Synthesis of 9-O-glycosyl-berberine derivatives and bioavailability evaluation

Article abstract of DOI:10.1007/s00044-011-9678-1

To increase the bioavailability of berberine, three new 9-O-glycosyl-berberine derivatives, 9-O-glucosyl-(4a), 9-O-arabinosyl-(4b), and 9-O-erythrol-(4c) were obtained and confirmed by UV, ¹HNMR, ¹³CNMR, and MS. The pharmacokinetic profiles of these synthetic compounds have been evaluated compared with berberine (1) and 9-O-alkyl-berberine (5) derivatives, which showed that maximum concentration (C_max) and area under concentration-time curve (AUC) of 9-O-glycosyl-berberine increased dramatically. The results indicated that hydrophilic modification could significantly improve the bioavailability of berberine; 9-O-glycosyl-berberine might be a promising prodrug. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9678-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:1641–1646
DOI 10.1007/s00044-011-9678-1
ORIGINAL RESEARCH
Synthesis of 9-O-glycosyl-berberine derivatives and bioavailability
evaluation
Zhu Chen
Xuegang Li
•
Xiaoli Ye
•
Jun Yi
•
Xin Chen
•
Received: 13 December 2010 / Accepted: 21 May 2011 / Published online: 3 June 2011
Ó Springer Science+Business Media, LLC 2011
Abstract To increase the bioavailability of berberine,
three new 9-O-glycosyl-berberine derivatives, 9-O-gluco-
syl-(4a), 9-O-arabinosyl-(4b), and 9-O-erythrol-(4c) were
anti-bacterial, anti-inflammatory, and antineoplastic (Cer-
nakova and Kostalova, 2002; Zhang et al., 2010; Kong et al.,
2004) effects, etc. The structure of 1 is shown in Fig. 1. Pre-
viousstudiesindicatedthatthelowbioavailabilityisoneofthe
most important factors influencing the therapeutic effects of 1
in vivo (Xiong et al., 1989; Wang et al., 2005; Sheng and Sun,
1993; Bao et al., 1997). It also leads to high dosage for
hypoglycemic and antihyperlipidemics oral treatment (Qian,
2010; Shen et al., 1996). Consequently, many researchers
attempted to increase the bioavailability of 1 to improve the
potency and decrease the oral dosage. It was found that
coadministration with oryzanol could improve the absorption
of 1 (Li et al., 2000).Our results indicated that some additives,
such as glutin, could increase the blood concentration and
bioavailability of 1 (Li et al., 2009). Studies on metabolites of
1 from human and rat urine indicated that they are existed as
glucoside and sulfate, moreover 9-O-glucosyl-berberine (4a)
shows the highest concentration (Pan et al., 2002; Qiu et al.,
2005). Therefore, the transformation from 1 to its water-sol-
uble derivatives supplied a new idea to increase the bio-
availability of berberine (1) by means of changing in
hydrophilicity.
1
13
obtained and confirmed by UV, HNMR, CNMR, and
MS. The pharmacokinetic profiles of these synthetic
compounds have been evaluated compared with berberine
(
1) and 9-O-alkyl-berberine (5) derivatives, which showed
that maximum concentration (Cmax) and area under con-
centration–time curve (AUC) of 9-O-glycosyl-berberine
increased dramatically. The results indicated that hydro-
philic modification could significantly improve the bio-
availability of berberine; 9-O-glycosyl-berberine might be
a promising prodrug.
Keywords Berberine ꢀ Structural modification ꢀ
Bioavailability ꢀ 9-O-glycosyl-berberine
Introduction
Berberine (1) is one of the most important alkaloids existed in
Coptis chinensis French. Reportedly, it has many important
bioactivities, such as hypoglycemic, antihyperlipidemics,
Studies upon structural modifications of 1 have been
reported frequently, which focus on the field of alkyl and
aromatic substitution. A compound possessing palmitate at
the C -position showed an effective inhibition on low-
9
Z. Chen
Department of Pharmacy, Chongqing Medical and
Pharmaceutical College, Chongqing 400030, China
density lipoprotein receptor (LDLR) expression (Li et al.,
2010). The 9-substituted derivatives of 1, especially with
terminal amino group at C -position, would significantly
9
J. Yi ꢀ X. Chen ꢀ X. Li (&)
improve the binding affinity with G-quadruplex, resulting in
increasing inhibitory effects on the amplification of telo21
DNA and on the telomerase activity (Zhang et al., 2007).
