Table 4.
Drug-like Properties and Inhibition of Tubulin Polymerization and Colchicine Binding of Active Compounds 6a−6g, 6i−6j, and 6q−6r
| parameters (pH 7.4) |
colchicine binding inhibitionb (%) |
||||
|---|---|---|---|---|---|
| aq. sol. (μg/mL) | log P | tubulin assemblya IC50 (μM) ± SD | 5 μM | 1 μM | |
| 6a | 13.4 ± 0.98 | 2.94 ± 0.15 | 1.60 ± 0.04 | 99 ± 1 | 88 ± 3 |
| 6b | 28.6 ± 7.35 | 2.77 ± 0.40 | 2.80 ± 0.3 | 88 ± 0.9 | 53 ± 5 |
| 6c | 2.74 ± 0.11 | 2.56 ± 0.10 | 0.63 ± 0.09 | 96 ± 1 | 78 ± 4 |
| 6d | 1.34 ± 0.10 | 3.91 ± 0.03 | 0.42 ± 0.01 | 96 ± 1 | 83 ± 0.8 |
| 6e | 80.9 ± 17.8 | 2.60 ± 0.27 | 1.90 ± 0.04 | 77 ± 0.5 | c |
| 6f | 67.8 ± 10.3 | 2.26 ± 0.13 | 2.90 ± 0.3 | 87 ± 0.7 | 47 ± 4 |
| 6g | 1.45 ± 0.12 | 2.33 ± 0.00 | 0.59 ± 0.01 | 70 ± 2 | c |
| 6i | 0.46 ± 0.01 | 2.48 ± 0.17 | 0.97 ± 0.1 | 90 ± 1 | 43 ± 4 |
| 6j | 0.58 ± 0.00 | 2.14 ± 0.01 | 0.48 ± 0.02 | 97 ± 2 | 85 ± 0.3 |
| 6q | 8.07 ± 0.47 | 2.70 ± 0.01 | 0.62 ± 0.05 | 95 ± 0.9 | 67 ± 1 |
| 6r | 19.1 ± 1.58 | 2.14 ± 0.01 | 0.58 ± 0.01 | 97 ± 0.7 | 75 ± 4 |
| 2d | 11.1 ± 0.30 | 2.63 ± 0.00 | 0.77 ± 0.07 | 99 ± 0.02 | 93 ± 0.8 |
| CA-4e | 0.54 ± 0.06 | 98 ± 1 | 82 ± 2 | ||
a
The tubulin assembly assay measured the extent of assembly of 10 μM tubulin after 20 min at 30 °C.
b
Inhibition of [3H]colchicine binding was performed by incubating with tested compounds at 5 or 1 μM for 10 min at 37 °C, with tubulin at 1.0 μM.
c
Not determined.
d
Tubulin assay data see ref 13.
e
Reference compound is a drug candidate in phase II/III clinical trials.