 | 46.53 |
10 | 0.07 | 7.94 | 4 | 1 | 55.77 |
11 | 0.01 | 8.39 | 4 | 1 | 55.77 |
12 | 0.03 | 8.01 | 4 | 1 | 55.77 |
13 | −0.17 | 7.67 | 4 | 1 | 55.77 |
14 | −0.24 | 8.01 | 4 | 1 | 55.77 |
15 | 0.04 | 8.37 | 3 | 0 | 43.38 |
16 | 0.14 | 8.16 | 3 | 0 | 43.38 |
17 | −0.21 | 8.76 | 3 | 0 | 43.38 |
18 | −0.7 | 9.56 | 3 | 0 | 43.38 |
19 | −0.1 | 8.32 | 3 | 0 | 43.38 |
20 | 0.07 | 7.99 | 4 | 0 | 52.61 |
21 | 0.03 | 8.26 | 4 | 0 | 52.61 |
22 | 0.07 | 8.17 | 4 | 0 | 52.61 |
23 | −0.11 | 7.79 | 4 | 0 | 52.61 |
24 | −0.15 | 8.12 | 4 | 0 | 52.61 |
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Bębenek, E.; Chrobak, E.; Marciniec, K.; Kadela-Tomanek, M.; Trynda, J.; Wietrzyk, J.; Boryczka, S. Biological Activity and In Silico Study of 3-Modified Derivatives of Betulin and Betulinic Aldehyde. Int. J. Mol. Sci. 2019, 20, 1372. https://doi.org/10.3390/ijms20061372
Bębenek E, Chrobak E, Marciniec K, Kadela-Tomanek M, Trynda J, Wietrzyk J, Boryczka S. Biological Activity and In Silico Study of 3-Modified Derivatives of Betulin and Betulinic Aldehyde. International Journal of Molecular Sciences. 2019; 20(6):1372. https://doi.org/10.3390/ijms20061372
Chicago/Turabian StyleBębenek, Ewa, Elwira Chrobak, Krzysztof Marciniec, Monika Kadela-Tomanek, Justyna Trynda, Joanna Wietrzyk, and Stanisław Boryczka. 2019. "Biological Activity and In Silico Study of 3-Modified Derivatives of Betulin and Betulinic Aldehyde" International Journal of Molecular Sciences 20, no. 6: 1372. https://doi.org/10.3390/ijms20061372