College of Pharmaceutical Science, Southwest University,
Chongqing 400716, China
e-mail: xuegangli2000@yahoo.com.cn
Introducing benzyl group into C -position showed an
7
X. Ye
College of Life Science, Southwest University,
Chongqing 400715, China
effective hypoglycemic activity in vitro (Bian et al., 2006).
Substitution on C and C -position with alkyl or phenyl
8
13
123

1
642
Med Chem Res (2012) 21:1641–1646
0
0
0
4
1
5
arabinosyl)-berberine (3b), and 9-O-(2 ,3 ,4 -triacetyl-
erythritol)-berberine (3c) to investigate the optimized
reaction condition. The synthetic procedure of intermediate
products 3 were the critical process for synthesis of end
product 4. The yields of compound 3 were related to
temperature and solvent. Tables 1 and 2 illustrated the
yields of compound 3a affected by different temperature
and solvents, respectively. It was concluded from experi-
mental results that with DMF as solvent at 45°C, we could
obtain the highest yield of compound 3.
O
O
3
2
6
+
7
N
8
OCH
3
9
13
12
10
OCH3
11
Fig. 1 Structure of berberine
group and on C -position with bromine group showed anti-
1
2
In vivo pharmacokinetic evaluation
bacterial activity (Iwasa et al., 1998a, b). A series of com-
pounds bearing 9-O-acyl and 9-O-alkyl-substituents were
synthesized and tested by Kim. It suggested that the pres-
ence of lipophilic substituents with moderate sizes might be
crucial for the optimal antimicrobial activity (Kim et al.,
These studies were carried out on six compounds 1, 4a–c,
5a, and 5b by way of oral administration for SPF rats to
investigate the in vivo pharmacokinetics. The pharmaco-
kinetic parameters were listed in Table 3. Large amount of
2
002). Our experiments on 8-alkyl-substituents suggested
1 were detected in plasma after 4a–c treatment, while 5a
and 5b had not degraded in plasma.
that 8-octyl-berberine significantly increases the activity of
anti-bacterial and antiatheroscloresis (Yang et al., 2007).
In current study, hydrophobic alkyl and hydrophilic
glycosyl as substituent groups were introduced into C9-
position of 1 to synthesize 9-O-glycosyl-(4a–c) and 9-O-
alkyl-berberine (5a–b) derivatives. Then, the effects of
hydrophilicity on the bioavailability of berberine were
investigated to develop new prodrugs with an improved
bioavailability.
The tested results of pharmacokinetic experiments in
vivo demonstrated that the maximization plasma con-
centration (Cmax) and area under concentration–time
curve (AUC) of all glycosylated synthesized derivatives
4a–c were remarkably improved after oral administra-
tion. Compound 4a showed the highest Cmax and AUC,
which were 9.3 and 11.1 times higher than that of
compound 1, respectively. Compared with compound 1
and 4, tested results above indicated that compound 5
modified with hydrophobic alkyl groups had lower
plasma concentration and bioavailability. Above results
demonstrated that glycosylated modification would
enhance the hydrophilic activity of a compound, thus
improve the dissolution rate of the compound in plasma,
which is one of the factors that lead to the increasing of
bioavailability. On the contrary, the hydrophobic struc-
tural modification on 9-O-position of berberine decreased
the bioavailability.
Results and discussion
Synthesis
In this study, five novel compounds have been synthesized,
and compounds 4a–c were synthesized for the first time.
