Editor / 香港大學中醫藥學院 藥學系(理科)碩士 / 林 佑
在全球人口老化的大趨勢下，老人癡呆症的患者不斷上升，數據顯示全球約有3600萬的老年痴呆症患者，估計到2050年，患者的數目可超過1億。
老年癡呆是一種神經退化疾病的總稱，其中一種最為常見的是阿爾茨海默氏症，它的特徵主要為記憶力衰退,伴隨語言表達，社交技能和情緒控制障礙，甚致失去自理能力。由於癡呆症是持續及漸進式改變神經功能，如能及早判斷相關的症狀，並配合各種的治療方法，包括物理治療，中藥治療與及情緒輔導，對減慢或改善癡呆症有良好的效果。
大多數人難以辦別癡呆與健忘的分別，一般癡呆的早期特徵是：持續至少6個月以上健忘為標誌。
目前對於中藥複方和中藥材用於老年癡呆症的預防或治療已有一定的科學依據。最為經典的中藥複方有 ─ 六味地黃丸(組成藥材：熟地黃、山萸肉、山藥、澤瀉、丹皮、茯苓)，西醫醫學研究證實具有增強學習和記憶能力，作為顯著預防癡呆症的重要方劑之一。除此以外，用治癡呆症的中藥材有很多，包括丹参、黃連、當歸、郁金、赤芍、黨蔘、枸杞子、肉蓯蓉、石菖蒲、麥門冬、茯苓、遠志、黃芪、黃精、冬蟲夏草、川芎等。它們的作用主要來自內含有效成分或活性物質。為了進一步確定中藥對阿爾茨海默氏症的成效，我們針對常用中藥黃連的活性成分(黃連素)的不同的化學結構進行了活性篩選分析。
 |
| 黃連藥材 |
 |
| 黃連活性成分(黃連素化學結構) |
針對於黃連素的90個異構體(人工合成與及洐生物)中進行高度篩選，結果顯示5種最具開發前景的化學結構，它們分別有強效抑制引起阿爾茨海默氏症的2種酶物質，一種名為乙酰膽堿酯酶(acetylcholinesterase enzyme)另一種是丁酰膽堿酯酶，butyrylcholinesterase enzyme)與及/或一種氨基酸(澱粉樣蛋白，Aβ-amyloid)
根據表1、2的篩選結果，5種最具開發前景的黃連素化學結構分別如下：
1). 9-N-[2-(o-Tolyl)]ethylberberine
2). 9-N-3-Phenoxypropyl berberine
3). 9-O-{3-{4-[(N,N-Di-isopropyl-amino)methyl]-1H-1,2,3triazol-1-yl}butyl}berberine bromide
4). 9-O-[3-(Naphthalene-2-ylthio)butyl]-berberine bromide
5). 9-O-2-(4-(3-Propoxy)phenyl) benzofuran-berberine bromide
表1.
