186
F. Liéby-Muller et al. / Bioorg. Med. Chem. Lett. 25 (2015) 184–187
Figure 2. Proton NMR spectrum of (À)-4, in deuterated pyridine, at 500 MHz (centered on the quinolizidine skeleton).
Supplementary data
Table 1
IC50 values of compounds (À)-2, 3, (À)-4 and cryptopleurine (À)-1 on four cancer cell
Supplementary data (1H and 13C NMR spectra of (À)-1, (À)-2, 3
and (À)-4) associated with this article can be found, in the online
data include MOL files and InChiKeys of the most important com-
pounds described in this article.
lines
Compound
IC50 (nM)
HCT116
A375
A549
Namalwa
(À)-2
1.6
56
2.5
65
1.4
21
4.1
60
3
(À)-4
0.3
1.2
1.4
1.9
0.3
0.7
1.1
2.6
References and notes
(À)-Cryptopleurine
at a higher field than d 3.8 ppm (Fig. 2).7 Moreover, proton 14a and
hydroxy 15 are in a trans relative configuration: proton 14a is in the
axial position, as it has a high coupling constant with proton 13
(J = 11.1 Hz; 2.1 Hz); proton 15 is in the equatorial position, as it
has a low coupling constant with proton 14a (J = 2.1 Hz). The same
methodology was applied for the attribution of the trans conforma-
tion of compounds (À)-1, (À)-2 and 3.
L.; Liu, Y.; Cui, M. WO2014/000586.
The absolute configuration of (À)-1 was confirmed by the mea-
surement of its specific rotation, and by comparison to literature
data.8
Compounds (À)-2, 3, and (À)-4 were evaluated for their anti-
proliferative activities against a panel of four human cancer cell
lines (A375 (melanoma), A549 (lung), HCT116 (colorectal) and
Namalwa (Burkitt’s lymphoma) (Table 1)) and compared to (À)-
cryptopleurine.9
Compound (À)-2 was found to be as potent as (À)-cryptopleu-
rine, suggesting that position 6 of the phenanthrene moiety does
not provide an ‘activity cliff’ as robust as expected.10 Compound
(À)-4 was slightly more potent—being subnanomolar on two cell
lines—whereas compound 3 was more than ten times less potent,
suggesting that the degree of oxidation of position 15 has an
unpredictable impact on antiproliferative activity.
In summary, a couple of enantiomerically enriched phenanthro-
quinolizidine alkaloid analogs of (À)-cryptopleurine were obtained
through a convergent and reproducible synthetic route. Although
removing the methyl group of position 6 of the phenanthrene moi-
ety did not lead to a strong potency gain, as it was hypothesized at
first sight, we identified that the introduction of a hydroxyl group
in position 15 led to the highly potent chemical entity (À)-4. Thus,
the chemistry described here may represent a convergent and sim-
ple route to new (À)-6-O-desmethylcryptopleurine derivatives of
pharmaceutical interest.
6. Cryptopleurine (À)-1: yellow solid, 1H NMR (500 MHz, DMSO-d6) d: 1.34–1.46
(2H, m), 1.57–1.64 (1H, m), 1.72 (1H, d, J = 11.4 Hz), 1.80 (1H, d, J = 11.4 Hz),
1.98 (1H, m), 2.17–2.20 (1H, m), 2.30 (1H14a, m), 2.74 (1H, dd, J = 16.1, 10.6 Hz),
3.12–3.19 (2H, m), 3.48 (1H, d, J = 15.3 Hz), 3.94 (3H, s), 3.98 (3H, s), 4.02 (3H,
s), 4.35 (1H, d, J = 15.3 Hz), 7.21 (1H, dd, J = 9.0, 2.4 Hz), 7.29 (1H, s), 7.81 (1H, d,
J = 9.0 Hz), 8.08 (2H, s); HRMS (ESI) calcd for C24H28NO3 [M+H]+, 378.2064.
