In-Vitro and In-Silico Evaluations of Heterocyclic-Containing Diarylpentanoids as Bcl-2 Inhibitors Against LoVo Colorectal Cancer Cells
Abstract
:1. Introduction
2. Results and Discussions
2.1. Chemistry
2.2. Biological Studies
2.2.1. In-Vitro Cytotoxicity Analysis
2.2.2. In-Vitro Anti-Proliferative Analysis
2.2.3. In-Vitro Cell Apoptosis Analysis
2.2.4. In-Silico Molecular Modelling Analysis
3. Materials and Methods
3.1. Chemistry
General Procedure for the Synthesis of 2a–2e
3.2. Biological Evaluations
3.2.1. Cell Culture
3.2.2. MTT Assay
3.2.3. Morphological Inspection
3.2.4. Colony Formation Assay
3.2.5. Cell Cycle Analysis
3.2.6. Cell Apoptosis Analysis
3.2.7. Measurement of Intracellular Reactive Oxygen Species (ROS) Levels
3.2.8. Western Blot Analyses
3.2.9. Molecular Docking
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Sample Availability: Samples of the compounds are available from the authors. |
Cmpd | Structure | Cmpd | Structure | Cmpd | Structure |
---|---|---|---|---|---|
2a | 2b | 2c | |||
2d | 2e | 2f |
Compound | X | R | IC50 (µM) | NHDF | Chemo- Therapeutic Index | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|
KRAS | BRAF | ||||||||||
T84 | SW620 | LoVo | HT29 | NCI-H508 | RKO | LS411N | |||||
5-FU | - | - | >10 | >10 | 3.3 | >10 | 8.6 | 2.9 | 4.6 | >20 | - |
2a | C | 2-OMe | >10 | >10 | >10 | >10 | >10 | >10 | >10 | >20 | - |
2b | C | 2-Br | >10 | 8.9 | >10 | >10 | 7.8 | >10 | >10 | >20 | - |
2c | C | 3,4-F | 3.3 | 3.2 | 3.3 | 5.4 | 3.3 | 2.6 | 3.7 | 12.9 | 2.3–5.0 |
2d | S | 2-OMe | >10 | >10 | 6.9 | >10 | 5.3 | 7.1 | 5.8 | 9.7 | 1.4–1.8 |
2e | S | 2-Br | 1.6 | 1.4 | 1.0 | 2.1 | 1.1 | 1.2 | 1.3 | 7.1 | 3.4–7.1 |
2f | S | 3,4-F | >10 | 2.9 | 5.1 | >10 | 6.2 | 2.4 | 5.9 | 2.0 | 0.3–0.8 |
Compound | Structure | Interacting Amino Acid Residue | Type of Interaction | Bonding Distance (Å) |
---|---|---|---|---|
2b | ALA-146 | Alkyl | 3.84 | |
MET-112 | Pi-Alkyl | 4.12 | ||
ARG-143 | Pi-Cation | 2.39 | ||
LEU-134 | Alkyl | 4.8 | ||
Carbon | 2.49 | |||
2e | ALA-146 | Pi-Alkyl | 5.20 | |
MET-112 | Pi-Alkyl | 4.76 | ||
Alkyl | 4.75 | |||
ARG-143 | Alkyl | 3.93 | ||
Pi-Cation | 3.67 | |||
Pi-Alkyl | 5.14 | |||
TYR-105 | Pi-Alkyl | 5.24 | ||
PHE-101 | Pi-Sulfur | 4.78 |
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Leong, S.W.; Chia, S.L.; Abas, F.; Yusoff, K. In-Vitro and In-Silico Evaluations of Heterocyclic-Containing Diarylpentanoids as Bcl-2 Inhibitors Against LoVo Colorectal Cancer Cells. Molecules 2020, 25, 3877. https://doi.org/10.3390/molecules25173877
Leong SW, Chia SL, Abas F, Yusoff K. In-Vitro and In-Silico Evaluations of Heterocyclic-Containing Diarylpentanoids as Bcl-2 Inhibitors Against LoVo Colorectal Cancer Cells. Molecules. 2020; 25(17):3877. https://doi.org/10.3390/molecules25173877
Chicago/Turabian StyleLeong, Sze Wei, Suet Lin Chia, Faridah Abas, and Khatijah Yusoff. 2020. "In-Vitro and In-Silico Evaluations of Heterocyclic-Containing Diarylpentanoids as Bcl-2 Inhibitors Against LoVo Colorectal Cancer Cells" Molecules 25, no. 17: 3877. https://doi.org/10.3390/molecules25173877