Table 1. The
berberine derivatives,
structures 1-32
|
|||||||
N
 |
Chemical structures
|
n
|
Inhibitory activity toward
|
Method of structural analysis
|
|||
AchE
(IC50μm)
|
BuChE
(IC50μm)
|
Aβ
(%)
|
|||||
1
|
berberine
|
-
|
-
|
0.374+0.024
|
18.2+0.683
|
36.3
|
-
|
2
|
9-O-[3-(Phenylol-2-yloxy) propyl] berberine bromide
|
 |
3
|
0.490+0.032
|
1.74+0.028
|
83.5
|
NMR, HRMS
|
3
|
9-O-[4-(Phenylol-2-yloxy)butyl] berberine bromide
|
 |
4
|
0.123+0.003
|
2.09+0.14
|
84.5
|
NMR, HRMS
|
4
|
9-O-[2-(Phenylol-3-yloxy)ethyl] berberine bromide
|
 |
2
|
0.422+0.034
|
2.64+0.063
|
62.5
|
NMR, HRMS
|
5
|
9-O-[3-(Phenylol-3-yloxy) prop yl] berberine bromide
|
 |
3
|
0.628+0.008
|
1.13+0.014
|
85.9
|
NMR, HRMS
|
6
|
9-O-[4-(Phenylol-3-yloxy)butyl] berberine bromide
|
4
|
0.547+0.002
|
2.40+0.021
|
72.8
|
NMR, HRMS
|
|
7
|
9-O-[3-(Phenylol-4-yloxy) prop yl] berberine bromide
|
 |
3
|
0.460+0.013
|
2.06+0.035
|
92
|
NMR, HRMS
|
8
|
9-O-[4-(Phenylol-4-yloxy)butyl] berberine bromide
|
|
4
|
0.304+0.005
|
1.04+0.077
|
86.6
|
NMR, HRMS
|
9
|
9-N-2-Phenoxyethyl berberine
|
-
|
2
|
0.688+0.016
|
0.727+0.038
|
-
|
IR, NMR, ESI-MS
|
10
|
9-N-3-Phenoxypropyl berberine
|
-
|
3
|
0.588+0.012
|
0.216+0.007
|
-
|
IR, NMR, ESI-MS
|
11
|
9-N-4-Phenoxybutyl berberine
|
-
|
4
|
0.349+0.020
|
1.201+0.028
|
-
|
IR, NMR, ESI-MS
|
12
|
9-N-5-Phenoxypentyl berberine
|
-
|
5
|
1.094+0.091
|
1.556+0.126
|
-
|
IR, NMR, ESI-MS
|
13
|
9-N-6-Phenoxyhexyl berberine
|
-
|
6
|
1.419+0.037
|
1.300+0.044
|
-
|
IR, NMR, ESI-MS
|
14
|
9-N-Benzylberberine
|
-
|
1
|
0.936+0.036
|
2.282+0.061
|
-
|
IR, NMR, HRMS
|
15
|
9-N-(2-Phenylethyl)berberine
|
-
|
2
|
0.209+0.011
|
0.406+0.039
|
-
|
IR, NMR, HRMS
|
16
|
9-N-(3-Phenylpropyl)berberine
|
-
|
3
|
0.680+0.017
|
0.785+0.013
|
-
|
IR, NMR, HRMS
|
17
|
9-N-[2-(5-Methoxy-1H-indol-3-yl)]ethylberberine
|
-
|
2
|
1.261+0.106
|
1.391+0.109
|
-
|
IR, NMR, ESI-MS
|
18
|
9-N-[2-(Thiophen-2-yl)]ethylberberine
|
-
|
2
|
0.608+0.029
|
0.555+0.032
|
-
|
NMR, ESI-MS
|
19
|
9-N-[2-(Pyridin-2-yl)]ethyl berberine
|
-
|
2
|
1.160+0.098
|
2.495+0.063
|
-
|
IR, NMR, ESI-MS
|
20
|
9-N-[2-(4-Methoxyphenyl)]ethylberberine
|
-
|
2
|
0.990+0.030
|
2.885+0.089
|
91.1
|
IR, NMR, HRMS
|
21
|
9-N-[2-(4-Fluorophenyl)]ethylberberine
|
-
|
2
|
0.238+0.021
|
0.445+0.017
|
90.4
|
IR, NMR, HRMS
|
22
|
