Synthesis and Biological Evaluation of Novel Dehydroabietic Acid-Oxazolidinone Hybrids for Antitumor Properties
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. Biological Assays
2.2.1. Cytotoxicity Measurement
2.2.2. Cell Cycle Analysis
2.2.3. Compound 4j Induces Apoptosis in MGC-803 Cells
2.2.4. Hoechst 33258 Staining Assay
3. Materials and Methods
3.1. Chemistry
3.2. Synthesis: General Procedure for Compounds 3a–o
3.2.1. (1R,4aS)-2-Hydroxy-3-(Phenylamino)Propyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4,4a,9,10,10a-Octahydrophenanthrene-1-Carboxylate (3a)
3.2.2. (1R,4aS)-2-Hydroxy-3-(2-Methylphenylamino)Propyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4,4a,9,10, 10a-Octahydrophenanthrene-1-Carboxylate (3b)
3.2.3. (1R,4aS)-2-Hydroxy-3-(3-Methylphenylamino)Propyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4,4a,9,10, 10a-Octahydrophenanthrene-1-Carboxylate (3c)
3.2.4. (1R,4aS)-2-Hydroxy-3-(4-Methylphenylamino)Propyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4,4a,9,10, 10a-Octahydrophenanthrene-1-Carboxylate (3d)
3.2.5. (1R,4aS)-2-Hydroxy-3-(2-Methoxyphenylamino)Propyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4,4a,9, 10,10a-Octahydrophenanthrene-1-Carboxylate (3e)
3.2.6. (1R,4aS)-2-Hydroxy-3-(3-Methoxyphenylamino)Propyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4,4a,9, 10,10a-Octahydrophenanthrene-1-Carboxylate (3f)
3.2.7. (1R,4aS)-2-Hydroxy-3-(4-Methoxyphenylamino)Propyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4,4a,9, 10,10a-Octahydrophenanthrene-1-Carboxylate (3g)
3.2.8. (1R,4aS)-2-Hydroxy-3-(2-Fluorophenylamino)Propyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4,4a,9,10, 10a-Octahydrophenanthrene-1-Carboxylate (3h)
3.2.9. (1R,4aS)-2-Hydroxy-3-(3-Fluorophenylamino)Propyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4,4a,9,10, 10a-Octahydrophenanthrene-1-Carboxylatev (3i)
3.2.10. (1R,4aS)-2-Hydroxy-3-(4-Fluorophenylamino)Propyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4,4a,9,10, 10a-Octahydrophenanthrene-1-Carboxylate (3j)
3.2.11. (1R,4aS)-2-Hydroxy-3-(3-Chlorophenylamino)Propyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4,4a,9,10, 10a-Octahydrophenanthrene-1-Carboxylate (3k)
3.2.12. (1R,4aS)-2-Hydroxy-3-(4-Chlorophenylamino)Propyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4,4a,9,10, 10a-Octahydrophenanthrene-1-Carboxylate (3l)
3.2.13. (1R,4aS)-2-Hydroxy-3-(3-Bromophenylamino)Propyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4,4a,9,10, 10a-Octahydrophenanthrene-1-Carboxylate (3m)
3.2.14. (1R,4aS)-2-Hydroxy-3-(4-Bromophenylamino)Propyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4,4a,9,10, 10a-Octahydrophenanthrene-1-Carboxylate (3n)
3.2.15. (1R,4aS)-2-Hydroxy-3-(3-Ethynylphenylamino)Propyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4,4a,9, 10,10a-Octahydrophenanthrene-1-Carboxylate 3o
3.3. Synthesis: General Procedure for Compounds 4a–o
3.3.1. (1R,4aS)-(2-Oxo-3-Phenyloxazolidin-5-yl)Methyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4,4a,9,10,10a-Octahydrophenanthrene-1-Carboxylate (4a)
3.3.2. (1R,4aS)-(3-(2-Methylphenyl)-2-Oxooxazolidin-5-yl)Methyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4, 4a,9,10,10a-Octahydrophenanthrene-1-Carboxylate (4b)
