Novel Benzenesulfonate Scaffolds with a High Anticancer Activity and G2/M Cell Cycle Arrest
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results and Discussion
2.1. Synthesis of Sulfonic Styrylquinazolines
2.2. Sulfonates Demonstrate Antiproliferative Activity toward Cancer Cell Lines
2.3. Sulfonates Modulate Tyrosine Kinases Activity
2.4. Sulfonates Inhibit Cell Cycle Progression
2.5. Sulfonates Induce Apoptosis and Autophagy
2.6. Sulfonates Change Expression of Genes and Proteins Associated with Cell Metabolism, Cell Cycle and Cell Death
3. Materials and Methods
3.1. Synthesis
- (BS1)
- 2-((E)-2-(2-methoxyphenyl)ethenyl)quinazolin-4-yl 1,3-benzodioxole-5-sulfonate 1H NMR (500 MHz, (CD3)2SO) δ 8.26 (d, J = 16.2 Hz, 1H), 8.15 (dd, J = 8.0, 1.5 Hz, 1H), 7.89 (ddd, J = 8.5, 7.2, 1.6 Hz, 1H), 7.73 (dd, J = 8.3, 1.1 Hz, 1H), 7.63 (dd, J = 7.8, 1.7 Hz, 1H), 7.56 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 7.47 (ddd, J = 8.8, 7.4, 1.7 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 16.3 Hz, 1H), 7.13 (dd, J = 8.0, 1.7 Hz, 1H), 7.08 (td, J = 7.5, 1.0 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.01 (s, 2H), 3.94 (s, 3H); 13C NMR (126 MHz, (CD3)2SO) δ 161.16, 158.94, 154.16, 147.71, 146.93, 143.74, 143.06, 139.23, 136.01, 133.18, 129.90, 127.84, 126.88, 123.54, 123.01, 121.53, 120.59, 119.88, 117.78, 112.61, 107.61, 106.72, 101.55, 56.28; HRMS (ESI) calcd for C24H18N2O6S [M − H]− 461.0813; found 461.0821; m.p. 223–225 °C.
- (BS2)
- 2-((E)-2-(2-methoxyphenyl)ethenyl)quinazolin-4-yl 6-bromo-1,3-benzodioxole-5-sulfonate 1H NMR (500 MHz, (CD3)2SO) δ 8.18 (ddd, J = 8.3, 1.5, 0.7 Hz, 1H), 8.08 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 8.01 (appdt, J = 8.4, 1.0 Hz, 1H), 7.92 (d, J = 16.1 Hz, 1H), 7.86 (s, 1H), 7.78 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.70 (dd, J = 7.7, 1.7 Hz, 1H), 7.62 (s, 1H), 7.41 (ddd, J = 8.9, 7.3, 1.7 Hz, 1H), 7.26 (d, J = 16.0 Hz, 1H), 7.13 (dd, J = 8.4, 1.1 Hz, 1H), 7.03 (apptd, J = 7.5, 1.1 Hz, 1H), 6.12 (s, 2H), 3.95 (s, 3H); 13C NMR (126 MHz, DMSO) δ 162.00, 158.43, 152.80, 148.39, 146.40, 141.67, 135.23, 132.10, 128.99, 126.86, 126.46, 123.66, 121.39, 121.27, 113.80, 112.41, 111.15, 109.47, 102.45, 56.16; HRMS (ESI) calcd for C24H17BrN2O6S [M + H]− 541.0063; found 541.0079; m.p. 149–151 °C.
- (BS3)
- 7-chloro-2-((E)-2-(2-methoxyphenyl)ethenyl)quinazolin-4-yl 4-methylbenzenesulfonate 1H NMR (500 MHz, (CD3)2SO) δ 8.19 (d, J = 16.2 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.61 (dd, J = 7.7, 1.9 Hz, 1H), 7.50 (dd, J = 8.5, 2.1 Hz, 1H), 7.49–7.46 (m, 2H), 7.43 (ddd, J = 8.9, 7.5, 1.8 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 7.13 –7.10 (m, 2H), 7.08 (d, J = 16.2 Hz, 1H), 7.04 (appt, J = 7.3 Hz, 1H), 3.92 (s, 2H), 2.29 (s, 3H); 13C NMR (126 MHz, (CD3)2SO) δ 161.64, 158.38, 153.86, 150.28, 146.25, 139.60, 138.04, 135.35, 132.05, 128.88, 128.51 (2H), 128.42, 126.76, 126.33, 125.97 (2H), 128.51, 123.65, 121.37, 121.18, 120.25, 112.38, 56.14, 21.25; HRMS (ESI) calcd for C24H19ClN2O4S [M − H]− 465.0681; found 465.0685; m.p. 196–197 °C.