9-N-[2-(4-Nitrophenyl)]ethylberberine
|
-
|
2
|
0.693+0.021
|
0.841+0.052
|
82.6
|
IR, NMR, HRMS
|
23
|
9-N-[2-(o-Tolyl)]ethylberberine
|
-
|
2
|
0.027+0.002
|
0.713+0.016
|
95
|
IR, NMR, HRMS
|
24
|
9-N-[2-(m-Tolyl)]ethylberberine
|
-
|
2
|
0.091+0.005
|
0.674+0.011
|
93.6
|
IR, NMR, HRMS
|
25
|
9-N-[2-(p-Tolyl)]ethylberberine
|
-
|
2
|
0.449+0.027
|
0.821+0.011
|
94
|
IR, NMR, HRMS
|
26
|
9-N-[2-(3,4-Dimethoxyphenyl)] ethylberberine
|
-
|
2
|
0.160+0.010
|
5.818+5.052
|
70.1
|
IR, NMR, HRMS
|
27
|
9-N-[2-(2,4-Dichlorophenyl)]ethylberberine
|
-
|
2
|
0.130+0.014
|
0.424+0.015
|
93.6
|
IR, NMR, HRMS
|
28
|
9-N-[4-(Naphthalen-1-yloxy) butyl] berberine
|
-
|
4
|
0.400+0.030
|
0.511+0.032
|
-
|
IR, NMR, ESI-MS
|
29
|
9-N-[4-(Pyridin-3-yloxy) butyl] berberine
|
-
|
4
|
1.167+0.032
|
2.936+0.089
|
-
|
IR, NMR, ESI-MS
|
30
|
9-N-(1-Phenylethyl)berberine
|
-
|
0
|
1.914+0.037
|
3.280+0.357
|
-
|
IR, NMR, ESI-MS
|
31
|
9-N-(2-Methylpropyl)berberine
|
-
|
1
|
1.143+0.094
|
2.016+0.099
|
-
|
IR, NMR, ESI-MS
|
32
|
9-N-[3-(N,N-Dimethylamino) propyl] berberine
|
-
|
3
|
0.576+0.036
|
6.323+0.046
|
-
|
IR, NMR, ESI-MS
|
表2.
Table 2. Synthesis of the
berberine-derivatives hybrids, structures 33-90
|
|||||||
N
|
Chemical
structures
|
n
|
Inhibitory activity toward
|
Method of structural analysis
|
|||
AchE (IC50μm)
|
BuChE (IC50μm)
|
Aβ
(%)
|
|||||
33
|
9-O-[(3-Oxo-tryptamino)propyl]-berberine bromide
|
H
|
-
|
1.11+0.021
|
1.64+0.206
|
82.8
|
NMR, HRMS
|
34
|
9-O-[(3-Oxo-5-methyltryptamino)propyl]
-berberine bromide
|
CH3
|
-
|
1.42+0.042
|
1.96+0.014
|
72.8
|
NMR, HRMS
|
35
|
9-O-[(3-Oxo-5-methoxytryptamino)
propyl]-berberine bromide
|
OCH3
|
-
|
1.44+0.054
|
2.72+0.035
|
79.5
|
NMR, HRMS
|
36
|
9-O-[3-(Ferulic acid)propyl] berberine bromide
|
-
|
-
|
3.21+0.155
|
2.40+0.042
|
75.8
|
NMR, HRMS
|
37
|
9-O-[3-(4-Methyl-phenoxyl) propyl]-berberine
bromide
|
R1=CH3, X=O, Y=C
|
3
|
0.878+0.061
|
1.81+0.134
|
-
|
NMR, LC/MS
|
38
|
9-O-[3-(4-Methoxy-phenoxyl)-propyl]-berberine
bromide
|
R1=OCH3, X=O, Y=C
|
3
|
1.00+0.075
|
2.86+0.127
|
-
|
NMR, LC/MS
|
39
|
9-O-[3-(4-Methoxy-phenoxyl)butyl]-berberine
bromide
|
R1=OCH3, X=O, Y=C
|
4
|
0.748+0.084
|
2.29+0.076
|
-
|
NMR, LC/MS
|
40
|
9-O-[3-(4-Chloro-phenoxyl)propyl]-berberine
bromide
|
R1=Cl, X=O, Y=C
|
3
|
0.715+0.109
|
1.80+0.141
|
-
|
NMR, LC/MS
|
41
|