Schemes 1 and 2 illustrated the synthetic route for the
preparation of target compounds. The spectra data and
other characteristic parameters of compounds 4a–c and 5a–
b were shown in the Experimental section. Compared with
1
13
H and C NMR data of 1, the peak data of 9-OCH3
disappeared and that of hydrogen or carbon in glucose,
arabinose or erythritol which has not been covered by
Conclusion
1
13
In conclusion, the current research undertakes the synthesis
of five novel derivatives of berberine. Three of them,
compounds 4a–c, were synthesized for the first time. All
the newly synthesized compounds have been tested for
their in vivo pharmacokinetic pattern. From the perspective
of present investigation, it can be inferred that the intro-
duction of hydrophobic alkyl groups will reduce the plasma
concentration and bioavailability of berberine, but the
glycosylated modification will improve the dissolution rate
of the compound in plasma and furthermore, improve its
bioavailability.
solvent peak emerged in the H and C NMR data of
compounds 4a–c. All spectral data can be analyzed rea-
sonably by their molecular structures. As a consequence,
we concluded that compounds 4a–c were synthesized
successfully.
Optimization of intermediate products synthesis
0
0
0
0
0
0
These studies were carried out on 9-O-(2 ,3 ,4 ,6 -O-Tet-
0
raacetyl-glucosyl)-berberine (3a), 9-O-(2 ,3 ,4 -O-triacetyl-
1
23

Med Chem Res (2012) 21:1641–1646
1643
Comp
R
R1
R2
R3
3a/4a
3
b/4b
3c/4c
Scheme 1 Synthetic route of 9-O-glycosyl-berberine
Materials and methods
chinensis French, whose purity was over 98% analyzed by
HPLC. Other reagents were from Pharmaceutical and
Chemical Reagent Inc. (Chongqing, China), which were of
analytical grade.
Experimental
1
13
Berberine standard and monosaccharide were purchased
from Sigma Chemical Co. (St. Louis, MO, USA). Ber-
berine used for synthesis was extracted from Coptis
UV, H NMR, C NMR, Mass spectrometry (MS), and
TLC were used to identify the structures of new com-
pounds. UV spectra were recorded on a Hitachi U-1800
123

1
644
Med Chem Res (2012) 21:1641–1646
Scheme 2 Synthetic route
of 9-O-alkyl-berberine
°
Comp
R
4
5
5
a
8 17
-C H
b
-C12H
25
1
13
UV apparatus. The H and C NMR spectra were recorded
on Bruker Model Advance DMX300 Spectrometer (300M)
using TMS as an internal standard and DMSO-d6 or
methonal-d4 as solvent. MS spectra were collected on
Shimadzu LCMS-2010A instrument. TLC analysis was
used to confirm the purity of the compounds, performed on
silica gel-GF254 thin layer chromatogram and spread with
corresponding mobile phase. The mobile phase for 9-O-
alkyl-berberine was C H /EtOAc/i-PrOH/MeOH/NH OH
Table 1 Yields of compound 3a at different temperatures with DMF
as solvent
Yields at different temperature (%)
Temperature (°C)
Yields
25
a
63
35
58
40
71
45
85
50
21
a
The reaction conducted at 25°C was lasted for 8 h while others
were lasted for 3 h
6
6
4
(
6:3:1.5:1.5:0.5), and 9-O-glycosyl-berberine derivatives
Table 2 Yields of compound 3a with different solvents at 45°C
were EtOAc/MeOH/light petroleum/NH OH (6:3:3:0.5).
4
Yields with different solvents (%)
Synthesis of acetyl-glycosyl bromide (glycosylated
reagent)
Solvent
Yields
CH
42
3
Cl
DMF
85
DMSO
84
CH
11
3
OH
Perchloric acid (0.15 ml) was dropped slowly into mono-
saccharide (glucose, arabinose, or erythrol, 0.27 mol) in
2
0 ml acetic anhydride at 0°C, then kept stirring at room
Table 3 Pharmacokinetic parameters of compounds 1, 4a–c, and 5a–
b
temperature for 5 min. Phosphorus tribromide (8.5 ml) was
then dropped into reaction solution at 0°C, and kept stirring
at room temperature for 2 h. The reaction solution was then
Compound
Tmax (h)
C
max (lg/l)
AUC (lg h/l)
t1/2 (h)
diluted by 50 ml CHCl , washed by sodium bicarbonate
3
1
2
3
3
3
3
6.79
63.42
48.74
37.49
4.39
24.184
268.94
205.146
180.316
17.329
14.592
7.88
7.58
7.43
7.31
7.85
7.86
solution at 0°C, dehydrated the solution, and kept in freezer.
