The Design and Synthesis of a New Class of RTK/HDAC Dual-Targeted Inhibitors
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemisty
2.2. Results and Discussion
2.2.1. In Vitro HDAC Inhibition
Compound | HDAC-1 | HDAC-3 | HDAC-6 |
---|---|---|---|
IC50 ± SD | IC50 ± SD | IC50 ± SD | |
[μM] | [μM] | [μM] | |
4a | - a | - | - |
4b | - | - | - |
5a | - | - | - |
5b | - | - | - |
8a | 5.57 ± 1.87 | 2.38 ± 0.38 | 1.66 ± 0.19 |
8b | - | - | 2.77 ± 1.02 |
9a | 0.16 ± 0.02 | 0.18 ± 0.05 | 0.56 ± 0.06 |
9b | 0.29 ± 0.05 | 0.15 ± 0.02 | 0.56 ± 0.05 |
12a | 2.83 ± 0.65 | 3.29 ± 0.34 | 5.71 ± 0.99 |
12b | 5.82 ± 1.15 | 3.90 ± 0.78 | 7.21 ± 0.76 |
13a | 1.03 ± 0.27 | 2.11 ± 0.34 | 7.63 ± 0.99 |
13b | 2.43 ± 0.50 | 1.57 ± 0.17 | 4.82 ± 0.37 |
SAHA | 0.25 ± 0.04 | 0.17 ± 0.02 | 0.23 ± 0.06 |
Lapatinib | - | - | - |
2.2.2. In Vitro RTK Inhibition
Compound | EGFR %Inhibition a | HER2 %Inhibition b |
---|---|---|
4a | 6.1 | 18.2 |
4b | 20.1 | 0 |
5a | 20.9 | 0 |
5b | 19.0 | 2.6 |
8a | 63.6 | 74.0 |
8b | 70.1 | 84.6 |
9a | 9.7 | 47.2 |
9b | 8.5 | 64.2 |
12a | 0 | 0 |
12b | 44.6 | 0.1 |
13a | 42.6 | 0 |
13b | 20.4 | 0 |
SAHA | 0 | 0 |
Lapatinib | 92.7 | 92.0 |
3. Experimental
3.1. General
3.2. Chemistry
3.2.1. General Procedure for the Synthesis of Compounds 2a, 2b, 3a, 3b
3.2.2. General Procedure for the Synthesis of Compounds 4a, 4b, 5a, 5b
3.2.3. General Procedure for the Synthesis of Compounds 6a, 6b, 7a, 7b
3.2.4. General Procedure for the Synthesis of Compounds 8a, 8b, 9a, 9b
3.2.5. General Procedure for the Synthesis of Compounds 10a, 10b, 11a, 11b
3.2.6. General Procedure for the Synthesis of Compounds 12a, 12b, 13a, 13b
3.3. Evaluation of Enzyme Activities
3.3.1. HDAC Enzymatic Assay in Vitro
3.3.2. EGFR and HER2 Inhibition Assay
4. Conclusions
Acknowledgments
Conflicts of Interest
References
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Zhang, X.; Su, M.; Chen, Y.; Li, J.; Lu, W. The Design and Synthesis of a New Class of RTK/HDAC Dual-Targeted Inhibitors. Molecules 2013, 18, 6491-6503. https://doi.org/10.3390/molecules18066491
Zhang X, Su M, Chen Y, Li J, Lu W. The Design and Synthesis of a New Class of RTK/HDAC Dual-Targeted Inhibitors. Molecules. 2013; 18(6):6491-6503. https://doi.org/10.3390/molecules18066491
Chicago/Turabian StyleZhang, Xuan, Mingbo Su, Yi Chen, Jia Li, and Wei Lu. 2013. "The Design and Synthesis of a New Class of RTK/HDAC Dual-Targeted Inhibitors" Molecules 18, no. 6: 6491-6503. https://doi.org/10.3390/molecules18066491