Table 4.
Chemical Structure, Growth Inhibition of MDA-MB-231 Breast Tumor Cell Line, and PDE5 Inhibitory Activity of Tetrahydro-β-carboline-piperazinedione Derivatives (41–68)
| compd | stereochemistry | X,Y | R | % growth inhibition at 10 μMa | growth inhibition IC50 (μM)b and CI at p < 0.05 | % PDE 5 inhibition at 10 μMa | PDE 5 inhibition IC50 (μM)b and CI at p < 0.05 |
|---|---|---|---|---|---|---|---|
| 41 | 6R,12aR | 2,4-dichloro | –CH3 | 10 | ND | 95 | 0.050 (0.03–0.068) |
| 42 | 6S,12aR | 2,4-dichloro | –CH3 | 65 | 3.26 (2.52–4.20) | 90 | 1.20 (0.82–2.34) |
| 43 | 6S,12aS | 2,4-dichloro | –CH3 | 70 | 7.10 (4.70–9.33) | 82 | 0.85 (0.70–1.03) |
| 44 | 6R,12aS | 2,4-dichloro | –CH3 | 23 | ND | 95 | 0.050 (0.041–0.067) |
| 45 | 6R,12aR | 2,4-dichloro | –C2H5 | 30 | ND | 91 | 0.002 (0.0006–0.008) |
| 46 | 6S,12aR | 2,4-dichloro | –C2H5 | 66 | 1.54 (1.21–1.95) | 90 | 0.26 (0.14–0.48) |
| 47 | 6S,12aS | 2,4-dichloro | –C2H5 | 52 | ND | 85 | 0.99 (0.87–1.13) |
| 48 | 6R,12aS | 2,4-dichloro | –C2H5 | 20 | ND | 95 | 0.010 (0.006–0.022) |
| 49 | 6R,12aR | 3,4-dichloro | –C2H5 | 30 | ND | 80 | 1.34 (0.60–2.87) |
| 50 | 6S,12aR | 3,4-dichloro | –C2H5 | 44 | ND | 45 | ND |
| 51 | 6S,12aS | 3,4-dichloro | –C2H5 | 35 | ND | 67 | 3.30 (1.11–4.60) |
| 52 | 6R,12aS | 3,4-dichloro | –C2H5 | 50 | ND | 78 | 2.04 (1.86–2.22) |
| 53 | 6R12aR | 2,6-dichloro | –C2H5 | 31 | ND | 40 | ND |
| 54 | 6S,12aS | 2,6-dichloro | –C2H5 | 24 | ND | 28 | ND |
| 55 | 6R,12aR | 2,4-dichloro | –C4H9 | 45 | ND | 95 | 0.27 (0.19–0.37) |
| 56 | 6S,12aR | 2,4-dichloro | –C4H9 | 65 | 1.20 (0.66–2.18) | 69 | 1.11 (0.56–2.21) |
| 57 | 6S,12aS | 2,4-dichloro | –C4H9 | 82 | 3.28 (2.75–3.86) | 78 | 4.46 (3.70–5.36) |
| 58 | 6R,12aS | 2,4-dichloro | –C4H9 | 42 | ND | 89 | 0.29 (0.23–0.35) |
| 59 | 6R,12aR | 2,4-dichloro | –C-(CH3)3 | 15 | ND | 94 | 0.19 (0.09–0.43) |
| 60 | 6S,12aR | 2,4-dichloro | –C-(CH3)3 | 70 | 2.92 (1.61–5.29) | 70 | 1.26 (0.70–2.35) |
| 61 | 6S,12aS | 2,4-dichloro | –C-(CH3)3 | 71 | 2.59 (1.48–4.56) | 78 | 1.35 (1.08–1.69) |
| 62 | 6R,12aS | 2,4-dichloro | –C-(CH3)3 | 30 | ND | 70 | 0.26 (0.20–0.32) |
| 63 | 6R,12aR | 3,4-dichloro | –C-(CH3)3 | 36 | ND | 35 | ND |
| 64 | 6S,12aR | 3,4-dichloro | –C-(CH3)3 | 40 | ND | 30 | ND |
| 65 | 6S,12aS | 3,4-dichloro | –C-(CH3)3 | 58 | ND | 35 | ND |
| 66 | 6R,12aS | 3,4-dichloro | –C-(CH3)3 | 50 | ND | 85 | 1.27 (1.11–1.45) |
| 67 | 6R,12aR | 2,6-dichloro | –C-(CH3)3 | 16 | ND | 21 | ND |
| 68 | 6S,12aS | 2,6-dichloro | –C-(CH3)3 | 20 | ND | 21 | ND |
a
Calculated from duplicate values.
b
Calculated from at least 8 concentrations, each with quadruple replicates, p < 0.05.