Solid-Phase Parallel Synthesis of Dual Histone Deacetylase-Cyclooxygenase Inhibitors
Abstract
:1. Introduction
2. Results and Discussion
2.1. Design and Synthesis of Dual HDAC-COX Inhibitors
2.2. Determination of COX Inhibition
2.3. Inhibition of HDAC1 and HDAC6
2.4. Determination of Lipophilicity
2.5. Antiproliferative Properties of Dual HDAC-COX Inhibitors
2.6. Intracellular Target Engagement and Apoptosis Induction
3. Materials and Methods
3.1. General Remarks
3.1.1. Materials and Experimental Procedures
3.1.2. High Performance Liquid Chromatography (HPLC)
3.1.3. Nuclear Magnetic Resonance Spectroscopy (NMR)
3.1.4. Mass Spectrometry (MS)
3.1.5. TNBS-Test
3.1.6. Determination of the Loading
3.1.7. Determination of the LogD7.4HPLC
3.2. General Procedures
General Procedure A: Coupling of the Cap Group
3.3. Syntheses
3.3.1. Building Block Synthesis
3.3.2. Library Synthesis
3.4. Biological Evaluation
3.4.1. Cell Lines and Cell Culture
3.4.2. MTT Cell Viability Assay
3.4.3. Apoptosis Assay
3.4.4. HDAC Whole Cell Assay
3.4.5. Immunoblot
3.4.6. In Vitro HDAC1 and HDAC6 Cell Assay
3.4.7. Determination of COX Inhibition
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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A1 | A2 | A3 |
A4 | A5 | A6 |
A7 | B1 | B2 |
B3 | B4 | B5 |
B6 | B7 | C2 |
C3 | C4 |
Cmpd 1 | COX-1 2 IC50 [µM] | COX-2 2 IC50 [µM] | SI COX-1/2 | HDAC1 IC50 [µM] | HDAC6 IC50 [µM] | SI HDAC1/6 | logD7.4HPLC 3 | AsPC1 IC50 [µM] 4 |
---|---|---|---|---|---|---|---|---|
A1 | >100 | 5.7 | >17 | 3.990 ± 0.143 | 3.039 ± 0.147 | 1.3 | 2.48 | 36.46 ± 6.36 |
A2 | 38.1 | 4.1 | 9.3 | 0.554 ± 0.059 | 0.055 ± 0.004 | 10 | 2.63 | 10.28 ± 1.95 |
A3 | 27.2 | 2.0 | 13.6 | 0.377 ± 0.004 | 0.084 ± 0.012 | 4 | 2.76 | 6.25 ± 1.07 |
A4 | 18.1 | 1.2 | 15.1 | >3.33 | 0.174 ± 0.012 | >19 | 2.89 | n.e. |
A5 | 6.5 | 1.6 | 4.0 | >3.33 | 0.052 ± 0.007 | >64 | 3.00 | 35.02 ± 5.08 |
A6 | 2.4 | 1.9 | 1.2 | >2.80 | 0.011 ± 0.001 | >254 | 3.14 | n.e. |
A7 | 3.5 | 1.8 | 2.2 | 0.542 ± 0.052 | 0.112 ± 0.008 | 5 | 3.31 | 19.20 ± 2.87 |
B1 | >100 | 43.0 | >2.3 | 2.502 ± 0.260 | 0.695 ± 0.017 | 4 | 1.23 | n.e. |
B2 | >100 | 3.3 | >30.3 | 0.099 ± 0.004 | 0.023 ± 0.0001 | 4 | 1.53 | 45.51 ± 15.83 |
B3 | 11.6 | 7.5 | 1.5 | 0.034 ± 0.001 | 0.006 ± 0.00001 | 6 | 1.79 | 3.49 ± 1.29 |
B4 | 10.8 | 1.4 | 7.7 | 0.039 ± 0.004 | 0.005 ± 0.0001 | 8 | 1.89 | 15.84 ± 4.26 |
