Table 2.
The indicated 31 betulin derivatives were analyzed for [3H]TC transport inhibition and [3H]preS1 binding inhibition in NTCP-HEK293 cells. IC50 values were calculated from a range of five inhibitor concentrations (0.1–1,000 µM) and are listed with their 95% confidence intervals. Selectivity indices for [3H]TC transport inhibition/[3H]preS1 binding inhibition were calculated from the IC50 means. The higher this index, the more selective the respective inhibitor.
| Compound | IC50 ([3H]TC uptake) [µM]a | IC50 ([3H]preS1 binding) [µM]b | Selectivity indexc |
|---|---|---|---|
| Betulinic acid (4) | 0.65–1.08 | 1.57–2.93 | 1 |
| 20,29-Dihydrobetulonic acid (20) | 2.74–5.46 | 2.95–7.66 | 1 |
| 3,28-Di-O-succinoylbetulin (9) | 3.11–5.02 | 2.94–10.15 | 1 |
| 28-O-(3,3-Dimethylglutaroyl)betulin (10) | 3.00–5.91 | 2.48–7.02 | 1 |
| 3-O-(3,3-Dimethylglutaroyl)betulinic acid (11) | 3.08–4.53 | 3.00–5.21 | 1 |
| 3,28-Di-O-(3,3-dimethylglutaroyl)betulin (12) | 4.17–10.71 | 4.97–10.14 | 1 |
| 3-O-Acetylbetulin (22) | 36.47–151.80 | 20.64–87.35 | 2 |
| Methyl betulinate (5) | 47.05–99.97 | 12.66–83.46 | 2 |
| 28-O-Succinoylbetulin (8) | 5.35–10.60 | 1.61–4.11 | 3 |
| Betulonaldehyde (18) | 88.53–175.00 | 25.98–52.00 | 3 |
| 28-O-Nicotinoylbetulin (14) | 185.40–531.50 | 36.48–109.10 | 5 |
| 3-O-Acetylbetulinic acid (21) | 7.19–30.33 | 1.81–5.31 | 5 |
| 3,28-Di-O-acetylbetulin (24) | > 1,000 | 52.55–756.00 | > 5 |
| 3,28-Di-O-(dihydrocinnamoyl)betulin (16) | 176.20–1232.00 | 24.79–229.20 | 6 |
| 4′-Ethyl-1′,2′,4′-triazoline-3′,5′-dione-fused 3,28-di-O-acetylbetulin (31) | 614.20–1286.00 | 89.71–224.60 | 6 |
| Betulin (1) | 568.80–983.40 | 48.29–247.10 | 7 |
| 28-O-Cinnamoylbetulin (15) | 72.39–235.50 | 10.89–31.75 | 7 |
| 3-O-Acetyl-28-(tetrahydro-2H-pyran-2-yl)betulin (23) | 119.00–947.20 | 10.95–113.70 | 10 |
| Lupenone (17) | 145.70–396.70 | 13.10–35.45 | 11 |
| 28-O-(Bromoacetyl)betulin (7) | 63.53–126.00 | 5.28–11.14 | 11 |
| 3,28-Di-O-acetyl-20,30-epoxybetulin (26) | 331.80–891.20 | 26.46–72.96 | 12 |
| 3,28-Di-O-acetyl-18,19-dehydro-20,29-dihydrobetulin (28) | > 1,000 | 29.95–132.80 | > 16 |
| Lupeol (3) | > 1,000 | 26.93–97.94 | > 19 |
| 28-(Tetrahydro-2H-pyran-2-yl)betulin (13) | 115.80–628.00 | 9.34–19.54 | 19 |
| 3-O-Caffeoylbetulin (27) | 84.98–195.00 | 3.35–10.00 | 22 |
| Allobetulin (29) | 212.30–674.80 | 9.67–20.80 | 27 |
| Betulonoyl dimethyl-L-aspartate (19) | 297.60–1430.00 | 21.84–202.60 | 28 |
| 3-Oxoallobetulin (30) | > 1,000 | 17.87–54.43 | > 32 |
| Betulinaldehyde oxime (6) | 359.80–759.00 | 6.61–18.29 | 48 |
| 20,29-Dihydrobetulin (2) | 157.80–428.90 | 1.74–7.14 | 65 |
| 3,28-Di-O-acetyl-29-hydroxybetulin (25) | > 1,000 | 5.29–13.04 | > 125 |
a Inhibition of 1 µM [3H]TC uptake; b inhibition of 5 nM [3H]preS1 binding; c calculated from mean IC50 TC:preS1.