Novel Tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline Chalcones Suppress Breast Carcinoma through Cell Cycle Arrests and Apoptosis
Abstract
:1. Introduction
2. Results
2.1. Synthesis of the Chalcones
2.2. In Vitro Cytotoxicity Screening of Chalcone-Based Compounds
2.3. Chalcone Analogues with the Methoxy Group Induced Cell Cycle Arrests and Apoptosis in Luc4T1 Cells
2.4. Modeling Simulation Analysis of Chalcone Analogues with the Methoxy Group
3. Discussion
4. Materials and Methods
4.1. Chemistry and Structure Elucidation
4.2. Synthesis of Chalcones (3a–c) and (5a–c) and NMR Analysis
- (E)-1-(8,9-Dimethoxy-1-(4-methoxyphenyl)-1,5,6,10b-tetrahydro-[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-3-(4-fluorophenyl)prop-2-en-1-one (3a). Yield: (78%) as a pale-yellow solid (from acetonitrile); m.p 138–140 °C. IR (KBr, cm−1): 1665 (CO); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 2.6–2.8 (m, 2H, H6), 3.4 (s, 3H, OMe), 3.5–3.6 (m, 1H, H5), 3.7 (s, 3H, OMe), 3.8 (s, 3H, OMe), 4.3–4.4 (m, 1H, H5), 6.6 (s, 1H, H10b), 6.7 (s, 1H, H7), 6.9 (s, 1H, H10), 7.0–7.9 (m, 10H, 2 vinyl-H + Ar-H); 13C NMR (100 MHz, DMSO-d6): δ, ppm: 27.3, 41.9, 55.7, 55.8, 55.9, 79.5, 109.8, 112.5, 115.1, 116.6, 118.4, 123.0, 126.7, 129.1, 131.4, 131.7, 137.0, 140.0, 147.3, 148.9, 149.5, 155.2, 162.5, 164.9, 178.8; MS (EI): m/z = 487 (M+). Anal. Calcd. for C28H26FN3O4 (487.53): C, 68.98; H, 5.38; N, 8.62. Found: C, 69.12; H, 5.51; N, 8.83.
- (E)-1-(1-(4-Chlorophenyl)-8,9-dimethoxy-1,5,6,10b-tetrahydro-[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-3-(4-fluorophenyl)prop-2-en-1-one (3b). Yield: (85%) as a pale-yellow solid (from dioxane); m.p 178–180 °C. IR (KBr, cm−1): 1668 (CO); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 2.7–2.9 (m, 2H, H6), 3.5 (s, 3H, OMe), 3.6–3.7 (m, 1H, H5), 3.7 (s, 3H, OMe), 4.1–4.2 (m, 1H, H5), 6.6 (s, 1H, H10b), 6.8 (s, 1H, H7), 6.9 (s, 1H, H10), 7.3–7.9 (m, 10H, 2 vinyl-H + Ar-H); 13C NMR (100 MHz, DMSO-d6): δ, ppm: 27.4, 41.9, 55.8, 56.0, 77.8, 109.1, 112.5, 116.5, 116.6, 122.7, 124.9, 127.4, 128.8, 129.6, 131.6, 141.1, 142.7, 147.6, 149.1, 150.2, 156.5, 162.7, 165.1, 179.5; MS (EI): m/z = 491 (M+). Anal. Calcd. for C27H23ClFN3O3 (491.95): C, 65.92; H, 4.71; N, 8.54. Found: C, 66.15; H, 4.56; N, 8.76.
- (E)-1-(1-(4-Bromophenyl)-8,9-dimethoxy-1,5,6,10b-tetrahydro-[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-3-(4-fluorophenyl)prop-2-en-1-one (3c). Yield: (88%) as a pale-yellow solid (from dioxane); m.p 174–176 °C. IR (KBr, cm−1): 1666 (CO); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 2.7–2.8 (m, 2H, H6), 3.5 (s, 3H, OMe), 3.7 (s, 3H, OMe), 3.9–3.9 (m, 1H, H5), 4.1–4.2 (m, 1H, H5), 6.6 (s, 1H, H10b), 6.8 (s, 1H, H7), 6.9 (s, 1H, H10), 7.3–7.9 (m, 10H, 2 vinyl-H + Ar-H); 13C NMR (100 MHz, DMSO-d6): δ, ppm: 27.4, 41.9, 55.8, 56.0, 66.8, 77.7, 109.1, 112.5, 112.6, 116.4, 116.7, 116.8, 127.4, 128.8, 131.6, 132.4, 141.1, 143.1, 147.6, 149.1, 150.2, 162.7, 165.2, 179.5; MS (EI): m/z = 536 (M+). Anal. Calcd. for C27H23BrFN3O3 (536.40): C, 60.46; H, 4.32; N, 7.83. Found: C, 60.61; H, 4.57; N, 7.97.