4
4
4
5
5
a
b
c
Synthesis of compound 3
a
b
Berberrubine (2) was obtained from compound 1 according
to previous literature (Iwasa et al., 1996). Glycosylated
3.5
3.71
1
23

Med Chem Res (2012) 21:1641–1646
1645
reagent (0.27 mol in 50 ml CHCl ) was dropped slowly
3
9.386(s, 1H, 13-Ar–H), 9.180(m, 1H, 1-Ar–H), 7.834(m,
1H, 4-Ar–H), 7.663(s, 1H, 12-Ar–H), 7.123(s, 1H, 11-Ar–
H), 6.242(s, 2H, 2,3-OCH O–), 4.695(s, 2H, 6-CH –),
into compound 2 (0.743 g, 2.7 mmol) dissolved in 20 ml
DMF with 3.2 g K CO as catalyst at 0°C under magnetic
2
3
2
2
stirring and nitrogen protection. After 3 h stirring at 45°C,
reaction solution was washed by distilled water and then
dehydrated. Organic phase was concentrated and purified
by a silica gel column (3 9 75 cm, 100 ml of 200–300
mesh silica gel), and the eluent was 400 ml EtOAc/MeOH/
light petroleum(2:1:1). The resulting eluent was concen-
trated and crystallized twice with ethanol at 6–8°C to
collect compound 3.
4.214(m, J = 7.2 Hz, 1H, Ery-1’-H), 3.865(s, 5H,
0
0
10-OCH , Ery-1 -H, Ery-4 -H), 3.192(s, 2H, 5-CH –);
3
2
1
3
CNMR d(ppm): 26.46, 55.45, 57.18, 62.18, 64.75, 72.81,
73.64, 102.27, 106.46, 109.10, 119.71, 120.33, 121.75,
123.42, 126.83, 131.62, 133.14, 137.55, 142.99, 145.36,
?
147.78, 149.91, 151.86; MS (m/z) [M] : Calcd: 426.4426;
Found: 426.
Synthesis of 9-O-alkyl-berberine (compound 5)
Synthesis of compound 4
Bromoalkane (bromooctane or bromododecane, 1.0 ml)
Compound 3 (2 mmol) was dissolved in 50% methanol
with 0.25 g NaHCO3 and 0.11 g Na CO . After 0.5 h
were added into compound 2 (1.0 g) and dissolved in
10 ml DMF. After 6 min microwave heating at 400 W, the
2
3
stirring below 40°C, the reaction solution was concentrated
and crystallized twice with ethanol at 8°C to get Compound
reaction solution were cooled and filtrated. The filtrate was
concentrated and filtrated again with diethyl ether. Col-
lected the sediments and crystals received from filtration
and then crystallized twice with ethanol at 6–8°C to collect
compound 5.
4
a–c.
9
-O-glucosyl-berberine 4a
Yield, 71%. Rf, 0.15; UV (MeOH) kmax 230, 265, 350 nm;
H NMR: d (ppm) (MeOD), 9.836(1H, m, 8-Ar–H), 8.714(s,
1
9-O-octyl-berberine 5a
1
H, 13-Ar–H), 8.126(m, 1H, 1-Ar–H), 8.097(m, 1H, 4-Ar–
1
Yield 48%, Rf, 0.43; HNMR: d (ppm) (DMSO-d ), 9.73(s,
6
H), 7.673(s, 1H, 12-Ar–H), 6.969(s, 1H, 11-Ar–H), 6.113(s,
0
1H, 8-Ar–H), 8.92(s, 1H, 13-Ar–H), 8.18(s, 1H, 1-Ar–H),
2
4
1
H, 2,3-OCH O–), 5.176(s, J = 7.0 Hz, 1H, Glu-1 –CH,),
2
0
0
7.96(s, 1H, 4-Ar–H), 7.78(d, 1H, 12-Ar–H), 7.08(d, 1H,
.121(t, 4H, 6-CH –, Glu-4 ,5 -H), 3.595–3.427(t, 13H,
2
0
0
0
0
0
0
0
0
0
11-Ar–H), 6.15(s, 2H, –OCH
O–), 4.93(t, 2H, 6-CH –),
2 2
0-OCH , Glu-2 ,3 ,4 ,5 -H, Glu-2 ,3 ,4 ,5 -OH, Glu-5 -
3
1
3
4.25 (t, 2H, –OCH –), 4.03 (s, 3H, –OCH ), 3.16(t, 2H,
3
2
CH2); CNMR d(ppm): 26.46, 55.45, 57.18, 62.86, 71.30,
5
-CH –), 1.85(m, 2H, –O–C–CH –), 1.46(m, 2H, –CH –),
2 2 2
7
1
1
2.59, 75.23, 80.22, 102.27, 104.34, 106.46, 109.10, 119.71,
1
.26(m, 8H, -(CH ) –), 0.85(t, 3H, –CH ); CNMR
3
1
2
4
3
20.33, 121.75, 123.42, 126.83, 131.62, 133.14, 137.55,
?
