Design and Synthesis of (2-oxo-1,2-Dihydroquinolin-4-yl)-1,2,3-triazole Derivatives via Click Reaction: Potential Apoptotic Antiproliferative Agents
Abstract
:1. Introduction
2. Results
2.1. Chemistry Section
2.2. Pharmacological Assays
2.2.1. Cell Viability Assay
2.2.2. Cytotoxic Activity and Evaluation of IC50
2.2.3. Apoptosis Assay
Activation of Proteolytic Caspases Cascade
Cytochrome C Assay
Bax and Bcl-2 Levels Assay
Flow Cytometric Cell Cycle Analysis
3. Conclusions
4. Experimental
4.1. Chemistry
4.1.1. Starting Materials
4.1.2. General Procedure for the Synthesis of Compounds 4a–c
4.1.3. General Procedure for the Synthesis of Compounds 8a–l
4.2. Pharmacological Assays
4.2.1. Cytotoxic Activity Using MTT Assay and Evaluation of IC50
MTT Assay
Assay for the Anti-Proliferative Effect
4.2.2. Caspase 3 Activation Assay
4.2.3. Caspase 8 Activation Assay
4.2.4. Bax Activation Assay
4.2.5. Bcl-2 Inhibition Assay
4.2.6. Cytochrome C Assay
4.2.7. Cell Apoptosis Assay
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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1H NMR | 1H-1HCOSY | Assignment | |
13.39 (bs; 1H) | OH-4/4’ | ||
12.90 (bs; 1H) | OH-4’/4 | ||
12.19 (bs; 1H) | NH-1/1’ | ||
12.08 (bs; 1H) | NH-1’/1 | ||
7.40 (d, J = 9.0; 2H) | 7.26 | H-8, 8’ | |
7.40 (bs; 1H) | H-5/5’ | ||
7.33 (bs; 1H) | H-5’/5 | ||
7.26 (bd, J = 8.6; 2H) | 7.40 | H-7, 7’ | |
7.02 (d, J = 8.5; 2H) | 6.89 | H-o | |
6.89 (d, J = 8.8; 2H) | 7.02 | H-m | |
6.14 (s; 1H) | H-a | ||
4.76 (d, J = 2.0; 2H) | 3.55 | H-b | |
3.77 (s; 6H) | H-6a, 6a’ | ||
3.55 (bs; 1H) | 4.76 | H-d | |
15N NMR | HSQC | HMBC | Assignment |
144.2 | 12.08 | 7.40 | N-1/1’ |
142.9 | 12.19 | 7.40 | N-1’/1 |
13C NMR | HSQC | HMBC | Assignment |
165.76, 164.10 | 6.14 | C-2, 2’ | |
161.84, 160.91 | 6.14 | C-4, 4’ | |
155.31 | 7.02, 6.89, 4.76 | C-p | |
154.80 | 7.40, 7.26, 3.77 | C-6, 6’ | |
131.52 | 7.40, 7.26 | C-8a, 8a’ | |
130.29 | 6.89, 6.14 | C-i | |
127.29 | 7.02 | 7.02, 6.14 | C-o |
120.63 | 7.26 | C-7, 7’ | |
117.46 | 7.40 | 7.40 | C-8, 8’ |
117.21, 116.70 | 7.40, 7.33 | C-4a, 4a’ | |
114.35 | 6.89 | 6.89, 6.89 | C-m |
111.74, 111.25 | 6.14 | C-3, 3’ | |
103.82 | 7.40, 7.33 | C-5, 5’ | |
79.43 | 4.76 | C-c | |
78.00 | 3.55 | 3.55 | C-d |
55.41 | 3.77 | C-6a, 6a’ | |
55.34 | 4.76 | C-b | |
