Table 2.
Antiproliferative Potencies and Topoisomerase I Inhibitory Activities of Substituted Indenoisoquinolines and Relevant Compounds.
| Compd | Cytotoxicity (GI50 in μM)a |
MGMb | Growth Percentc | Top1 Cleavaged | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Lung | Colon | CNS | Melanoma | Ovarian | Renal | Prostate | Breast | |||||
| HOP-62 | HCT-116 | SF-539 | UACC-62 | OVCAR-3 | SN12C | DU-145 | MCF7 | |||||
| 117 | 0.01 | 0.03 | 0.01 | 0.01 | 0.22 | 0.02 | 0.01 | 0.01 | 0.0405 ± 0.0187f | -d | ++++ | |
| 417,44 | 1.3 | 35 | 41 | 4.2 | 73 | 68 | 37 | 1.58 | 20.0 ± 14 | - | ++ | |
| 517,44 | 0.02 | 0.10 | 0.04 | 0.03 | 0.5 | <0.01 | <0.01 | <0.01 | 0.11 | - | ++++ | |
| 623,45 | 1.78 | 1.15 | 0.04 | 0.03 | 74.1 | 0.813 | 0.155 | 0.37 | 4.64 ± 1.25 | - | ++++ | |
| 723,45 | <0.01 | <0.01 | 0.037 | <0.01 | 0.085 | <0.01 | <0.01 | 0.01 | 0.079 ± 0.023 | - | ++++ | |
| 12a | 5.01 | - | 7.41 | 5.37 | 14.5 | 6.92 | 5.75 | 4.90 | 8.71 | - | +++ | |
| 12b | 3.79 | 4.47 | 5.72 | 4.36 | 16.1 | 3.77 | 2.34 | 3.04 | 6.24 ± 0.22 | - | 0/+ | |
| 12c | 7.76 | 4.36 | 5.89 | 7.58 | 18.6 | 2.95 | 2.88 | 3.55 | 5.13 | - | ++ | |
| 17a | 8.71 | 5.62 | 7.59 | 7.41 | >100 | 20.0 | 16.6 | 4.57 | 19.9 | 58.44 | ++ | |
| 17b | 2.95 | 3.39 | 2.14 | 3.23 | 13.5 | 2.40 | 1.32 | 1.38 | 3.31 | 17.28 | 0 | |
| 17c | - | - | - | - | - | - | - | - | - | 97.16e | ++ | |
| 17d | 3.23 | 3.39 | 7.94 | 2.88 | 24.0 | 2.24 | 2.75 | 1.74 | 4.07 | 34.91 | ++ | |
| 17e | 6.46 | 3.39 | 11.2 | 6.31 | 13.2 | 5.01 | 3.98 | 1.90 | 7.76 | 50.62 | +++ | |
| 17f | - | - | - | - | - | - | - | - | 69.35 | + | ||
| 17g | - | - | - | - | - | - | - | - | 67.99 | + | ||
| 17h | 3.23 | 4.17 | 5.75 | 2.95 | 13.8 | 3.39 | 3.31 | 1.78 | 5.75 | 49.31 | - | |
| 19 | 7.35 | 5.08 | 2.61 | 2.98 | 4.26 | 17.7 | 4.76 | 0.88 | 4.60 ± 0.53 | 58.05 | ++++ | |
| 22a | - | - | - | - | - | - | - | - | - | ++ | ||
| 22b | - | - | - | - | - | - | - | - | 78.60 | + | ||
| 22c | 17.6 | 15.9 | 14.4 | 11.7 | 25.7 | 37.1 | 23.7 | 34.4 | 15.6 ± 2.15 | - | + | |
| 25 | 40.7 | 30.9 | 20.0 | 58.9 | 5.23 | 81.3 | 17.8 | 32.3 | 20.9 | 72.36 | + | |
| 27a | 3.39 | 5.52 | 6.31 | 10.2 | 21.4 | 9.33 | 8.32 | 3.23 | 10.2 | 55.23 | +++ | |
| 27b | - | - | - | - | - | - | - | - | 54.88 | +++ | ||
| 27c | 3.46 | 5.75 | 6.76 | 6.16 | 16.2 | 3.98 | 4.36 | 3.80 | 7.9 | 50.24 | + | |
| 27d | 0.276 | 0.263 | 0.344 | 0.318 | 1.32 | 0.206 | 0.130 | 0.198 | 0.348 ± 0.109 | -23.49 | ++ | |
| 29 | 0.336 | 0.230 | 0.214 | 0.144 | 0.287 | 0.501 | 0.419 | 0.097 | 0.401 ± 0.055 | - | +++ | |
| 30 | 0.089 | 0.025 | 0.157 | 0.098 | 0.309 | 0.241 | 0.040 | 0.016 | 0.156 ± 0.061 | - | ++++ | |
The cytotoxicity GI50 values are the concentrations corresponding to 50% growth inhibition.
Mean graph midpoint for growth inhibition of all human cancer cell lines successfully tested, ranging from 10−8 to 10−4 molar.
Percentage of cell growth in a one-dose assay at 10 μM. This data has recently been incorporated into the NCI protocol (implemented ca. 2006), thus, growth percent is only available for select compounds.
Compound-induced DNA cleavage due to Top1 inhibition is graded by the following rubric relative to 1 uM camptothecin: 0, no inhibitory activity; +, between 20 and 50% activity; ++, between 50 and 75% activity; +++, between 75% and 95% activity; ++++, equipotent. The 0/+ ranking is between 0 and +.
Some compounds were not selected for further testing, refer to text for details.
For MGM GI50 values in which a standard error appears, the GI50 values for individual cell lines are the average of two determinations; values without standard error are from one determination. The values for 1, 4, 5, 6, and 7 are from many determinations.