Curcumin-1,2,3-Triazole Conjugation for Targeting the Cancer Apoptosis Machinery
Abstract
:1. Introduction
2. Results
2.1. Synthesis
2.2. Biologic Evaluation
2.2.1. Cytotoxicity
2.2.2. Cell-Cycle Progression
2.2.3. Phosphatidylserine Exposure and Cell Death Analysis
2.2.4. Mitochondrial Transmembrane Potential
2.2.5. Caspase-8
2.2.6. Physicochemical Properties Prediction
2.2.7. FACS analysis to Study PAINS-Like Behavior
2.2.8. Chemical Stability Study
3. Discussion
4. Materials and Methods
4.1. Chemistry
4.1.1. Huisgen 1,3-Dipolar Cycloaddition. General Procedure for the Synthesis of Curcumin-Triazole Conjugates 1, 2 and Intermediates 13, 14
- (1E,4Z,6E)-4-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-trien-3-one (1-KE); (1E,6E)-4-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (1-KK).
- (1E,4Z,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-4-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)hepta-1,4,6-trien-3-one (2-KE); (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-4-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)hepta-1,6-diene-3,5-dione (2-KK).
- 4-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (13).
- 4-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (14).
4.1.2. Pabon Reaction. General Procedure for the Synthesis of Curcumin-Triazole Conjugates 3–6 and Intermediates 8 and 11
- (1E,4Z,6E)-1-(4-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-trien-3-one (3).
- (1E,4Z,6E)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-(4-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)hepta-1,4,6-trien-3-one (4).
- (1E,4Z,6E)-1,7-bis(4-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-5-hydroxyhepta-1,4,6-trien-3-one (5).
- (1E,4Z,6E)-5-hydroxy-1,7-bis(4-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)hepta-1,4,6-trien-3-one (6).
- (1E,4Z,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-4-(prop-2-yn-1-yl)hepta-1,4,6-trien-3-one (8-KE); (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-4-(prop-2-yn-1-yl)hepta-1,6-diene-3,5-dione (8-KK).
- General Procedure for the Synthesis of Azido Intermediates 9 and 10.
- 1-(azidomethyl)-4-fluorobenzene (9)
- 1-(azidomethyl)-4-methoxybenzene (10)
- 4-(Prop-2-yn-1-yloxy)benzaldehyde (12) [46]
- (Z)-3-(1-hydroxyethylidene)hex-5-yn-2-one (7-KE); 3-(prop-2-yn-1-yl)pentane-2,4-dione (7-KK).
4.2. Cell Cultures and Treatments
4.3. Analysis of Cell Viability
4.4. Analysis of Cell Cycle
4.5. Analysis of Cell Death
4.6. Analysis of Mitochondrial Transmembrane Potential
4.7. Evaluation of Caspase-8 Activity
4.8. Flow Cytometry
4.9. Statistical Analysis
4.10. Chemical Stability Study
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Sample Availability: Samples of the compound 1 is available from the authors. |
Compound | R | CCRF–CEM Cell Line IC50 (µM) a | |
---|---|---|---|
24 h | 48 h | ||
1 | 68.30 | 3.13 | |
2 | 55.63 | 3.95 | |
3 | 38.68 | 38.00 | |
4 | >150 | 69.07 | |
5 | >150 | 88.94 | |
6 | 122.1 | 93.40 | |
curcumin | / | >150 | 10.51 |
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Seghetti, F.; Di Martino, R.M.C.; Catanzaro, E.; Bisi, A.; Gobbi, S.; Rampa, A.; Canonico, B.; Montanari, M.; Krysko, D.V.; Papa, S.; et al. Curcumin-1,2,3-Triazole Conjugation for Targeting the Cancer Apoptosis Machinery. Molecules 2020, 25, 3066. https://doi.org/10.3390/molecules25133066
Seghetti F, Di Martino RMC, Catanzaro E, Bisi A, Gobbi S, Rampa A, Canonico B, Montanari M, Krysko DV, Papa S, et al. Curcumin-1,2,3-Triazole Conjugation for Targeting the Cancer Apoptosis Machinery. Molecules. 2020; 25(13):3066. https://doi.org/10.3390/molecules25133066
Chicago/Turabian StyleSeghetti, Francesca, Rita Maria Concetta Di Martino, Elena Catanzaro, Alessandra Bisi, Silvia Gobbi, Angela Rampa, Barbara Canonico, Mariele Montanari, Dmitri V. Krysko, Stefano Papa, and et al. 2020. "Curcumin-1,2,3-Triazole Conjugation for Targeting the Cancer Apoptosis Machinery" Molecules 25, no. 13: 3066. https://doi.org/10.3390/molecules25133066