Sphaerococcenol A Derivatives: Design, Synthesis, and Cytotoxicity
Abstract
:1. Introduction
2. Results
2.1. Hemi-Synthesis of New Sphaerococcenol A Analogues
2.2. Cytotoxicity on Malignant Cell Lines
2.3. Effects of Analogue 1 on Cell Viability and Mitochondrial Function
2.4. Reactive Oxygen Species Levels
2.5. Mitochondrial Dysfunction and Apoptosis
3. Discussion
4. Materials and Methods
4.1. Hemi-Synthesis of Analogues
4.1.1. Reagents
4.1.2. Extraction and Isolation of Sphaerococcenol A
4.1.3. General Procedure for Thio-Michael Addition to Sphaerococcenol A (GP1)
(4S,4aS,4bS,8S,8aS,10aS)-8a-(Bromomethyl)-4-hydroxy-8-isopropyl-4,10a-dimethyl-1-(phenylthio)-1,4,4a,4b,7,8,8a,9,10,10a-decahydrophenanthren-3(2H)-one (1)
(4S,4aS,4bS,8S,8aS,10aS)-8a-(Bromomethyl)-4-hydroxy-8-isopropyl-4,10a-dimethyl-1-(propylthio)-1,4,4a,4b,7,8,8a,9,10,10a-decahydrophenanthren-3(2H)-one (2 and 3)
(4S,4aS,4bS,8S,8aS,10aS)-1-(Benzylthio)-8a-(bromomethyl)-4-hydroxy-8-isopropyl-4,10a-dimethyl-1,4,4a,4b,7,8,8a,9,10,10a-decahydrophenanthren-3(2H)-one (4)
4.1.4. Reduction of Sphaerococcenol A
4.1.5. Studies on Thiol Attack: Thiol-Michael Addition versus SN2
Sphaerococcenol A with Nucleophile in Excess (20.0 equiv)
1-Bromo-2,2-d’imethylpropane as Surrogate Molecule
4.2. Cell Culture Conditions
4.2.1. Cytotoxicity of Compounds
4.2.2. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium Bromide (MTT)
4.2.3. Lactate Dehydrogenase (LDH) Activity
4.2.4. Calcein-AM Assay
4.3. Levels of Reactive Oxygen Species
4.4. Mitochondrial Membrane Potential
4.5. Biomarkers Related to Apoptosis
4.5.1. Caspase-3 Activity
4.5.2. DAPI Staining
4.6. Data and Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
References
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IC50 (µM) | |||||||
---|---|---|---|---|---|---|---|
A549 | SI | DU-145 | SI | MCF-7 | SI | FL83B | |
Sphaerococcenol A | 14.99 * (12.30–18.19) | 2.5 | 3.75 c,e,* (3.17–4.44) | 10.0 | 6.53 c,* (4.43–9.57) | 5.7 | 37.40 (31.49–44.92) |
Compound 1 | 18.70 (12.82–26.76) | 1.8 | 15.82 c,e (13.33–18.92) | 2.2 | 16.44 c (11.46–22.40) | 2.1 | 34.56 (17.89–64.68) |
Compound 2 | 33.78 (27.63–41.19) | 1.4 | 25.80 e (17.97–36.39) | 1.9 | 70.26 * (49.57–101.7) | 0.7 | 48.02 a (36.77–64.07) |
Compound 3 | 22.53 (18.36–27.56) | 2.5 | 20.13 e (16.43–24.52) | 2.8 | 14.31 c,* (10.01–21.61) | 4.0 | 56.69 (35.40–98.96) |
Compound 4 | 35.45 a (29.72–42.43) | 1.1 | 70.11 a (39.63–145.8) | 0.6 | 30.40 c (23.46–39.22) | 1.3 | 40.32 (32.10–50.92) |
Compound 5 | 22.68 * (18.17–27.88) | 3.7 | 18.53 e,* (16.25–21.68) | 4.4 | 31.95 c,* (23.36–45.45) | 2.6 | 82.12 a,b,c,d,e (67.32–n.d.) |
Compound 6 | 33.54 * (29.48–38.55) | 1.9 | 20.46 e,* (16.73–24.92) | 3.1 | 22.19 c,* (14.49–31.98) | 2.9 | 63.29 b,* (53.21–75.49) |
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Sousa, D.; Fortunato, M.A.G.; Silva, J.; Pingo, M.; Martins, A.; Afonso, C.A.M.; Pedrosa, R.; Siopa, F.; Alves, C. Sphaerococcenol A Derivatives: Design, Synthesis, and Cytotoxicity. Mar. Drugs 2024, 22, 408. https://doi.org/10.3390/md22090408
Sousa D, Fortunato MAG, Silva J, Pingo M, Martins A, Afonso CAM, Pedrosa R, Siopa F, Alves C. Sphaerococcenol A Derivatives: Design, Synthesis, and Cytotoxicity. Marine Drugs. 2024; 22(9):408. https://doi.org/10.3390/md22090408
Chicago/Turabian StyleSousa, Dídia, Milene A. G. Fortunato, Joana Silva, Mónica Pingo, Alice Martins, Carlos A. M. Afonso, Rui Pedrosa, Filipa Siopa, and Celso Alves. 2024. "Sphaerococcenol A Derivatives: Design, Synthesis, and Cytotoxicity" Marine Drugs 22, no. 9: 408. https://doi.org/10.3390/md22090408