3.3.3. (1R,4aS)-(3-(3-Methylphenyl)-2-Oxooxazolidin-5-yl)Methyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4, 4a,9,10,10a-Octahydrophenanthrene-1-Carboxylate (4c)
3.3.4. (1R,4aS)-(3-(4-Methylphenyl)-2-Oxooxazolidin-5-yl)Methyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4, 4a,9,10,10a-Octahydrophenanthrene-1-Carboxylate (4d)
3.3.5. (1R,4aS)-(3-(2-Methoxyphenyl)-2-Oxooxazolidin-5-yl)Methyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4, 4a,9,10,10a-Octahydrophenanthrene-1-Carboxylate (4e)
3.3.6. (1R,4aS)-(3-(3-Methoxyphenyl)-2-Oxooxazolidin-5-yl)Methyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4, 4a,9,10,10a-Octahydrophenanthrene-1-Carboxylate (4f)
3.3.7. (1R,4aS)-(3-(4-Methoxyphenyl)-2-Oxooxazolidin-5-yl)Methyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4, 4a,9,10,10a-Octahydrophenanthrene-1-Carboxylate (4g)
3.3.8. (1R,4aS)-(3-(2-Fluorophenyl)-2-Oxooxazolidin-5-yl)Methyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4,4a, 9,10,10a-Octahydrophenanthrene-1-Carboxylate (4h)
3.3.9. (1R,4aS)-(3-(3-Fluorophenyl)-2-Oxooxazolidin-5-yl)Methyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4,4a, 9,10,10a-Octahydrophenanthrene-1-Carboxylate (4i)
3.3.10. (1R,4aS)-(3-(4-Fluorophenyl)-2-Oxooxazolidin-5-yl)Methyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4, 4a,9,10,10a-Octahydrophenanthrene-1-Carboxylate (4j)
3.3.11. (1R,4aS)-(3-(3-Chlorophenyl)-2-Oxooxazolidin-5-yl)Methyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4, 4a,9,10,10a-Octahydrophenanthrene-1-Carboxylate (4k)
3.3.12. (1R,4aS)-(3-(4-Chlorophenyl)-2-Oxooxazolidin-5-yl)Methyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4, 4a,9,10,10a-Octahydrophenanthrene-1-Carboxylate (4l)
3.3.13. (1R,4aS)-(3-(3-Bromophenyl)-2-Oxooxazolidin-5-yl)Methyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4, 4a,9,10,10a-Octahydrophenanthrene-1-Carboxylate (4m)
3.3.14. (1R,4aS)-(3-(4-Bromophenyl)-2-Oxooxazolidin-5-yl)Methyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4, 4a,9,10,10a-Octahydrophenanthrene-1-Carboxylate (4n)
3.3.15. (1R,4aS)-(3-(3-Ehynylphenyl)-2-Oxooxazolidin-5-yl)Methyl-7-Isopropyl-1,4a-Dimethyl-1,2,3,4, 4a,9,10,10a-Octahydrophenanthrene-1-Carboxylate 4o
3.4. Cytotoxicity Assay
3.5. Cell Cycle Analysis
3.6. Apoptosis Analysis
3.7. Hoechst 33258 Staining Assay
3.8. Statistics
4. Conclusions
Supplementary Materials
Author Contributions
Acknowledgments
Conflicts of Interest
Abbreviations
BTC | bis(trichloromethyl)carbonate |
DCM | dichloromethane |
DHAA | dehydroabietic acid |
DMEM | dulbecco’s modified eagle medium |
DMSO | dimethyl sulfoxide |
FBS | fetal bovine serum |
FITC | fluorescein isothiocyanate |
HR-MS | high resolution mass spectrometr |
IR | infrared radiation |
Mp | melting point |
MRSA | methicillin-resistant staphylococcus aureus |
MRSE | methicillin-resistant staphylococcus epidermidis |
MTT | methyl thiazolytetrazolium |
NMR | nuclear magnetic resonance |
PI | propidium iodide |
THF | tetrahydrofuran |
TLC | thin-layer chromatography |
TMS | tetramethylsilane |
VRE | vancomycin-resistant enterococcus |
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Compound | IC50 (μM) | ||||
