Table 1.
Stimulation of ATPase activity, inhibition of verapamil-induced ATPase activity, IC50’s for calcein AM (CAM) uptake and tritiated vinblastine (VIN) efflux by thiorhodamine amide and thioamide analogues, and n-octanol/water partition coefficients (log P) for thiorhodamines 112 and VER.
| Isolated | Human | P-gp-His10 | MDCKII-MDR1 | Cells | ||
|---|---|---|---|---|---|---|
|
|
|
|||||
| Compd |
Vmaxa, Fold stimulation |
KMb 10−6 M |
IC50,c 10−6 M |
IC50 CAM uptake, 10− 6 Md |
IC50 VIN efflux, 10−6 Md |
log P |
| VER | 17.9 ± 2.0 | 24 ± 2.6 | -- | -- | -- | |
| 1 | 12.1 ± 1.6 | 5.7 ± 1.0 | -- | >100 | -- | 1.2 |
| 2 | 12.1 ± 1.9 | 5.8 ± 0.6 | -- | 14 ± 1 | -- | 1.2 |
| 3 | 8.6 ± 2.3 | 6.4 ± 0.4 | -- | >100 | -- | 1.5 |
| 4 | 6.6 ± 0.7 | 5.5 ± 1.3 | -- | NDf (19 ± 2)g |
-- | (1.7)g |
| 5 | 5.6 ± 0.6 | 3.6 ± 0.4 | -- | 10.0 ± 1.6 | -- | 1.9 |
| 6 | 4.6 ± 1.6 | 2.3 ± 0.4 | -- | 9.6 ± 1.2 | -- | 1.7 |
| 7 | 4.1 ± 0.6 | 1.9 ± 0.4 | -- | 56 ± 1 | -- | 1.4 |
| 8 | 3.5 ± 0.9 | 2.5 ± 0.4 | -- | 12.0 ± 1.1 (2.1 ± 1.2)g |
-- | (2.7)g |
| 9 | 4.7 ± 0.3 | 2.2 ± 1.0 | -- | 7.1 ± 1.2 | 8.0 ± 1.2 | 1.4 |
| 10 | 4.3 ± 0.5 | 3.1 ± 0.7 | -- | 8.8 ± 1.1 | 8.7 ± 1.1 | 2.7 |
| 11 | < 2 | NDe | 1.1 ± 0.2 | 13.0 ± 1.1 | 5.6 ± 1.1 | 1.7 |
| 12 | < 2 | NDe | 1.7 ± 0.3 | 9.3 ± 1.1 | 8.9 ± 1.1 | 2.6 |
Vmax is the ratio of maximum stimulation in the presence of compound to that without compound (basal activity).
KM is the concentration of compound required to achieve 50% maximal stimulation.
IC50 is the concentration of compound required to inhibit 50% of verapamil-stimulated ATPase activity.
Details for methods are provided in Experimental Procedures. Error limits represent ± standard deviation.
ND, not determined because stimulation of ATPase activity too low.
ND, not determined because of limited solubility in BSA-buffer.
Values in parentheses from reference 15.