34.69 | 6.14 | 7.02, 6.14 | C-a |
1H NMR | 1H-1HCOSY | Assignment | |
13.41 (bs; 1H) | OH-4/4’ | ||
12.91 (bs; 1H) | OH-4’/4 | ||
12.20 (s; 2H) | 6.81 | NH-1/1’, 1″ | |
12.09 (bs; 1H) | NH-1’/1 | ||
8.84 (s; 1H) | H-d | ||
7.47 (d, J = 8.3; 1H) | 7.38, 7.22 | H-7″ | |
7.40 (d, J = 9.2; 2H) | 7.26 | H-8, 8’ | |
7.38 (d, J = 8.4; 2H) | 7.47, 7.26, 2.29 | H-5/5’, 8″ | |
7.33 (m; 1H) | 7.26 | H-5’/5 | |
7.26 (d, J = 8.1; 2H) | 7.40, 7.38, 7.33 | H-7, 7’ | |
7.22 (s; 1H) | 7.47, 2.29 | H-5″ | |
7.05 (d, J = 8.2; 2H) | 7.01, 6.15 | H-o | |
7.01 (d, J = 8.2; 2H) | 7.05 | H-m | |
6.81 (s; 1H) | 12.20 | H-3″ | |
6.15 (bs; 1H) | 7.05 | H-a | |
5.27 (s; 2H) | H-b | ||
3.82 (s; 6H) | H-6b, 6b’ | ||
2.29 (s; 3H) | 7.40, 7.38, 7.26 | H-6a″ | |
13C NMR | HSQC | HMBC | Assignment |
165.85, 164.13 | 6.15 | C-2, 2’ | |
161.84 | C-4, 4’ | ||
160.84 | C-2″, 4″ | ||
156.06 | 7.05, 5.27 | C-p | |
154.81 | 7.40, 3.82 | C-6, 6’ | |
143.42 | 8.84, 7.40, 7.22, 6.81, 5.27 | C-c | |
137.50 | 7.47, 7.22 | C-8a″ | |
133.15 | 7.47 | 7.47, 7.22 | C-7″ |
131.73, 131.51 | 7.38, 7.26, 2.29 | C-8a, 8a’ | |
130.07 | C-i | ||
127.40 | 7.05 | C-o, 6″ | |
126.50 | 8.84 | 8.84,3 7.01, 5.27 | C-d |
123.15 | 7.22 | 7.47, 7.05, 2.29 | C-5″ |
120.82 | 7.26 | 7.01 | C-7, 7’ |
117.69 | 6.81 | 7.05, 6.813 | C-3″ |
117.45 | 7.40 | 7.403 | C-8, 8’ |
116.69 | 7.38, 7.33 | C-4a, 4a’ | |
115.89 | 7.38 | C-8″ | |
114.38 | 7.01 | 7.38, 6.81 | C-m, 4a″ |
111.86, 110.18 | 6.15 | C-3, 3’ | |
103.81 | 7.38, 7.33 | C-5, 5’ | |
60.85 | 5.27 | C-b | |
55.40 | 3.82 | 3.823 | C-6b, 6b’ |
34.71 | 6.15 | C-a | |
20.50 | 2.29 | 7.47, 7.22, 2.293 | C-6a″ |
15N NMR | HSQC | HMBC | Assignment |
247.4 | 8.84, 6.81 | N-e | |
151.6 | 12.20 | 7.38, 6.81 | N-1″ |
144.2 | 12.09 | N-1’/1 | |
142. | 12.20 | N-1/1‘ | |
N-f, g n/o. |
Comp. | Cell Viability% (50 µM) | Anti-Proliferative Activity IC50 ± SEM (µM) | ||||
---|---|---|---|---|---|---|
A-549 | MCF-7 | Panc-1 | HT-29 | Average (IC50) | ||
8a | 89 | 5.7 ± 0.4 | 5.3 ± 0.8 | 5.6 ± 0.6 | 5.7 ± 0.4 | 5.575 |
8b | 87 | 7.6 ± 0.8 | 6.9 ± 0.8 | 7.6 ± 0.6 | 7.5 ± 0.4 | 7.400 |
8c | 91 | 3.9 ± 0.5 | 3.2 ± 0.08 | 4.1 ± 0.2 | 4.2 ± 0.2 | 3.850 |
8d | 89 | 12.9 ± 0.8 | 11.5 ± 1.1 | 11.6 ± 0.8 | 11.4 ± 1.2 | 11.850 |
8e | 85 | 2.1 ± 0.2 | 1.5 ± 0.7 | 1.7 ± 0.1 | 2.2 ± 0.4 | 1.875 |