---|---|---|---|---|---|
MGC-803 | CNE-2 | SK-OV-3 | NCI-H460 | LO2 | |
3a | 7.10 ± 1.51 | 27.87 ± 0.25 | 15.08 ± 0.57 | 18.56 ± 0.97 | >100 |
3b | 22.56 ± 2.71 | >100 | >100 | >100 | >100 |
3c | 12.34 ± 4.87 | 14.61 ± 0.19 | 14.81 ± 4.03 | 20.13 ± 2.95 | 34.67 ± 0.45 |
3d | 21.84 ± 2.66 | 44.13 ± 2.89 | 29.95 ± 0.80 | 44.76 ± 5.26 | >100 |
3e | 28.47 ± 1.35 | 27.37 ± 0.51 | 19.48 ± 2.23 | 26.14 ± 1.92 | 32.34 ± 1.56 |
3f | 18.37 ± 1.45 | 17.44 ± 4.32 | 18.01 ± 0.09 | 21.87 ± 8.61 | >100 |
3g | 51.69 ± 1.85 | >100 | >100 | >100 | >100 |
3h | 17.50 ± 3.51 | 45.74 ± 5.80 | >100 | 30.24 ± 3.40 | >100 |
3i | >100 | >100 | >100 | >100 | >100 |
3j | 14.21 ± 1.70 | 20.73 ± 2.31 | 18.91 ± 1.66 | 15.59 ± 1.45 | 28.69 ± 0.55 |
3k | 13.10 ± 2.66 | 18.17 ± 4.06 | 25.07 ± 4.80 | 18.14 ± 2.33 | 35.32 ± 0.57 |
3l | 34.48 ± 0.02 | >100 | >100 | >100 | >100 |
3m | 16.48 ± 5.20 | 23.17 ± 2.78 | 30.29 ± 0.59 | 19.63 ± 1.12 | >100 |
3n | 9.91 ± 7.00 | 17.89 ± 4.47 | 19.03 ± 2.11 | 19.05 ± 5.23 | >100 |
3o | 13.38 ± 5.41 | 20.01 ± 1.09 | 23.08 ± 2.23 | 22.30 ± 2.74 | >100 |
4a | 11.00 ± 4.41 | 9.69 ± 0.13 | >100 | 4.83 ± 0.77 | >100 |
4b | 24.99 ± 5.02 | >100 | >100 | 27.72 ± 5.03 | >100 |
4c | 10.50 ± 1.44 | 31.96 ± 0.23 | >100 | 9.13 ± 2.77 | 36.22 ± 2.68 |
4d | 5.97 ± 0.87 | 21.14 ± 1.96 | 19.74 ± 1.33 | 2.91 ± 2.38 | 30.55 ± 1.99 |
4e | 13.23 ± 1.15 | 20.51 ± 0.97 | >100 | 7.99 ± 6.35 | 40.56 ± 1.96 |
4f | 19.71 ± 2.80 | 23.53 ± 1.20 | 42.97 ± 1.05 | 17.25 ± 1.38 | >100 |
4g | 6.10 ± 0.35 | 19.76 ± 0.30 | 4.10 ± 2.45 | 14.05 ± 8.04 | 26.36 ± 0.15 |
4h | 49.90 ± 1.14 | >100 | >100 | >100 | >100 |
4i | 11.48 ± 0.25 | 28.02 ± 3.95 | 9.86 ± 4.30 | 25.09 ± 4.50 | >100 |
4j | 3.82 ± 0.18 | 17.76 ± 4.69 | 4.66 ± 2.13 | 8.44 ± 0.36 | >100 |
4k | 7.43 ± 1.42 | 31.24 ± 2.50 | 10.33 ± 5.46 | 22.96 ± 2.62 | 37.20 ± 3.14 |
4l | 5.82 ± 4.82 | 27.58 ± 1.50 | 15.71 ± 2.32 | 26.55 ± 0.08 | 44.49 ± 2.77 |
4m | 9.80 ± 2.37 | >100 | >100 | 25.06 ± 1.39 | 34.16 ± 2.88 |
4n | 5.34 ± 3.45 | 42.49 ± 5.68 | >100 | 30.24 ± 2.66 | >100 |
4o | 18.22 ± 2.36 | 51.36 ± 5.06 | 23.66 ± 2.02 | 72.36 ± 1.07 | >100 |
DHA | 29.81 ± 2.06 | 62.59 ± 1.60 | >100 | >100 | >100 |
cisplatin | 14.9 ± 1.78 | 21.02 ± 2.25 | 10.44 ± 0.25 | 24.14 ± 1.74 | 36.37 ± 0.79 |
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Wang, X.; Pang, F.-H.; Huang, L.; Yang, X.-P.; Ma, X.-L.; Jiang, C.-N.; Li, F.-Y.; Lei, F.-H. Synthesis and Biological Evaluation of Novel Dehydroabietic Acid-Oxazolidinone Hybrids for Antitumor Properties. Int. J. Mol. Sci. 2018, 19, 3116. https://doi.org/10.3390/ijms19103116
Wang X, Pang F-H, Huang L, Yang X-P, Ma X-L, Jiang C-N, Li F-Y, Lei F-H. Synthesis and Biological Evaluation of Novel Dehydroabietic Acid-Oxazolidinone Hybrids for Antitumor Properties. International Journal of Molecular Sciences. 2018; 19(10):3116. https://doi.org/10.3390/ijms19103116
Chicago/Turabian StyleWang, Xiu, Fu-Hua Pang, Lin Huang, Xin-Ping Yang, Xian-Li Ma, Cai-Na Jiang, Fang-Yao Li, and Fu-Hou Lei. 2018. "Synthesis and Biological Evaluation of Novel Dehydroabietic Acid-Oxazolidinone Hybrids for Antitumor Properties" International Journal of Molecular Sciences 19, no. 10: 3116. https://doi.org/10.3390/ijms19103116