- (BS4)
- 2-((E)-2-(2-methoxyphenyl)ethenyl)quinazolin-4-yl 4-methylbenzenesulfonate 1H NMR (500 MHz, (CD3)2SO) δ 1H NMR (500 MHz, DMSO) δ 8.26 (d, J = 16.3 Hz, 1H), 8.14 (dd, J = 8.0, 1.5 Hz, 1H), 7.88 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.73 (dd, J = 8.3, 1.1 Hz, 1H), 7.63 (dd, J = 7.7, 1.7 Hz, 1H), 7.56 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 7.49–7.47 (m, 2H), 7.47 (ddd, J = 6.9, 1.8 Hz, 1H), 7.17 (dd, J = 8.4, 1.1 Hz, 1H), 7.15 (d, J = 16.4 Hz, 1H), 7.13–7.11 (m, 1H), 7.08 (td, J = 7.5, 1.0 Hz, 1H), 3.94 (s, 3H), 2.29 (s, 3H); 13C NMR (126 MHz, (CD3)2SO) δ 161.40, 159.96, 158.05, 153.16, 146.79, 136.23, 134.66, 131.60, 130.57, 129.26, 128.99, 128.40, 128.10, 127.13, 124.08, 123.55, 121.34, 114.50, 112.24, 56.24, 21.70; HRMS (ESI) calcd for C24H21N2O4S [M − H]− 431.1070; found 431.1068; m.p. 168–169 °C.
- (BS5)
- 2-((E)-2-(4-methoxyphenyl)ethenyl)quinazolin-4-yl 4-methylbenzenesulfonate 1H NMR (500 MHz, (CD3)2SO) δ 8.16 (dd, J = 8.0, 1.5 Hz, 1H), 8.12 (d, J = 16.3 Hz, 1H), 7.92 (ddd, J = 8.5, 7.2, 1.5 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.69–7.64 (m, 2H), 7.60 (ddd, J = 8.1, 7.2, 1.1 Hz, 1H), 7.52–7.48 (m, 2H), 7.13 (dd, J = 8.5, 0.8 Hz, 2H), 7.10–7.06 (m, 2H), 6.91 (d, J = 16.3 Hz, 1H), 3.84 (s, 3H), 2.29 (s, 3H); 13C NMR (126 MHz, (CD3)2SO) δ 161.80, 160.20, 153.64, 145.17, 143.61, 142.35, 137.76, 135.42, 130.17, 127.95, 127.23, 126.56, 126.31, 125.36, 122.21, 119.72, 114.76, 113.19, 55.36, 20.56. HRMS (ESI) calcd for C24H20N2O4S [M + H]− 433.1217; found 433.1214; m.p. 176–178 °C
- (BS6)
- 2-((E)-2-(2,4-dimethoxyphenyl)ethenyl)quinazolin-4-yl 4-methylbenzenesulfonate 1H NMR (500 MHz, (CD3)2SO) δ 8.18–8.14 (m, 2H), 8.09 (ddd, J = 8.2, 1.4, 0.7 Hz, 1H), 8.03 (ddd, J = 8.2, 7.0, 1.4 Hz, 1H), 8.01 (d, J = 16.2 Hz, 1H), 7.95 (appdt, J = 8.5, 1.0 Hz, 1H), 7.72 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.53 (m, 2H), 7.15 (d, J = 16.0 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 6.65 (dd, J = 8.5, 2.4 Hz, 1H), 3.99 (s, 3H), 3.86 (s, 3H), 2.42 (s, 3H); 13C NMR (126 MHz, DMSO) δ 162.57, 161.29, 160.38, 159.53, 153.25, 146.74, 136.14, 134.75, 133.52, 130.55, 129.80, 129.23, 128.63, 127.95, 124.48, 123.52, 117.06, 114.32, 106.69, 98.96, 56.33, 55.96, 21.71; HRMS (ESI) calcd for C25H23N2O5S [M + H]− 463.1322; found 463.1325; m.p. 178–180 °C.
