Y.-H. Li et al. / Bioorg. Med. Chem. 18 (2010) 6422–6428
6427
(
m, 2H), 1.73 (m, 2H), 2.86 (t, 2H, J = 7.2 Hz), 3.21 (t, 2H, J = 6.0 Hz),
.02 (s, 3H), 4.92 (t, 2H, J = 6.0 Hz), 6.17 (s, 2H), 7.09 (s, 1H), 7.80 (s,
5.4.10. 2,3-Methenedioxy-9-cinnamate-10-methoxyprotober-
berine chloride (5j)
Cl; Yield: 50%; Yellow solid; mp 214–216 °C; H NMR
d: 3.20 (t, 2H, J = 6.0 Hz), 4.04 (s, 3H), 4.92 (t, 2H, J = 6.0 Hz), 6.18 (s,
2H), 7.06 (d, 1H, J = 16.0 Hz), 7.08 (s, 1H), 7.50 (s, 1H), 7.51–8.13
4
1
9
1
H), 8.19 (d, 1H, J = 9.2 Hz), 8.27 (d, 1H, J = 9.2 Hz), 9.02 (s, 1H),
28 5
C H22NO
+
.86 (s, 1H); HRMS: calcd for C26
H
28NO
5
Cl (MÀCl) 434.1967,
found 434.1954.
(
m, 5H), 7.99 (d, 1H, J = 16.0 Hz), 8.23 (d, 1H, J = 9.2 Hz), 8.32 (d,
1
C
H, J = 9.2 Hz), 9.05 (s, 1H), 9.95 (s, 1H); HRMS: calcd for
5
.4.4. 2,3-Methenedioxy-9-capryloyloxy-10-methoxyprotober-
+
H22NO
5
Cl (MÀCl) 452.1498, found 452.1490.
berine chloride (5d)
28
Using the previous procedure, yield: 48%; Yellow solid; mp
10–212 °C; H NMR d: 0.88 (t, 3H, J = 7.2 Hz,), 1.35 (m, 6H), 1.44
1
5.4.11. 2,3-Methenedioxy-9-benzoxy-10-methoxyprotoberberine
chloride (5k)
2
(
m, 2H), 1.73 (m, 2H), 2.86 (t, 2H, J = 7.2 Hz), 3.21 (t, 2H,
J = 6.0 Hz), 4.02 (s, 3H), 4.92 (t, 2H, J = 6.0 Hz), 6.17 (s, 2H), 7.09
s, 1H), 7.80 (s, 1H), 8.19 (d, 1H, J = 9.2 Hz), 8.27 (d, 1H,
J = 9.2 Hz), 9.02 (s, 1H), 9.86 (s, 1H); HRMS: calcd for C27 Cl
Using the previous procedure, yield: 67%; Yellow solid; mp
1
2
10–212 °C; H NMR d: 3.20 (t, 2H, J = 6.0 Hz), 4.03 (s, 3H), 4.91
(
(
t, 2H, J = 6.0 Hz), 6.19 (s, 2H), 7.09 (s, 1H), 7.50–7.60 (m, 2H),
H30NO
5
+
7.69–7.73 (m, 2H), 8.15–8.36 (m, 4H), 9.09 (s, 1H), 10.00 (s, 1H);
(
MÀCl) 448.2124, found 448.2117.
+
HRMS: calcd for C26
H20NO
5
Cl (MÀCl) 426.1341, found 426.1337.