- (E)-1-(8,9-Dimethoxy-1-(4-methoxyphenyl)-1,5,6,10b-tetrahydro-[1,2,4]triazolo [3,4-a]isoquinolin-3-yl)-3-(thiophen-2-yl)prop-2-en-1-one (5a). Yield: (80%) as a red solid (from acetonitrile); m.p 168–170 °C. IR (KBr, cm−1): 1670 (CO); 1H NMR (300 MHz, DMSO-d6): δ, ppm: 2.6–2.8 (m, 2H, H6), 3.4 (s, 3H, OMe), 3.7 (s, 3H, OMe), 3.7–3.7 (m, 1H, H5), 4.2–4.3 (m, 1H, H5), 6.6 (s, 1H, H10b), 6.7 (s, 1H, H7), 6.9 (s, 1H, H10), 7.0–7.00 (m, 2H, Ar-H and vinyl-H), 7.2–7.2 (dd, 1H, thiophene-H, J = 3.6, 5.0 Hz), 7.3–7.4 (m, 3H, Ar-H), 7.6 (d, 1H, thiophene-H, J = 3.6 Hz), 7.7 (d, 1H, thiophene-H, J = 5.0 Hz), 7.80 (d, 1H, vinyl-H, J = 15.6 Hz);13C NMR (75 MHz, DMSO-d6): δ, ppm: 27.3, 41.9, 55.7, 55.8, 55.9, 79.6, 109.7, 112.4, 115.2, 118.3, 121.5, 126.6, 129.1, 129.3, 130.4, 133.3, 134.1, 137.1, 140.2, 147.3, 148.9, 149.6, 155.3, 178.4; MS (EI): m/z = 483 (M+). Anal. Calcd. for C26H25N3O4S (475.56): C, 65.67; H, 5.30; N, 8.84. Found: C, 65.79; H, 5.47; N, 8.98.
- (E)-1-(1-(4-Chlorophenyl)-8,9-dimethoxy-1,5,6,10b-tetrahydro-[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-3-(thiophen-2-yl)prop-2-en-1-one (5b). Yield: (84%) as a red solid (from acetonitrile); m.p 178–180 °C. IR (KBr, cm−1): 1671 (CO); 1H NMR (300 MHz, DMSO-d6): δ, ppm: 2.7–2.9 (m, 2H, H6), 3.5 (s, 3H, OMe), 3.6–3.7 (m, 1H, H5), 3.7 (s, 3H, OMe), 4.1–4.2 (m, 1H, H5), 6.6 (s, 1H, H10b), 6.8 (s, 1H, H7), 6.9 (s, 1H, H10), 7.2–7.2 (m, 1H, thiophene-H), 7.3–7.4 (m, 5H, vinyl-H), 7.6 (d, 1H, thiophene-H, J = 3.6 Hz), 7.8 (d, 1H, thiophene-H, J = 5.0 Hz), 7.9 (d, 1H, vinyl-H, J = 15.7 Hz);13C NMR (75 MHz, DMSO-d6): δ, ppm: 27.3, 41.9, 55.8, 56.1, 77.8, 109.1, 112.5, 116.4, 121.2, 124.8, 127.4, 128.8, 129.4, 129.7, 130.9, 133.8, 135.2, 140.0, 142.7 147.6, 149.1, 150.3, 178.9; MS (EI): m/z = 479 (M+). Anal. Calcd. for C25H22ClN3O3S (479.98): C, 62.56; H, 4.62; N, 8.75. Found: C, 62.41; H, 4.81; N, 8.95.
- (E)-1-(1-(4-Bromophenyl)-8,9-dimethoxy-1,5,6,10b-tetrahydro-[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-3-(thiophen-2-yl)prop-2-en-1-one (5c). Yield: (78%) as a red solid (from acetonitrile); m.p 182–184 °C. IR (KBr, cm−1): 1668 (CO); 1H NMR (300 MHz, DMSO-d6): δ, ppm: 2.7–2.8 (m, 2H, H6), 3.5 (s, 3H, OMe), 3.9 (s, 3H, OMe), 4.1–4.2 (m, 2H, H5), 6.6 (s, 1H, H10b), 6.8 (s, 1H, H7), 6.9 (s, 1H, H10), 7.2–7.9 (m, 8H, Ar + thiophene-H + vinyl-H), 7.9 (d, 1H, vinyl-H, J = 15.7 Hz);13C NMR (75 MHz, DMSO-d6): δ, ppm: 27.4, 41.9, 55.8, 55.8, 56.0, 77.7, 109.0, 112.5, 112.6, 116.7, 121.2, 128.8, 129.4, 131.0, 132.5, 133.8, 135.2, 140.0, 143.1 147.6, 149.1, 150.3, 179.0; MS (EI): m/z = 524 (M+). Anal. Calcd. for C25H22BrN3O3S (524.43): C, 57.26; H, 4.23; N, 8.01. Found: C, 57.42; H, 4.41; N, 8.13.