3.2. Cell Culture
3.3. Cytotoxicity Studies
3.4. Tyrosine Kinase Assay
3.5. Cell Cycle Assay
3.6. Tubulin Polymerization Assay
3.7. Annexin V Binding Assay
3.8. Autophagy Assay
3.9. Analysis of the mRNA Expression
3.10. Immunoblotting
3.11. Statistical Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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No. | Activity IC50 Value [μM] | |||||||
---|---|---|---|---|---|---|---|---|
K562 | HCT 116 p53+/+ | HCT 116 p53−/− | MCF-7 | A549 | U-251 | PANC-1 | NHDF | |
BS1 | 0.172 ± 0.034 | 0.880 ± 0.086 | 0.563 ± 0.121 | 8.325 ± 1.940 | >25 | 1.897 ± 0.649 | 3.981 ± 0.597 | 12.540 ± 0.855 |
BS2 | 0.246 ± 0.055 | 1.200 ± 0.132 | 1.312 ± 0.290 | 16.760 ± 2.060 | >25 | 2.303 ± 0.234 | 2.905 ± 0.622 | 15.670 ± 1.410 |
BS3 | 0.078 ± 0.027 | 0.363 ± 0.028 | 0.239 ± 0.030 | 4.599 ± 1.022 | 7.652 ± 0.987 | 1.757 ± 0.388 | 0.097 ± 0.030 | 9.415 ± 1.652 |
BS4 | 0.173 ± 0.031 | 1.567 ± 0.357 | 3.724 ± 0.487 | 9.128 ± 2.053 | 11.340 ± 1.760 | 1.907 ± 0.214 | 0.235 ± 0.042 | >25 |
BS5 | 10.190 ± 0.819 | >25 | >25 | >25 | >25 | >25 | >25 | >25 |
BS6 | 2.699 ± 0.519 | >25 | 21.670 ± 1.185 | 9.791 ± 1.232 | >25 | >25 | >25 | >25 |
CP-31398 | 3.087 ± 0.360 | 18.63 ± 0.92 | 26.28 ± 1.41 | 26.96 ± 2.10 | >25 | 18.77 ± 1.65 | >25 | 12.26 ± 0.54 |
Imatinib | 0.133 ± 0.030 | 44.55 ± 2.41 | 51.21 ± 4.09 | >25 | >25 | >25 | >25 | >25 |
No. | Inhibitory Effect of the Tyrosine Kinase Activity [%] at 0.5 μM | |||||||
---|---|---|---|---|---|---|---|---|
ABL1 | BRK | BTK | CSK | Fyn A | Lck | Lyn B | Src | |
BS1 | 28.39 | 15.30 | 18.80 | 0 | 23.68 | 25.78 | 0 | 0.19 |
BS2 | 0 | 9.33 | 40.18 | 34.25 | 0 | 9.93 | 37.96 | 26.32 |
BS3 | 0 | 26.46 | 30.66 | 0 | 34.07 | 42.65 | 0 | 2.73 |
BS4 | 0 | 35.45 | 26.89 | 28.30 | 3.51 | 19.50 | 0 | 0 |
BS5 | 0 | 20.23 | 8.59 | 20.10 | 0 | 11.20 | 0 | 0 |
BS6 | 0 | 0 | 17.95 | 21.14 | 62.60 | 37.26 | 0 | 0 |
CP-31398 | 10.02 | 34.70 | 36.83 | 0.98 | 30.65 | 27.87 | 47.10 | 15.73 |
Imatinib | 77.17 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
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Malarz, K.; Mularski, J.; Kuczak, M.; Mrozek-Wilczkiewicz, A.; Musiol, R. Novel Benzenesulfonate Scaffolds with a High Anticancer Activity and G2/M Cell Cycle Arrest. Cancers 2021, 13, 1790. https://doi.org/10.3390/cancers13081790
Malarz K, Mularski J, Kuczak M, Mrozek-Wilczkiewicz A, Musiol R. Novel Benzenesulfonate Scaffolds with a High Anticancer Activity and G2/M Cell Cycle Arrest. Cancers. 2021; 13(8):1790. https://doi.org/10.3390/cancers13081790
Chicago/Turabian StyleMalarz, Katarzyna, Jacek Mularski, Michał Kuczak, Anna Mrozek-Wilczkiewicz, and Robert Musiol. 2021. "Novel Benzenesulfonate Scaffolds with a High Anticancer Activity and G2/M Cell Cycle Arrest" Cancers 13, no. 8: 1790. https://doi.org/10.3390/cancers13081790