5
.4.5. 2,3-Methenedioxy-9-decoyloxy-10-methoxyprotoberberine
5
.4.12. 2,3-Methenedioxy-9-ethyloxyformyl-10-methoxyproto-
chloride (5e)
berberine chloride (5l)
Using the previous procedure, yield: 53%; Yellow solid; mp
Using the previous procedure, yield: 37%; Yellow solid; mp
1
2
1
4
22–224 °C; H NMR d: 0.86 (t, 3H, J = 7.2 Hz), 1.36 (m, 10H),
.42 (m, 2H), 1.73 (m, 2H), 2.84 (m, 2H,), 3.21 (t, 2H, J = 6.0 Hz),
.02 (s, 3H), 4.92 (t, 2H, J = 6.0 Hz), 6.17 (s, 2H), 7.09 (s, 1H), 7.80
1
2
18–220 °C; H NMR d: 1.36 (t, 3H, J = 7.2 Hz), 3.21 (t, 2H,
J = 6.0 Hz), 4.06 (s, 3H), 4.36 (q, 2H, J = 7.2 Hz), 4.93 (t, 2H,
J = 6.0 Hz), 6.17 (s, 2H), 7.09 (s, 1H), 7.80 (s, 1H), 8.21 (d, 1H,
J = 9.2 Hz), 8.30 (d, 1H, J = 9.2 Hz,), 9.03 (s, 1H), 9.97 (s, 1H); HRMS:
calcd for C22
(
s, 1H), 8.19 (d, 1H, J = 9.2 Hz), 8.27 (d, 1H, J = 9.2 H), 9.02 (s, 1H),
+
9
.86 (s, 1H); HRMS: calcd for C29
H
34NO
5
Cl (MÀCl) 476.2437,
+
H20NO
6
Cl (MÀCl) 394.1291, found 394.1281.
found 476.2443.
5
.5. General procedure for the synthesis of compounds 5m–n
5
.4.6. 2,3-Methenedioxy-9-lauroyloxy-10-methoxyprotoberberine
(
Route B)
chloride (5f)
Using the previous procedure, yield: 52%; Yellow solid; mp
To a solution of 2 (0.56 mmol), one molar equivalent of relevant
1
2
1
4
(
1
30–232 °C; H NMR d: 0.85 (t, 3H, J = 7.2 Hz), 1.31 (m, 14H),
.42 (m, 2H), 1.73 (m, 2H), 2.86 (m, 2H), 3.21 (t, 2H, J = 6.0 Hz),
.02 (s, 3H,), 4.95 (t, 2H, J = 6.0 Hz), 6.17 (s, 2H), 7.09 (s, 1H), 7.80
1
was added, the resulting system wad heated to 95–100 °C for 4 h.
Anhydrous CH CN (12 mL) and NaI (0.84 g, 0.56 mmol) was then
added and stirred at rt overnight to generate the intermediate 4.
To a solution of CH CN (70 mL) was added M1 (0.10 g,
.28 mmol) at rt, and then heated to form a dark-red solution, to
which was then added anhydrous K CO (0.77 g, 0.56 mmol) and
3
s, 1H), 8.19 (d, 1H, J = 9.2 Hz), 8.27 (d, 1H, J = 9.2 Hz), 9.05 (s,
3
+
H), 9.95 (s, 1H); HRMS: calcd for
04.2750, found 504.2751.
C
31
H
38NO
5
Cl (MÀCl)
0
5
2
3
intermediate 4. The resulting mixture was stirred at 60 °C for 4 h
and cooled to precipitate completely. The residue filtrated was
then purified by flash chromatography over silica gel using dichlo-
romethane/methanol (40:1) to give 5m–n.
5
.4.7. 2,3-Methenedioxy-9-palmitate-10-methoxyprotoberberine
chloride (5g)
Using the previous procedure, yield: 55%; Yellow solid; mp
1
2
1
4
15–216 °C; H NMR d: 0.85 (t, 3H, J = 7.2 Hz), 1.33 (m, 22H),
.42 (m, 2H), 1.73 (m, 2H), 2.84 (m, 2H), 3.21 (t, 2H, J = 6.0 Hz),
.02 (s, 3H), 4.91 (t, 2H, J = 6.0 Hz), 6.17 (s, 2H), 7.09 (s, 1H), 7.80
5.5.1. 2,3-Methenedioxy-9-pivalyloxymethylenoxy-10-methoxy-
protoberberine iodide (5m)
(
1
5
s, 1H), 8.19 (d, 1H, J = 9.2 Hz), 8.27 (d, 1H, J = 9.2 Hz), 9.02 (s,
Using the previous procedure, yield: 34%; Yellow solid; mp
220–222 °C; H NMR d: 1.05 (s, 9H, J = 7.2 Hz), 3.18 (t, 2H,
J = 6.0 Hz), 4.06 (s, 3H), 4.93 (t, 2H, J = 6.0 Hz), 5.94 (s, 2H), 6.17
+
1
H), 9.85 (s, 1H); HRMS: calcd for
60.3376, found 560.3376.
