Synthesis and Biological Evaluation of Indole-2-Carboxamides with Potent Apoptotic Antiproliferative Activity as EGFR/CDK2 Dual Inhibitors
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Evaluation of Biological Activities
2.2.1. In Vitro Anticancer Activity
Cell Viability Assay
Antiproliferative Activity
2.2.2. EGFR Inhibitory Activity
2.2.3. CDK2 Inhibitory Assay
2.2.4. Apoptosis Assay
Activation of Proteolytic Caspases Cascade
Cytochrome C Assay
Bax and Bcl-2 Levels Assay
Effect of Compounds 5d and 5e on p53 Transcription in MCF-7
2.3. Docking Study
3. Materials and Methods
3.1. Chemistry
3.1.1. 5-Chloro-3-methyl-N-phenethyl-1H-indole-2-carboxamide (5a)
3.1.2. 5-Chloro-N-(4-(dimethylamino)phenethyl)-3-methyl-1H-indole-2-carboxamide (5b)
3.1.3. 5-Chloro-3-methyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (5c)
3.1.4. 5-Chloro-3-methyl-N-(4-morpholinophenethyl)-1H-indole-2-carboxamide (5d)
3.1.5. 5-Chloro-3-methyl-N-(4-(2-methylpyrrolidin-1-yl)phenethyl)-1H-indole-2-carboxamide (5e)
3.1.6. 6-Chloro-3-methyl-N-phenethyl-1H-indole-2-carboxamide (5f)
3.1.7. 6-Chloro-3-methyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (5g)
3.1.8. 5,7-Dichloro-3-methyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (5h)
3.1.9. 5,7-Dichloro-3-methyl-N-(4-morpholinophenethyl)-1H-indole-2-carboxamide (5i)
3.1.10. 5,7-Difluoro-3-methyl-N-phenethyl-1H-indole-2-carboxamide (5j)
3.1.11. 5,7-Difluoro-3-methyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (5k)
3.1.12. (5-Chloro-3-methyl-1H-indol-2-yl)(4-phenylpiperazin-1-yl)methanone (6a)
3.1.13. (6-Chloro-3-methyl-1H-indol-2-yl)(4-phenylpiperazin-1-yl)methanone (6b)
3.1.14. (5,7-Difluoro-3-methyl-1H-indol-2-yl)(4-phenylpiperazin-1-yl)methanone (6c)
3.1.15. N-Benzyl-5-chloro-3-methyl-1H-indole-2-carboxamide (7)
3.2. Biology
3.2.1. In Vitro Anticancer Activity
Cell Viability Assay
Antiproliferative Activity
3.2.2. EGFR Inhibitory Activity
3.2.3. CDK2 Inhibitory Assay
3.2.4. Apoptosis Assay
Activation of Proteolytic Caspases Cascade
Cytochrome C Assay
Bax and Bcl-2 Levels Assay
Effect of Compounds 5d and 5e on p53 Transcription in MCF-7
4. Conclusions
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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| ||||||
---|---|---|---|---|---|---|
Compd. | Cell Viability % | Antiproliferative Activity IC50 ± SEM (µM) | ||||
A-549 | MCF-7 | Panc-1 | HT-29 | Average | ||
5a | 89 | 3.70 ± 0.30 | 3.20 ± 0.30 | 3.90 ± 0.30 | 3.90 ± 0.30 | 3.70 |
5b | 87 | 3.20 ± 0.30 | 2.90 ± 0.30 | 3.50 ± 0.30 | 3.60 ± 0.30 | 3.30 |
5c | 87 | 1.70 ± 0.20 | 1.40 ± 0.20 | 1.80 ± 0.20 | 1.80 ± 0.20 | 1.70 |
5d | 89 | 1.05 ± 0.10 | 0.90 ± 0.10 | 1.10 ± 0.10 | 1.10 ± 0.10 | 1.05 |
5e | 93 | 0.95 ± 0.05 | 0.80 ± 0.05 | 1.00 ± 0.20 | 1.10 ± 0.10 | 0.95 |
5f | 90 | 1.90 ± 0.20 | 1.70 ± 0.20 | 2.10 ± 0.20 | 2.10 ± 0.20 | 1.95 |
5g | 89 | 4.90 ± 0.50 | 4.80 ± 0.50 | 5.20 ± 0.50 | 5.10 ± 0.50 | 5.00 |
5h | 87 | 1.00 ± 0.10 | 0.90 ± 0.10 | 1.20 ± 0.10 | 1.20 ± 0.10 | 1.10 |
5i | 90 | 1.55 ± 0.20 | 1.30 ± 0.10 | 1.60 ± 0.20 | 1.65 ± 0.20 | 1.50 |
5j | 83 | 1.20 ± 0.10 | 1.00 ± 0.10 | 1.30 ± 0.10 | 1.30 ± 0.10 | 1.20 |
5k | 87 | 1.40 ± 0.20 | 1.20 ± 0.10 | 1.50 ± 0.20 | 1.50 ± 0.20 | 1.40 |
6a | 90 | 2.90 ± 0.30 | 2.60 ± 0.20 | 2.80 ± 0.20 | 2.90 ± 0.20 | 2.80 |
6b | 91 | 2.50 ± 0.20 | 2.30 ± 0.20 | 2.65 ± 0.20 | 2.80 ± 0.20 | 2.60 |