B5 | 8.8 | 2.7 | 3.3 | 0.155 ± 0.032 | 0.003 ± 0.0004 | 52 | 2.05 | n.e. |
B6 | 1.8 | 1.4 | 1.3 | 0.829 ± 0.038 | 0.005 ± 0.0001 | 166 | 2.39 | n.e. |
B7 | 7.5 | 1.9 | 3.9 | 0.014 ± 0.001 | 0.060 ± 0.011 | 0.2 | 2.28 | 2.54 ± 0.68 |
C2 | 70.9 | 3.3 | 21.5 | 0.123 ± 0.004 | 0.038 ± 0.002 | 3 | 1.75 | 59.32 ± 8.47 |
C3 | 93.8 | 0.98 | 95.7 | 0.043 ± 0.002 | 0.009 ± 0.001 | 5 | 1.99 | 2.39 ± 0.92 |
C4 | 11.5 | 4.1 | 2.8 | 0.058 ± 0.001 | 0.010 ± 0.001 | 6 | 2.11 | 4.28 ± 0.93 |
Vorinostat | n.d. | n.d. | - | 0.094 ± 0.013 | 0.027 ± 0.004 | 3 | n.d. | 1.04 ± 0.37 |
Cele-coxib | >100 | 0.04 ± 0.02 (n = 6) | >2500 | n.d. | n.d. | n.d. | n.d. | n.e. |
Compound | AsPC1 IC50 [µM] | MV3 IC50 [µM] | PC-3 IC50 [µM] | MDA-MB-231 IC50 [µM] | FaDu IC50 [µM] | HT-29 IC50 [µM] | U-87 IC50 [µM] |
---|---|---|---|---|---|---|---|
A7 | 19.20 ± 2.87 | 20.94 ± 5.75 | 10.59 ± 1.75 | 24.45 ± 2.03 | 6.61 ± 0.74 | 6.18 ± 1.26 | 17.46 ± 4.96 |
B7 | 2.54 ± 0.68 | 11.59 ± 5.33 | 7.75 ± 2.30 | 12.47 ± 4.33 | 4.79 ± 0.45 | 6.40 ± 0.67 | 17.76 ± 2.25 |
C3 | 2.39 ± 0.92 | 3.37 ± 0.98 | 2.67 ± 0.10 | 3.55 ± 0.62 | 2.21 ± 0.73 | 3.56 ± 0.74 | 6.91 ± 0.31 |
C4 | 4.28 ± 0.93 | 9.82 ± 3.02 | 7.59 ± 1.98 | 9.57 ± 2.06 | 3.67 ± 0.50 | 5.46 ± 0.80 | 10.63 ± 0.97 |
Vorinostat | 1.04 ± 0.37 | 1.72 ± 0.35 | 1.40 ± 0.57 | 1.60 ± 0.46 | 1.50 ± 0.28 | 1.58 ± 0.71 | 4.25 ± 0.84 |
Celecoxib | n.e. | n.e. | n.e. | n.e. | n.e. | n.e. | n.e. |
V + C (1:1) 2 | 1.21 ± 0.12 | 1.62 ± 0.34 | 1.30 ± 0.50 | 1.46 ± 0.29 | 1.50 ± 0.41 | 1.52 ± 0.54 | 4.94 ± 0.72 |
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Bachmann, L.M.; Hanl, M.; Feller, F.; Sinatra, L.; Schöler, A.; Pietzsch, J.; Laube, M.; Hansen, F.K. Solid-Phase Parallel Synthesis of Dual Histone Deacetylase-Cyclooxygenase Inhibitors. Molecules 2023, 28, 1061. https://doi.org/10.3390/molecules28031061
Bachmann LM, Hanl M, Feller F, Sinatra L, Schöler A, Pietzsch J, Laube M, Hansen FK. Solid-Phase Parallel Synthesis of Dual Histone Deacetylase-Cyclooxygenase Inhibitors. Molecules. 2023; 28(3):1061. https://doi.org/10.3390/molecules28031061
Chicago/Turabian StyleBachmann, Luisa M., Maria Hanl, Felix Feller, Laura Sinatra, Andrea Schöler, Jens Pietzsch, Markus Laube, and Finn K. Hansen. 2023. "Solid-Phase Parallel Synthesis of Dual Histone Deacetylase-Cyclooxygenase Inhibitors" Molecules 28, no. 3: 1061. https://doi.org/10.3390/molecules28031061