Table 1.
In vitro biological evaluation of compounds 4a–4p and 4a′–4p′a.
| Compd. | R1 | R2 | Inhibition rate at 1.0 μmol/L (%, 4/4′) |
Anti-proliferative activity (IC50, μmol/L, 4/4′) |
|||
|---|---|---|---|---|---|---|---|
| MDM2 | CDK4 | U87MG | U251 | T98G | |||
| 4a/4a′ | H | COOEt | 71.6 ± 3.8/47.8 ± 7.3 | 42.7 ± 4.3/26.9 ± 6.2 | 25.3 ± 2.7/64.7 ± 10.9 | 43.6 ± 5.5/>50 | 62.4 ± 7.9/>50 |
| 4b/4b′ | 5-F | COOEt | 81.4 ± 10.2/55.6 ± 10.6 | 53.9 ± 8.3/32.6 ± 5.1 | 25.7 ± 1.4/>50 | 32.6 ± 3.5/>50 | 49.0 ± 6.3/>50 |
| 4c/4c′ | 7-F | COOEt | 76.5 ± 13.7/45.3 ± 6.4 | 52.6 ± 7.7/32.6 ± 5.1 | 19.4 ± 2.3/59.9 ± 9.8 | 34.3 ± 4.0/>50 | 51.6 ± 6.2/>50 |
| 4d/4d′ | 5-Cl | COOEt | 82.6 ± 8.4/54.2 ± 6.7 | 70.2 ± 7.8/45.2 ± 3.5 | 8.3 ± 1.5/60.4 ± 4.8 | 17.8 ± 3.2/>50 | 21.6 ± 4.5/>50 |
| 4e/4e′ | 6-Cl | COOEt | 76.4 ± 6.0/48.3 ± 5.1 | 61.2 ± 8.2/38.6 ± 2.9 | 19.2 ± 4.4/>50 | 28.6 ± 2.9/>50 | 22.5 ± 4.2/>50 |
| 4f/4f′ | 4-Br | COOEt | 66.9 ± 9.1/54.8 ± 7.2 | 45.6 ± 4.2/29.4 ± 3.6 | 20.7 ± 3.5/69.8 ± 6.2 | 25.8 ± 4.2/>50 | 27.2 ± 3.0/>50 |
| 4g/4g′ | 5-Br | COOEt | 92.3 ± 11.2/51.9 ± 6.5 | 76.3 ± 8.7/34.1 ± 2.9 | 4.9 ± 0.5/>50 | 8.6 ± 0.6/>50 | 9.5 ± 0.7/>50 |
| 4h/4h′ | 6-Br | COOEt | 76.7 ± 5.2/61.2 ± 5.2 | 59.0 ± 5.7/32.9 ± 2.4 | 20.4 ± 3.3/47.6 ± 5.7 | 18.3 ± 1.5/>50 | 14.4 ± 2.8/>50 |
| 4i/4i′ | 5-NO2 | COOEt | 47.7 ± 4.1/39.3 ± 2.6 | 42.8 ± 5.4/37.9 ± 5.7 | 25.6 ± 2.8/47.9 ± 8.8 | 36.2 ± 4.6/>50 | 41.2 ± 6.1/>50 |
| 4j/4j′ | 5-Me | COOEt | 64.4 ± 7.2/49.2 ± 4.7 | 67.8 ± 6.9/27.1 ± 1.5 | 31.1 ± 1.76/>50 | 38.9 ± 4.5/>50 | 39.3 ± 3.6/>50 |
| 4k/4k′ | H | Bz | 46.4 ± 4.9/35.4 ± 2.4 | 39.5 ± 0.83/30.8 ± 5.1 | 38.73 ± 6.5/>50 | 53.8 ± 9.0/>50 | 43.7 ± 6.6/>50 |
| 4l/4l′ | H | 2-FBz | 47.2 ± 5.71/31.6 ± 2.4 | 38.9 ± 6.4/29.3 ± 2.7 | 32.5 ± 4.7/>50 | 38.7 ± 6.1/>50 | 43.6 ± 4.8/>50 |
| 4m/4m′ | H | 4-FBz | 44.6 ± 3.7/36.2 ± 2.5 | 48.2 ± 4.3/23.2 ± 3.0 | 47.2 ± 3.8/>50 | 39.5 ± 3.8/>50 | 37.1 ± 3.2/>50 |
| 4n/4n′ | H | 3,4-Cl2Bz | 38.4 ± 2.7/36.3 ± 5.2 | 35.6 ± 3.9/18.5 ± 2.1 | 34.9 ± 2.62/>50 | 25.9 ± 3.5/>50 | 32.5 ± 2.9/>50 |
| 4o/4o′ | H | 4-BrBz | 47.1 ± 5.8/29.0 ± 3.5 | 29.5 ± 2.3/18.6 ± 0.9 | 41.6 ± 4.3/>50 | 44.2 ± 4.6/>50 | 45.7 ± 6.7/>50 |
| 4p/4p′ | H | 4-MeOBz | 35.7 ± 4.9/26.9 ± 1.1 | 39.3 ± 5.2/18.4 ± 2.2 | 39.9 ± 4.2/>50 | 43.2 ± 5.9/>50 | 45.9 ± 8.1/>50 |
| Nutlin-3a | – | – | 86.9 ± 9.3 | N.D. | 25.3 ± 2.5 | >50 | >50 |
| Palbociclib | – | – | N.D. | 95.9 ± 6.4 | 26.4 ± 3.8 | 18.9 ± 2.4 | 29.5 ± 4.5 |
a
Each compound was tested in triplicate; data are mean ± SD (n = 3). The IC50 value of anti-proliferation assays was obtained after 24-h incubation. –Not applicable.