42.99, 145.36, 147.78, 149.91, 151.86; MS (m/z) [M] :
d(ppm): 14.02, 22.15, 25.35, 26.43, 28.75, 28.87, 29.56,
1.32, 55.42, 57.16, 74.35, 102.17, 105.52, 108.50, 120.31,
3
1
1
Calcd: 484.4784; Found: 484.
20.54, 121.75, 123.36, 126.83, 130.79, 133.14, 137.55,
42.99, 145.36, 147.78, 149.91, 150.48; MS (m/z) [M-
?
Br] : Calcd: 434.2332; Found: 434.
9
-O-arabinosyl-berberine 4b
Yield 69%. Rf, 0.13; UV (MeOH) kmax 235, 265, 350 nm;
1
H NMR: d (ppm) (MeOD), 10.304(m, 1H, 8-Ar–H),
9-O-dodecyl-berberine 5b
9
.387(s, 1H, 13-Ar–H), 9.188(m, 1H, 1-Ar–H), 7.840(m,
1
1
H, 4-Ar–H), 7.663(s, 1H, 12-Ar–H), 7.123(s, 1H, 11-Ar–
Yield 31.7%,Rf, 0.53; HNMR: d (ppm) (DMSO-d
6
),
H), 6.241(s, 2H, 2,3-OCH O–), 4.694(m, 2H, 6-CH –),
9.73(s, 1H, 8-Ar–H), 8.92(s, 1H, 13-Ar–H), 8.18(s, 1H,
2
2
0
.940–3.865(s, 4H, 10-OCH , Ara-2 -H), 3.191(s, 2H,
3
3
5
7
1
1
1-Ar–H), 7.96(s, 1H, 4-Ar–H), 7.78(d, 1H, 12-Ar–H),
1
3
-CH –); CNMR d(ppm): 26.46, 55.45, 57.18, 66.71,
7.08(d, 1H, 11-Ar–H), 6.15(s, 2H, –OCH
6-CH –), 4.25 (t, 2H, –OCH –), 4.03 (s, 3H, –OCH
3.16(t, 2H, 5-CH –), 1.85(m, 2H, –O–C–CH –), 1.45(m,
2H, –CH –), 1.22(m, 16H, –(CH –),0.81(t, 3H, –CH );
2
O–), 4.93(t, 2H,
2
0.30, 71.23, 72.41, 102.27, 104.34, 106.46, 109.10,
2
2
3
),
19.71, 120.33, 121.75, 123.42, 126.83, 131.62, 133.14,
2
2
37.55, 142.99, 145.36, 147.78, 149.91, 151.86; MS (m/z)
?
M] : Calcd: 454.4526; Found: 454.
2
2
)
8
3
13
[
CNMR d(ppm): 14.02, 22.15, 25.35, 26.43, 28.75, 28.80,
8.81, 28.81, 28.82, 28.87, 29.56, 31.32, 55.42, 57.16,
2
9
-O-erythrol-berberine 4c
74.35, 102.17, 105.52, 108.50, 120.31, 120.54, 121.75,
23.36, 126.83, 130.79, 133.14, 137.55, 142.99, 145.36,
1
?