20
Found: 378.2065; UV (MeOH) kmax (log
e
) 256 (3.62) nm; [
a
]
À174° (c 0.047
D
MeOH) {lit.8
[a
]
D
À63.8° (c 0.05 MeOH)}.
22
(À)-6-O-Desmethylcryptopleurine (À)-2: yellow solid, 1H NMR (400 MHz,
DMSO-d6) d: 1.36–1.44 (2H, m), 1.57–1.65 (1H, m), 1.73 (1H, d, J = 12.5 Hz),
1.80 (1H, d, J = 10.3 Hz), 1.98 (1H, d, J = 10.3 Hz), 2.22 (1H, m), 2.30 (1H14a, m),
2.68–2.76 (2H, m), 3.11 (1H, d, J = 16.4 Hz), 3.19 (1H, m), 3.44–3.49 (1H, m),
3.94 (3H, s), 3.99 (3H, s), 4.34 (1H, d, J = 15.6 Hz), 7.09 (1H, dd, J = 9.2, 2.4 Hz),
7.72 (1H, d, J = 9.2 Hz), 7.93 (1H, s), 7.95 (1H, d, J = 2.4 Hz), 9.66 (1H, s); HRMS
(ESI) calcd for C23H26NO3 [M+H]+, 364.1907. Found: 364.1910; UV (MeOH) kmax
20
(log
e
) 256 (3.73) nm; [
a
]
À97° (c 0.05 MeOH); m.p. 154°C (dec).
D
(À)-6-O-Desmethyl-14-oxo-cryptopleurine 3: light brown solid, 1H NMR
(400MHz, DMSO-d6) d: 1.37–1.54 (3H, m), 1.66 (1H, d, J = 12.1 Hz), 1.86 (1H,
d, J = 9.1 Hz), 2.29–2.37 (2H, m), 2.83 (1H14a, d, J = 10.1 Hz), 3.17 (1H, d,
J = 11.0 Hz), 3.77 (1H, dd, J = 16.6, 1.9 Hz), 3.90 (3H, s), 4.00 (3H, s), 4.63 (1H, d,
J = 16.6 Hz), 7.19 (1H, dd, J = 9.0, 2.2 Hz), 7.93 (1H, s), 8.00 (1H, d, J = 2.2 Hz),
8.07 (1H, d, J = 9.0 Hz), 8.97 (1H, s), 10.34 (1H, br s); LCMS (ES, m/z): 378.0
[M+H]+.
(À)-6-O-Desmethyl-(14R)-hydroxycryptopleurine (À)-4: off-white solid, 1H
NMR (500 MHz, pyr-d5) d: 1.30–1.39 (1H, m), 1.58 (1H, d, J = 11.6 Hz), 1.70–
1.88 (3H, m), 2.14 (1H, t, J = 11.6 Hz), 2.40 (1H14a, dt, J = 11.1, 2.1 Hz), 2.51–2.61
(1H, m), 3.07 (1H, d, J = 10.8 Hz), 3.44 (1H, d, J = 15.6 Hz), 3.88 (3H, s), 3.89 (3H,
s), 4.011 (1H, d, J = 15.6 Hz), 5.11 (1H15, d, J = 2.1 Hz), 7.46 (1H, dd, J = 9.2,
2.4 Hz), 7.62 (1H, d, J = 9.2 Hz), 8.12 (1H, s), 8.18 (1H, s), 8.45 (1H, d, J = 2.4 Hz),
Acknowledgments
11.90 (1H, s); HRMS (ESI) calcd for C23H26NO4 [M+H]+, 380.1856. Found:
20
380.1849; UV (MeOH) kmax (log
mp 251–252 °C.
e) 268 (5.19) nm; [
a
]
À122° (c 0.091 DMSO);
D
The authors would like to thank Christophe Long and Isabelle
Pouny for providing analytical data of compounds (À)-1, (À)-2
and (À)-4, and Camille Larrouquet for NMR spectra interpretation
of (À)-4.