C
35
H
46NO
5
Cl (MÀCl)
(
s, 2H), 7.09 (s, 1H), 7.79 (s, 1H), 7.99 (d, 1H, J = 9.2 Hz), 8.19 (d,
1
C
H, J = 9.2 Hz), 8.94 (s, 1H), 9.93 (s, 1H); HRMS: calcd for
5
.4.8. 2,3-Methenedioxy-9-stearate-10-methoxyprotoberberine
+
25
H26NO
6
I (MÀI) 436.1760, found 436.1779.
chloride (5h)
Using the previous procedure, yield: 56%; Yellow solid; mp
28–230 °C; H NMR d: 0.84 (t, 3H, J = 7.2 Hz), 1.31 (m, 26H),
.42 (m, 2H), 1.73 (m, 2H), 2.83 (t, 2H, J = 7.2 Hz), 3.21 (t, 2H,
1
5.5.2. 2,3-Methenedioxy-9-phenacyloxymethylenoxy-10-
methoxyprotoberberine iodide (5n)
2
1
Using the previous procedure, yield: 36%; Yellow solid; mp
J = 6.0 Hz), 4.02 (s, 3H), 4.95 (t, 2H, J = 6.0 Hz), 6.17 (s, 2H), 7.09
s, 1H), 7.80 (s, 1H), 8.19 (d, 1H, J = 9.2 Hz), 8.27 (d, 1H,
J = 9.2 Hz), 9.05 (s, 1H), 9.95 (s, 1H); HRMS: calcd for C37 Cl
1
2
20–222 °C; H NMR d: 3.13 (t, 2H, J = 6.0 Hz), 4.06 (s, 3H), 4.89
(
(
t, 2H, J = 6.0 Hz), 6.15 (s, 2H), 6.20 (s, 2H), 7.07 (s, 1H, 13), 7.50–
7.54 (m, 5H), 7.79 (s, 1H), 7.99 (d, 1H, J = 9.2 Hz), 8.19 (d, 1H,
J = 9.2 Hz), 8.96 (s, 1H), 9.98 (s, 1H); HRMS: calcd for C27
MÀI) 456.1447, found 456.1438.
H50NO
5
+
(
MÀCl) 588.3689, found 588.3638.
H
6
22NO I
+
(
5
.4.9. 2,3-Methenedioxy-9-pivaloyloxy-10-methoxyprotoberberine
chloride (5i)
5
5
1
.6. Biological methods
.6.1. Cell culture
HepG2 cells were maintained in RPMI-1640 medium containing
0% fetal bovine serum (FBS) and 1% antibiotics at 37 °C with 5%
Using the previous procedure, yield: 56%; Yellow solid; mp
1
2
18–220 °C; H NMR d: 1.46 (s, 9H), 3.21 (t, 2H, J = 6.0 Hz), 4.02
(
s, 3H), 4.96 (t, 2H, J = 6.0 Hz), 6.17 (s, 2H), 7.10 (s, 1H), 7.81 (s,
1
H), 8.19 (d, 1H, J = 8.8 Hz), 8.27 (d, 1H, J = 9.2 Hz), 9.04 (s, 1H),
+
9
.52 (s, 1H); HRMS: calcd for C24
H24NO
5
Cl (MÀCl) 406.1654,
CO
2
. Twenty-four hours before drug treatment, the cells were
found 406.1648.
trypsinized and grown in RPMI-1640 containing 10% lipoprotein-