8f | 87 | 2.9 ± 0.5 | 2.6 ± 0.8 | 3.1 ± 0.2 | 3.4 ± 0.2 | 3.000 |
8g | 84 | 1.9 ± 0.2 | 1.2 ± 0.2 | 1.4 ± 0.2 | 1.8 ± 0.4 | 1.575 |
8h | 90 | 10.7 ± 2.5 | 10.6 ± 2.9 | 10.8 ± 1.9 | 10.8 ± 1.6 | 10.725 |
8i | 90 | 17.9 ± 0.3 | 17.8 ± 1.6 | 17.6 ± 1.5 | 17.9 ± 1.1 | 17.800 |
8j | 81 | 22.5 ± 0.2 | 22.1 ± 0.1 | 22.4 ± 0.2 | 22.9 ± 0.6 | 22.474 |
8k | 90 | 14.5 ± 2.6 | 13.6 ± 2.2 | 14.6 ± 2.9 | 14.8 ± 1.4 | 14.375 |
8l | 96 | 25.3 ± 2.5 | 24.9 ± 1.8 | 24.5 ± 2.3 | 24.2 ± 1.4 | 24.725 |
Doxorubicin | -- | 1.21 ± 0.80 | 0.90 ± 0.62 | 1.41 ± 0.58 | 1.01 ± 0.82 | 1.136 |
Compound No. | 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 | |
8e | 475.20 ± 4.27 | 7.23 | 1.29 | 7.58 | 12.89 | 13.86 | 0.548 | 11.90 |
8f | 365.60 ± 3.20 | 5.57 | ND | ND | ND | ND | ND | ND |
8g | 489.20 ± 4.13 | 7.54 | 1.52 | 8.94 | 13.98 | 15.03 | 0.587 | 12.76 |
Doxorubicin | 503.20 ± 4.22 | 7.66 | 1.75 | 10.07 | 16.23 | 17.40 | 0.604 | 13.13 |
Control | 65.64 | 1 | 0.17 | 1 | 0.93 | 1 | 0.046 | 1 |
Compound No. | Bax | Bcl-2 | ||
---|---|---|---|---|
Conc (pg/mL) | Fold Change | Conc (ng/mL) | Fold Reduction | |
8e | 247.65 | 29.98 | 1.278 | 3.97 |
8g | 264.90 | 32.07 | 1.085 | 4.68 |
Doxorubicin | 276.19 | 33.42 | 0.983 | 5.17 |
Cont. | 8.26 | 1 | 5.086 | 1.00 |
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El-Sheref, E.M.; Elbastawesy, M.A.I.; Brown, A.B.; Shawky, A.M.; Gomaa, H.A.M.; Bräse, S.; Youssif, B.G.M. Design and Synthesis of (2-oxo-1,2-Dihydroquinolin-4-yl)-1,2,3-triazole Derivatives via Click Reaction: Potential Apoptotic Antiproliferative Agents. Molecules 2021, 26, 6798. https://doi.org/10.3390/molecules26226798
El-Sheref EM, Elbastawesy MAI, Brown AB, Shawky AM, Gomaa HAM, Bräse S, Youssif BGM. Design and Synthesis of (2-oxo-1,2-Dihydroquinolin-4-yl)-1,2,3-triazole Derivatives via Click Reaction: Potential Apoptotic Antiproliferative Agents. Molecules. 2021; 26(22):6798. https://doi.org/10.3390/molecules26226798
Chicago/Turabian StyleEl-Sheref, Essmat M., Mohammed A. I. Elbastawesy, Alan B. Brown, Ahmed M. Shawky, Hesham A. M. Gomaa, Stefan Bräse, and Bahaa G. M. Youssif. 2021. "Design and Synthesis of (2-oxo-1,2-Dihydroquinolin-4-yl)-1,2,3-triazole Derivatives via Click Reaction: Potential Apoptotic Antiproliferative Agents" Molecules 26, no. 22: 6798. https://doi.org/10.3390/molecules26226798