6c | 89 | 2.20 ± 0.20 | 2.10 ± 0.20 | 2.40 ± 0.20 | 2.50 ± 0.20 | 2.30 |
7 | 91 | 4.10 ± 0.40 | 4.00 ± 0.40 | 4.40 ± 0.40 | 4.60 ± 0.40 | 4.30 |
Doxorubicin | - | 1.20 ± 0.20 | 0.90 ± 0.10 | 1.40 ± 0.20 | 1.00 ± 0.10 | 1.10 |
| ||||||
---|---|---|---|---|---|---|
Compd. | R1 | R2 | R3 | R4 | EGFR Inhibition IC50 ± SEM (nM) | CDK2 Inhibition IC50 ± SEM (nM) |
5d | Cl | H | H | | 89 ± 6 | 23 ± 2 |
5e | Cl | H | H | | 93 ± 8 | 13 ± 1 |
5h | Cl | H | Cl | | 118 ± 10 | 11 ± 1 |
5i | Cl | H | Cl | | 137 ± 12 | 27 ± 3 |
5j | F | H | F | H | 98 ± 8 | 34 ± 3 |
5k | F | H | F | | 129 ± 11 | 19 ± 2 |
Erlotinib | -- | -- | -- | -- | 80 ± 5 | ND |
Dinaciclib | -- | -- | -- | -- | ND | 20 ± 2 |
Compound Number | Caspase-3 | Caspase-8 | Caspase-9 | Cytochrome C | ||||
---|---|---|---|---|---|---|---|---|
Conc (pg/mL) | Fold Change | Conc (ng/mL) | Fold Change | Conc (ng/mL) | Fold Change | Conc (ng/mL) | Fold Change | |
5d | 570.00 ± 5.00 | 8.70 | 1.94 | 9.70 | 16.90 | 17.80 | 0.70 | 14 |
5e | 635.50 ± 5.50 | 9.70 | 2.17 | 10.90 | 17.25 | 18.15 | 0.80 | 16 |
5h | 537.50 ± 5.00 | 8.20 | 1.88 | 9.50 | 16.65 | 17.50 | 0.65 | 13 |
Doxorubicin | 503.50 ± 4.50 | 7.70 | 1.80 | 9.00 | 16.25 | 17.00 | 0.60 | 12 |
Control | 65.50 | 1 | 0.20 | 1 | 0.95 | 1 | 0.05 | 1 |
Compd. No. | Bax | Bcl-2 | ||
---|---|---|---|---|
Conc (pg/mL) | Fold Change | Conc (ng/mL) | Fold Change | |
5d | 289.70 ± 2.50 | 35 | 0.89 | 5.70 |
5e | 296.50 ± 2.50 | 36 | 0.87 | 5.90 |
Doxorubicin | 275.80 ± 2.50 | 33 | 0.98 | 5.20 |
Cont. | 8.25 | 1 | 5.10 | 1.00 |
Compd. No. | p53 | |
---|---|---|
Conc (pg/mL) | Fold Change | |
5d | 1375 ± 15 | 27 |
5e | 1435 ± 15 | 28 |
Doxorubicin | 1265 ± 10 | 25 |
Cont. | 51.50 | 1 |
Compd. | EFGR (PDB ID: 1M17) | CDK2 (PDB ID: 1PYE) | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
S a | RMSD (Å) | Binding Interactions | S | RMSD (Å) | Binding Interactions | |||||
a.a. Residue | Type | Distance (Å) | a.a. Residue | Type | Distance (Å) | |||||
5d | −6.90 | 1.49 | THR 766 | H-acceptor | 2.91 | −6.03 | 1.77 | GLN 131 | H-donor | 3.60 |
LEU 694 | pi-H | 3.99 | ||||||||
5e | −6.79 | 1.51 | LEU 694 | pi-H | 3.70 | −6.99 | 1.68 | LYS 33 | pi-cation | 4.65 |
Ref | −7.3 b | 1.28 | GLN 767 | H-donor | 3.15 | −5.89 c | 1.84 | GLU 81 | H-donor | 3.05 |
MET 769 | H-acceptor | 2.70 | LEU 83 | H-acceptor | 3.07 |
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Al-Wahaibi, L.H.; Mostafa, Y.A.; Abdelrahman, M.H.; El-Bahrawy, A.H.; Trembleau, L.; Youssif, B.G.M. Synthesis and Biological Evaluation of Indole-2-Carboxamides with Potent Apoptotic Antiproliferative Activity as EGFR/CDK2 Dual Inhibitors. Pharmaceuticals 2022, 15, 1006. https://doi.org/10.3390/ph15081006
Al-Wahaibi LH, Mostafa YA, Abdelrahman MH, El-Bahrawy AH, Trembleau L, Youssif BGM. Synthesis and Biological Evaluation of Indole-2-Carboxamides with Potent Apoptotic Antiproliferative Activity as EGFR/CDK2 Dual Inhibitors. Pharmaceuticals. 2022; 15(8):1006. https://doi.org/10.3390/ph15081006
Chicago/Turabian StyleAl-Wahaibi, Lamya H., Yaser A. Mostafa, Mostafa H. Abdelrahman, Ali H. El-Bahrawy, Laurent Trembleau, and Bahaa G. M. Youssif. 2022. "Synthesis and Biological Evaluation of Indole-2-Carboxamides with Potent Apoptotic Antiproliferative Activity as EGFR/CDK2 Dual Inhibitors" Pharmaceuticals 15, no. 8: 1006. https://doi.org/10.3390/ph15081006