Design, Synthesis and Evaluation of New Indolylpyrimidylpiperazines for Gastrointestinal Cancer Therapy
Abstract
1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Evaluation
2.2.1. Functional Activity Studies at hA2AAR and hA3AR
2.2.2. Cytotoxicity Assays of Compound 4 against Human Colorectal Cancer Cell Lines, a Normal Colon Cell Line and a Liver Cancer Cell Line.
2.3. UV-Vis Stability Study of Compound 4
2.4. Induced-Fit Docking of Compound 1 and Compounds 3–6 in hA3AR Homology Model
3. Materials and Methods
3.1. Chemistry
3.2. Biological Evaluation
3.2.1. TGFα Shedding Assays for hA2AAR and hA3AR
3.2.2. Cytotoxicity Assays
3.3. UV-Vis Stability Assay
3.4. Molecular Modeling
3.4.1. Homology Modelling and Protein Preparation
3.4.2. Ligand Docking Studies
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Sample Availability: Not available. |
Compound | EC50 (μM) | Emax (%) |
---|---|---|
3 | Inactive | N.A. |
4 | 2.89 ± 0.55 | 31 |
5 | 13.4 ± 2.96 | 77 |
6 | 33.2 ± 16.50 | 72 |
Adenosine | 0.35 ± 0.03 | 100 |
IC50 (μM) | ||
---|---|---|
4 | 2-Cl-IB-MECA | |
HCT-116 | 84 ± 9 | 21 ± 6 |
Caco-2 | 77 ± 10 | 31 ± 4 |
HepG2 | 30 ± 7 | 13 ± 3 |
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Tan, A.; Babak, M.V.; Venkatesan, G.; Lim, C.; Klotz, K.-N.; Herr, D.R.; Cheong, S.L.; Federico, S.; Spalluto, G.; Ong, W.-Y.; et al. Design, Synthesis and Evaluation of New Indolylpyrimidylpiperazines for Gastrointestinal Cancer Therapy. Molecules 2019, 24, 3661. https://doi.org/10.3390/molecules24203661
Tan A, Babak MV, Venkatesan G, Lim C, Klotz K-N, Herr DR, Cheong SL, Federico S, Spalluto G, Ong W-Y, et al. Design, Synthesis and Evaluation of New Indolylpyrimidylpiperazines for Gastrointestinal Cancer Therapy. Molecules. 2019; 24(20):3661. https://doi.org/10.3390/molecules24203661
Chicago/Turabian StyleTan, Aaron, Maria V. Babak, Gopalakrishnan Venkatesan, Clarissa Lim, Karl-Norbert Klotz, Deron Raymond Herr, Siew Lee Cheong, Stephanie Federico, Giampiero Spalluto, Wei-Yi Ong, and et al. 2019. "Design, Synthesis and Evaluation of New Indolylpyrimidylpiperazines for Gastrointestinal Cancer Therapy" Molecules 24, no. 20: 3661. https://doi.org/10.3390/molecules24203661
APA StyleTan, A., Babak, M. V., Venkatesan, G., Lim, C., Klotz, K.-N., Herr, D. R., Cheong, S. L., Federico, S., Spalluto, G., Ong, W.-Y., Chen, Y. Z., Loo, J. S. E., & Pastorin, G. (2019). Design, Synthesis and Evaluation of New Indolylpyrimidylpiperazines for Gastrointestinal Cancer Therapy. Molecules, 24(20), 3661. https://doi.org/10.3390/molecules24203661