Table 1. Structures of and CMGC kinase inhibition by 3-phenyl-6,7-dihydropyrrolo[3,4-g]indol-8(1H)-ones (IC50-values [μM])a.
| R1 | R2 | R3 | R4 | R5 | CDK1/cyclin B | CDK2/cyclinA | CDK5/p25 | CDK9/cyclin T | CK1 | CLK 1 | CLK 2 | CLK 3 | CLK 4 | DYRK 1A | DYRK 1B | DYRK 2 | DYRK 3 | GSK3 | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 8a | H | H | H | H | H | > 10 | > 10 | > 10 | > 10 | > 10 | 0.046 | 0.21 | > 10 | 0.12 | > 10 | 4.8 | 0.72 | > 10 | > 10 |
| 8b | 2-Cl | H | H | H | H | > 10 | > 10 | > 10 | > 10 | > 10 | 0.14 | nd | nd | nd | 1.1 | nd | nd | nd | > 10 |
| 8c | 3-Cl | H | H | H | H | > 10 | > 10 | > 10 | > 10 | > 10 | 0.088 | 0.51 | > 10 | 0.028 | > 10 | > 10 | > 10 | > 10 | > 10 |
| 8d | 4-Cl | H | H | H | H | > 10 | > 10 | > 10 | > 10 | > 10 | 0.10 | 0.17 | 1.8 | 0.13 | > 10 | > 10 | 9.3 | > 10 | > 10 |
| 8e | 3,4-dichloro | H | H | H | H | > 10 | > 10 | > 10 | > 10 | > 10 | 0.11 | 0.69 | > 10 | 0.13 | > 10 | > 10 | > 10 | > 10 | > 10 |
| 8f | 3-OCH3 | H | H | H | H | > 10 | > 10 | > 10 | > 10 | > 10 | 0.11 | 0.32 | 2.8 | 0.11 | 3.8 | 1.9 | 2.1 | 5.4 | > 10 |
| 8g | 3-OH | H | H | H | H | > 10 | > 10 | > 10 | 1.1 | > 10 | 0.044 | 0.082 | 1.7 | 0.081 | 0.74 | 0.39 | 0.59 | 2.2 | > 10 |
| 8h | 3-OCOCH3 | H | H | H | H | > 10 | > 10 | > 10 | > 10 | > 10 | 0.17 | 0.32 | 3.3 | 0.13 | 1.4 | 1.5 | 2.4 | 6.1 | > 10 |
| 8i | 3-CH3 | H | H | H | H | > 10 | > 10 | > 10 | > 10 | > 10 | 0.061 | 0.41 | 5.1 | 0.14 | 2.6 | 4.1 | 3.1 | > 10 | > 10 |
| 8j | 3-NO2 | H | H | H | H | > 10 | > 10 | > 10 | > 10 | > 10 | 0.038 | 0.37 | 8.5 | 0.061 | > 10 | 1.5 | 4.9 | 1.9 | > 10 |
| 8k | H | H | H | H | CH3 | > 10 | > 10 | > 10 | > 10 | > 10 | 0.093 | nd | nd | nd | 1.5 | nd | nd | nd | > 10 |
| 8l | H | H | H | H | C2H5 | > 10 | > 10 | > 10 | > 10 | 6.1 | 0.12 | nd | nd | nd | 0.81 | nd | nd | nd | > 10 |
| 12a | H | Br | H | H | H | 2.8 | > 10 | 5.3 | > 10 | 1.7 | 0.043 | nd | nd | nd | 0.20 | nd | nd | nd | > 10 |
| 12b | H | Br | H | H | CH3 | > 10 | > 10 | > 10 | > 10 | > 10 | 0.023 | 0.025 | 7.1 | < 0.03 | 0.11 | 0.11 | 0.11 | 0.12 | > 10 |
| 12c | H | Cl | H | H | H | nd | > 10 | > 10 | > 10 | > 10 | 0.38 | 0.033 | 2.2 | 0.3 | 0.32 | 1.8 | 2.3 | > 10 | > 10 |
| 12d | H | H | CH3 | H | H | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 |
| 15a | H | H | H | CH3 | H | > 10 | > 10 | > 10 | > 10 | > 10 | 0.19 | 1.1 | > 10 | 0.16 | > 10 | > 10 | > 10 | > 10 | > 10 |
| 15b | H | H | H | C2H5 | H | > 10 | > 10 | > 10 | > 10 | > 10 | 0.38 | nd | nd | nd | 3.9 | nd | nd | nd | > 10 |
| 15c | H | H | H | CH2CONH2 | H | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 |
| 15d | H | H | H | CH2COOC2H5 | H | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | nd | nd | nd | > 10 | nd | nd | nd | > 10 |
| 15e | H | H | CH3 | CH3 | H | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 | > 10 |
| 16 | H | H | H | H | Br | > 10 | > 10 | > 10 | > 10 | > 10 | 0.11 | 0.11 | 2.8 | 0.029 | 1.9 | 1.3 | 1.8 | 3.9 | > 10 |
| 17a | H | Ph | H | H | H | > 10 | > 10 | > 10 | > 10 | > 10 | 8.8 | 7.2 | > 10 | 1.3 | > 10 | > 10 | > 10 | > 10 | > 10 |
| 17b | H | 2-F-Ph | H | H | H | > 10 | > 10 | > 10 | > 10 | > 10 | 5.8 | 4.1 | > 10 | 0.91 | > 10 | > 10 | > 10 | > 10 | > 10 |
| 17c | H | 3-F-Ph | H | H | H | > 10 | > 10 | > 10 | > 10 | > 10 | 7.2 | > 10 | > 10 | 3.2 | > 10 | > 10 | > 10 | > 10 | > 10 |
a IC50 values below 1 μM are highlighted in bold. All data points for construction of dose response curves were recorded in triplicate. Typically, the standard deviation of single data points was below 10%. nd: not determined.