4.3. Cell Culture
4.4. SRB Assay
4.5. MTT Assay
4.6. Cell Cycle Analysis
4.7. Quantitative PCR Analysis
4.8. Caspase-Glo 3/7 Assay
4.9. Molecular Docking Analysis
4.10. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Compound | Cell Viability (%) | |
---|---|---|
Luc-4T1 | MDA-MB-231 | |
3a | 52.5 ± 11.9 | 49.7 ± 12.7 |
3b | 64.3 ± 15.6 | 30.9 ± 8.3 |
3c | 57.6 ± 13.2 | 40.6 ± 6.8 |
5a | 79.6 ± 9.2 | 39.4 ± 12.5 |
5b | 92.1 ± 2.1 | 31.7 ± 11.5 |
5c | 81.6 ± 4.3 | 25.9 ± 3.3 |
5-FU | 88.5 ± 0.6 | 64.0 ± 11.6 |
1m17 (EGFRTK) | 2c6o (CDK2) | 4kmn (cIAP1) | 4wt2 (MDM2) | 2w3l (BCL2) | |
---|---|---|---|---|---|
S | −23.91 | −26.73 | −14.40 | −41.29 | −18.25 |
RMSD | 1.15 | 2.29 | 5.00 | 1.06 | 4.61 |
E-Place | −57.22 | −90.37 | −77.58 | −79.71 | −44.35 |
E-Score | −10.29 | −11.27 | −9.38 | −11.88 | −9.72 |
1m17 (EGFRTK) | 2c6o (CDK2) | 4kmn (cIAP1) | 4wt2 (MDM2) | 2w3l (BCL2) | |
---|---|---|---|---|---|
3a | |||||
S | −23.60 | −21.54 | −22.12 | −24.72 | −18.09 |
RMSD | 2.16 | 2.244 | 1.21 | 1.64 | 2.13 |
E-Place | −44.22 | −69.75 | −79.61 | −53.25 | −43.34 |
E-Score | −8.80 | −9.64 | −7.65 | −8.87 | −7.77 |
5a | |||||
S | −22.56 | −20.47 | −24.08 | −24.60 | −20.07 |
RMSD | 1.94 | 3.22 | 1.97 | 1.79 | 1.25 |
E-Place | −67.01 | −58.25 | −65.40 | −75.19 | −78.05 |
E-Score | −8.79 | −9.06 | −9.95 | −9.22 | −8.96 |
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Darwish, M.I.M.; Moustafa, A.M.; Youssef, A.M.; Mansour, M.; Yousef, A.I.; El Omri, A.; Shawki, H.H.; Mohamed, M.F.; Hassaneen, H.M.; Abdelhamid, I.A.; et al. Novel Tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline Chalcones Suppress Breast Carcinoma through Cell Cycle Arrests and Apoptosis. Molecules 2023, 28, 3338. https://doi.org/10.3390/molecules28083338
Darwish MIM, Moustafa AM, Youssef AM, Mansour M, Yousef AI, El Omri A, Shawki HH, Mohamed MF, Hassaneen HM, Abdelhamid IA, et al. Novel Tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline Chalcones Suppress Breast Carcinoma through Cell Cycle Arrests and Apoptosis. Molecules. 2023; 28(8):3338. https://doi.org/10.3390/molecules28083338
Chicago/Turabian StyleDarwish, Mahmoud I. M., Ahmed M. Moustafa, Asmaa M. Youssef, Mohamed Mansour, Ahmed I. Yousef, Abdelfatteh El Omri, Hossam H. Shawki, Magda F. Mohamed, Hamdi M. Hassaneen, Ismail A. Abdelhamid, and et al. 2023. "Novel Tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline Chalcones Suppress Breast Carcinoma through Cell Cycle Arrests and Apoptosis" Molecules 28, no. 8: 3338. https://doi.org/10.3390/molecules28083338
APA StyleDarwish, M. I. M., Moustafa, A. M., Youssef, A. M., Mansour, M., Yousef, A. I., El Omri, A., Shawki, H. H., Mohamed, M. F., Hassaneen, H. M., Abdelhamid, I. A., & Oishi, H. (2023). Novel Tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline Chalcones Suppress Breast Carcinoma through Cell Cycle Arrests and Apoptosis. Molecules, 28(8), 3338. https://doi.org/10.3390/molecules28083338