Design, Synthesis, and Anticancer Activity of Novel Enmein-Type Diterpenoid Derivatives Targeting the PI3K/Akt/mTOR Signaling Pathway
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis of Enmein-Type Diterpenoid Derivatives
2.2. In Vitro Anti-Proliferative Activity and SAR Analysis
2.3. Cell Cycle Analysis
2.4. Apoptosis Analysis
2.5. Reactive Oxygen Species (ROS) Analysis
2.6. Mitochondrial Membrane Potential (MMP) Analysis
2.7. The Predicted Potential Targets and Pathways of 7h
2.8. Western Blot Analysis
2.9. Molecular Docking Study
3. Conclusions
4. Materials and Methods
4.1. Chemistry
4.1.1. Reagents and Apparatus
4.1.2. Synthesis of Ent-6β,7β,14β-trihydroxy-1,15-dioxo-7,20-epoxy-16-kaurene (2)
4.1.3. Synthesis of Ent-6β,14α-Dihydroxy-(1,7–1,14)-epoxy-7,15-dioxo-6,20-hemiketal-6,7-seco-16-kaurene (4)
4.1.4. General Procedure for the Synthesis of Target Derivatives 5a–m
4.1.5. Synthesis of 4-(Ent-6β,14α-dihydroxy-(1,7–1,14)-epoxy-7,15-dioxo-6,20-hemi-ketal-6,7-seco-16-kaurene-6β-yloxy)-4-oxobutanoic Acid (6)
4.1.6. General Procedure for the Synthesis of Target Derivatives 7a–h
4.2. Biological Testing
4.2.1. Cell Culture
4.2.2. In Vitro Anti-Proliferative Activity
4.2.3. Experimental Method for Cell Cycle Analysis
4.2.4. Experimental Methods for Apoptosis Analysis
Cell Apoptosis Morphological Detection
Cell Apoptosis Rate Detection
4.2.5. Experimental Methods for ROS Measurement
Cell Morphological Detection
ROS Content Determination
4.2.6. Experimental Method for MMP Measurement
Cell Morphological Detection
Cell Morphological Detection
4.2.7. Experimental Methods for GO and KEGG Analysis
4.2.8. Experimental Method of Western Blot Analysis
4.2.9. Experimental Method of Molecular Docking Study
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Compounds | IC50 (µM) a | |||
---|---|---|---|---|
A549 | HepG2 | MCF-7 | L-02 | |
5a | 14.72 ± 1.54 | 17.12 ± 1.39 | 30.72 ± 1.16 | >50.00 |
5b | 15.84 ± 1.50 | 15.22 ± 1.58 | 17.57 ± 2.40 | >50.00 |
5c | 20.25 ± 1.46 | 22.54 ± 3.42 | 21.87 ± 2.72 | >50.00 |
5d | 8.76 ± 1.56 | 11.04 ± 1.45 | 15.56 ± 1.61 | 30.36 ± 3.44 |
5e | 10.71 ± 1.81 | 11.57 ± 1.96 | 14.11 ± 2.35 | 36.68 ± 2.43 |
5f | 13.43 ± 2.19 | 18.30 ± 1.36 | 20.71 ± 1.20 | 45.88 ± 2.30 |
5g | 15.26 ± 2.40 | 21.10 ± 2.50 | 22.81 ± 2.13 | >50.00 |
5h | 18.37 ± 1.13 | 20.18 ± 1.33 | 24.04 ± 2.55 | >50.00 |
5i | 14.39 ± 1.42 | 23.65 ± 3.40 | 25.12 ± 3.34 | 38.15 ± 2.82 |
5j | 23.30 ± 2.25 | 34.07 ± 3.52 | 32.84 ± 2.95 | >50.00 |
5k | 17.16 ± 1.43 | 25.68 ± 2.16 | 26.27 ± 2.30 | >50.00 |
5l | 8.30 ± 2.55 | 11.15 ± 1.82 | 15.87 ± 1.90 | >50.00 |
5m | 6.85 ± 1.68 | 10.87 ± 1.25 | 12.34 ± 1.11 | 32.51 ± 1.62 |
7a | 10.21 ± 1.10 | 13.77 ± 2.19 | 10.80 ± 1.65 | >50.00 |
7b | 7.48 ± 1.31 | 10.53 ± 1.68 | 12.76 ± 1.64 | >50.00 |
7c | 8.37 ± 1.53 | 12.83 ± 1.73 | 8.35 ± 1.96 | 34.42 ± 4.37 |
7d | 6.41 ± 1.90 | 11.54 ± 1.58 | 7.64 ± 2.52 | 35.74 ± 2.66 |
7e | 7.12 ± 1.52 | 11.60 ± 1.34 | 9.85 ± 1.53 | >50.00 |
7f | 7.38 ± 0.96 | 8.61 ± 1.14 | 8.20 ± 1.21 | >50.00 |
7g | 8.60 ± 2.65 | 8.78 ± 1.46 | 13.00 ± 1.52 | >50.00 |
7h | 2.16 ± 1.40 | 6.10 ± 1.24 | 6.74 ± 1.94 | >50.00 |
4 | 23.83 ± 1.86 | 27.35 ± 0.83 | 25.75 ± 1.14 | 30.25 ± 1.58 |
Oridonin | 21.10 ± 1.58 | 22.62 ± 1.20 | 18.46 ± 1.37 | 23.62 ± 1.65 |
Taxol | 4.21 ± 0.73 | 6.60 ± 1.61 | 5.15 ± 0.80 | 8.31 ± 1.82 |
Compound | Receptor Protein | Binding Energy (kcal/mol) a |
---|---|---|
7h | PI3Kα | −11.6 |
Akt1 | −11.3 | |
mTOR | −11.4 | |
4 | PI3Kα | −10.1 |
Akt1 | −9.0 | |
mTOR | −10.4 |
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Wang, J.; Wang, L.; Zhang, Y.; Pan, S.; Lin, Y.; Wu, J.; Bu, M. Design, Synthesis, and Anticancer Activity of Novel Enmein-Type Diterpenoid Derivatives Targeting the PI3K/Akt/mTOR Signaling Pathway. Molecules 2024, 29, 4066. https://doi.org/10.3390/molecules29174066
Wang J, Wang L, Zhang Y, Pan S, Lin Y, Wu J, Bu M. Design, Synthesis, and Anticancer Activity of Novel Enmein-Type Diterpenoid Derivatives Targeting the PI3K/Akt/mTOR Signaling Pathway. Molecules. 2024; 29(17):4066. https://doi.org/10.3390/molecules29174066
Chicago/Turabian StyleWang, Jiafeng, Lu Wang, Yingbo Zhang, Siwen Pan, Yu Lin, Jiale Wu, and Ming Bu. 2024. "Design, Synthesis, and Anticancer Activity of Novel Enmein-Type Diterpenoid Derivatives Targeting the PI3K/Akt/mTOR Signaling Pathway" Molecules 29, no. 17: 4066. https://doi.org/10.3390/molecules29174066