147.78, 149.91, 150.48; MS (m/z) [M-Br] : Calcd:
490.2958; Found: 490.
Yield 59%. Rf, 0.18; UV (MeOH) kmax 232, 264, 350 nm;
H NMR: d (ppm) (MeOD), 10.296(m, 1H, 8-Ar–H),
1
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Med Chem Res (2012) 21:1641–1646
Pharmacokinetic evaluation
Kim SH, Lee SJ, Lee J (2002) Antimicrobial activity of 9-O-acyl- and
9
-O-alkylberberrubine derivatives. Planta Med 63:277–281
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ZZ, Si SY, Pan HN, Wang SK, Wu JD, Wang Y, Li ZR, Liu JW,
Jiang JD (2004) Berberine is a novel cholesterol-lowering drug
working through a unique mechanism distinct from statins. Nat
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Li BX, Yang BF, Hao XM (2000) Study on the pharmacokinetics of
berberine in single dosage and coadministration with oryzanol in
rabbits and healthy volunteers. Chin Pharm J 35:33–35
Li YM, Ye XL, Li XM, Zhu HF, Liu GY, Zhu Y, Chen X, Zhou JZ,
Li XG (2009) Effect of additives on absorption of Coptis
chinensis total alkaloids and pharmacokinetics in mice. Chin J
Chin Mat Med 34:344–348
Li YH, Yang P, Kong WJ (2010) Design, synthesis and cholesterol-
lowering efficacy for prodrugs of berberrubine. Bioorg Med
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Healthy SPF rats (200 ± 20 g) were purchased from
Laboratory Animal Centre of Chongqing Medical Univer-
sity (Chongqing, China). They were housed in stainless
cages in a room with controlled temperature (23 ± 2°C)
and humidity (40–60%) and a 12 h light/dark cycle. The
protocol complied with the guidelines of Chongqing City
Laboratory Animal Administration Committee of China for
the care and use of laboratory animals. The rats were
randomly divided into six groups with six each for plasma
drug concentration test. Compounds 1 and 4 were dissolved
in 2% Tween-80 aqueous solution, while compound 5 was
dispersed in 0.7% CMC-Na solution with hyperacoustic
treatment for 1 h at 60°C, all compounds were given to rats
by oral administration (100 mg/kg body wt), respectively.
After 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, and 12 h,
respectively, 0.4 ml plasma samples were taken from the
orbital veins of rats for HPLC analysis (Wang et al., 2010)
to investigate the pharmacokinetics of compounds 1, 4, and
Qian HY (2010) Clinical observation of Jin-Qi-Jiang-Tang-Pian on
type 2 diabetes therapy. Jil Med J 31:2212
Qiu F, Zhu ZY, Piao SJ (2005) Studies on urinary metabolites of
orally administered berberine chloride in humans. Chin Med Res
Clin 3:6–9
5
.
Shen ZF, Xie MZ, Liu HF (1996) Effect of Jinqi hypoglycemic tablet
on blood glucose in experimental animals. Trad Chin Drug Res
Clin Pharmacol 7:24–26
Sheng MP, Sun Q (1993) Studies on the intrvenous pharmacokinetics
and oral absorbtion of berberine HCl in beagle dogs. Chin
Pharmacol Bull 9:64–67
Acknowledgment This study was supported by the Major Technol-
ogies R & D Program (2010ZX09401-306-3-10, CSTC2008AA5021
and 2010AC5007), the Graduate School of Southwest University
(kb2009017), National Science and Technology Pillar program of
China (2011BAI13B02-1).
Wang X, Xing D, Wang W (2005) The uptake and transport behavior
of berberine in Coptidis Rhizoma extract through rat primary
cultured cortical neurons. Neurosci Lett 379:132–137
Wang L, Ye XL, Li XG, Chen Z, Gao Y, Zhao ZQ, Zhang FR, Chen
X, Yi J (2010) Metabolism, transformation and distribution of
Coptis Chinensis total alkaloids in rat. Chin J Chin Mat Med
35:2017–2020
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