New Estrone Oxime Derivatives: Synthesis, Cytotoxic Evaluation and Docking Studies
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. Biological Testing
2.2.1. Cell Proliferation Studies
2.2.2. Cell Survival, Cell Cycle Distribution Evaluation and Hoechst 33,258 Staining
2.3. Molecular Docking Studies
3. Materials and Methods
3.1. Chemistry
3.1.1. Procedures for the Synthesis of Intermediates—Compounds 3, 4, 7, 8 and 9
Synthesis of 3-hydroxy-2-nitroestra-1,3,5(10)-trien-17-one (3) and 3-hydroxy-2,4-dinitroestra-1,3,5(10)-trien-17-one (4)
3-Hydroxy-2-nitroestra-1,3,5(10)-trien-17-one (3)
3-Hydroxy-2,4-dinitroestra-1,3,5(10)-trien-17-one (4)
3.1.2. General Procedure for the Synthesis of Oximes
Synthesis of 17-hydroxyiminoestra-1,3,5(10)-trien-3-ol (2)
Synthesis of 17-hydroxyimino-2-nitroestra-1,3,5(10)-trien-3-ol (5)
Synthesis of 17-hydroxyimino-2,4-dinitroestra-1,3,5(10)-trien-3-ol (6)
Synthesis of 17-hydroxyimino-2,4-diiodooestra-1,3,5(10)-trien-3-ol (10)
Synthesis of 17-hydroxyimino-3-hydroxyestra-1,3,5(10),9(11)-tetraen-3-ol (11)
Synthesis of 17-hydroxyimino-2,4-dibromo-3-hydroxyestra-1,3,5(10)-trien-3-ol (12)
3.2. Biology
3.2.1. Cell Culture
3.2.2. Preparation of Stock Solutions
3.2.3. Antiproliferative Activities against Six Cell Lines
3.2.4. E-Screening Assay in T47-D Cells
3.2.5. Analysis of LNCaP Cells Viability by Flow Cytometry
3.2.6. Cell Cycle Distribution of LNCaP Cells
3.2.7. Fluorescence Microscopy in LNCaP Cells after DNA Staining
3.2.8. Data Analysis
3.3. Molecular Docking Studies
3.3.1. Preparation of Proteins for Molecular Docking
3.3.2. Preparation of Ligands
3.3.3. Grid Parameters
3.3.4. Docking Simulations
3.3.5. Validation of the Molecular Docking Performance
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Compound | MCF-7 | T47-D | LNCaP | HepaRG | Caco-2 | NHDF |
---|---|---|---|---|---|---|
1 | 41.93 | ND | ND | 29.53 | 42.69 | 61.82 |
2 | 26.65 | 29.26 | ND | 16.94 | ND | 43.88 |
5 | 16.75 | ND | ND | 12.32 | 18.51 | ND |
10 | ND | ND | ND | 28.00 | ND | ND |
11 | 25.63 | 43.45 | 3.59 | 18.35 | 24.33 | 30.84 |
12 | ND | ND | ND | 21.94 | ND | ND |
5-FU | 1.71 | 0.54 | 7.79 | 1.78 | 1.31 | 3.61 |
Compound | MCF-7 | T47-D | LNCaP | HepaRG | Caco-2 |
---|---|---|---|---|---|
1 | 1.47 | ND | ND | 2.09 | 1.45 |
2 | 1.65 | 1.50 | ND | 2.59 | ND |
11 | 1.20 | 0.71 | 8.59 | 1.68 | 1.27 |
5-FU | 2.11 | 6.69 | 0.46 | 2.03 | 2.76 |
Compound | Lowest Energy (kcal.mol−1) | |||
---|---|---|---|---|
ERα | ST | 17β−HSD1 | β−Tubulin | |
1 | −10.3 b | −6.2 b | −8.1 b | −9.0 |
2 | −9.7 | −6.7 | −8.1 | −8.9 |
3 | −8.8 | −7.0 | −8.2 | −8.7 |
4 | −6.6 | −7.0 | −8.1 | −8.5 |
5 | −7.9 | −6.9 | −8.3 | −8.9 |
6 | −5.3 | −6.8 | −8.1 | −8.4 |
7 | −4.3 b | −6.0 b | −7.7 b | −8.4 |
8 | −10.9 b | −5.9 b | −8.2 b | −9.0 |
9 | −6.8 b | −6.3 b | −8.1 b | −9.0 |
10 | −5.8 | −6.6 | −7.7 | −8.5 |
11 | −10.5 | −6.5 | −8.3 | −9.1 |
12 | −5.0 | −6.3 | −7.6 | −8.5 |
E2 | −9.9 a | − | − | − |
N−acetyl−D−glucosamine | − | −7.2 a | − | − |
5α−Dihydrotestosterone | − | − | −8.3 a | − |
Colchicine | − | − | − | −8.4 a |
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Canário, C.; Matias, M.; Brito, V.; Santos, A.O.; Falcão, A.; Silvestre, S.; Alves, G. New Estrone Oxime Derivatives: Synthesis, Cytotoxic Evaluation and Docking Studies. Molecules 2021, 26, 2687. https://doi.org/10.3390/molecules26092687
Canário C, Matias M, Brito V, Santos AO, Falcão A, Silvestre S, Alves G. New Estrone Oxime Derivatives: Synthesis, Cytotoxic Evaluation and Docking Studies. Molecules. 2021; 26(9):2687. https://doi.org/10.3390/molecules26092687
Chicago/Turabian StyleCanário, Catarina, Mariana Matias, Vanessa Brito, Adriana O. Santos, Amílcar Falcão, Samuel Silvestre, and Gilberto Alves. 2021. "New Estrone Oxime Derivatives: Synthesis, Cytotoxic Evaluation and Docking Studies" Molecules 26, no. 9: 2687. https://doi.org/10.3390/molecules26092687