9-O-[3-(4-Chloro-phenoxyl) butyl]-berberine
bromide
|
R1=Cl, X=O, Y=C
|
4
|
1.50+0.020
|
2.20+0.170
|
-
|
NMR, LC/MS
|
42
|
9-O-[3-(4-Bromo-phenoxyl)propyl]-berberine
bromide
|
R1=Br, X=O, Y=C
|
3
|
0.265+0.024
|
4.24+0.148
|
-
|
NMR, LC/MS
|
43
|
9-O-[3-(4-Bromo-phenoxyl)butyl]-berberine
bromide
|
R1=Br, X=O, Y=C
|
4
|
0.743+0.069
|
5.44+0.050
|
-
|
NMR, LC/MS
|
44
|
9-O-[3-(4-Nitro-phenoxyl)propyl]-berberine
bromide
|
R1=NO2, X=O, Y=C
|
3
|
0.400+0.050
|
2.83+0.136
|
-
|
NMR, LC/MS
|
45
|
9-O-[3-(4-Nitro-phenoxyl)butyl]-berberine
bromide
|
R1=NO2, X=O, Y=C
|
4
|
0.490+0.087
|
2.05+0.121
|
-
|
NMR, LC/MS
|
46
|
9-O-[3-(2-Pyridinoxyl)butyl]-berberine bromide
|
R1=H, X=O, Y=N
|
4
|
0.340+0.013
|
4.16+0.05
|
-
|
NMR, LC/MS
|
47
|
9-O-[3-(Phenylamino)propyl]-berberine
bromide
|
R1=H, X=NH, Y=N
|
3
|
0.138+0.009
|
1.76+0.114
|
-
|
NMR, LC/MS
|
48
|
9-O-[3-(N-Methyl-phenylamino)propyl]-berberine
bromide
|
R1=H, X=NCH3, Y=N
|
3
|
0.156+0.013
|
2.17+0.040
|
-
|
NMR, LC/MS
|
49
|
9-O-[3-(Naphthalen-2-yloxy)propyl]-berberine
bromide
|
X=O
|
3
|
0.359+0.044
|
2.20+0.127
|
-
|
NMR, LC/MS
|
50
|
9-O-[3-(Naphthalen-2-yloxy)butyl]-berberine
bromide
|
X=O
|
4
|
1.899+0.894
|
1.10+0.899
|
-
|
NMR, LC/MS
|
51
|
9-O-[3-(Naphthalene-2-ylthio)propyl]-berberine
bromide
|
X=S
|
3
|
0.500+0.015
|
0.548+0.014
|
-
|
NMR, LC/MS
|
52
|
9-O-[3-(Naphthalene-2-ylthio)butyl]-berberine
bromide
|
X=S
|
4
|
1.35+0.092
|
0.078+0.011
|
-
|
NMR, LC/MS
|
53
|
9-O-[(3-Oxo-3-phenylamino)propyl]-berberine
bromide
|
R2=H
|
-
|
0.535+0.008
|
2.18+0.085
|
-
|
NMR, LC/MS
|
54
|
9-O-[(3-Oxo-3-p-tolylamino)propyl]-berberine
bromide
|
R2=CH3
|
-
|
1.46+0.036
|
1.31+0.148
|
-
|
NMR, LC/MS
|
55
|
9-O-[(3-Oxo-3-p-methoxyamino)propyl]-berberine
bromide
|
R2=OCH3
|
-
|
2.80+0.027
|
1.01+0.061
|
-
|
NMR, LC/MS
|
56
|
9-O-[(3-Oxo-3-p-chlorophenylamino)
propyl]-berberine bromide
|
R2=Cl
|
-
|
3.86+0.014
|
1.68+0.190
|
-
|
NMR, LC/MS
|
57
|
9-O-[(3-Oxo-3-p-nitrophenylamino)
propyl]-berberine bromide
|
R2=NO2
|
-
|
6.50+0.056
|
5.53+0.090
|
-
|
NMR, LC/MS
|
58
|
9-O-N-(3-Bromopropyl)-1H-indole-2-carboxamideberberine
bromide
|
Z=NH
|
-
|
0.976+0.06
|
2.19+0.127
|
73.5
|
NMR, HRMS
|
59
|
9-O-N-(3-Propyl)benzofuran-2-carboxamide-berberine
bromide
|
Z=O
|
-
|
1.94+0.094
|
1.54+0.137
|
69.1
|
NMR, HRMS
|
60
|
9-O-2-(4-(2-Ethoxy)phenyl)benzofuran-berberine
bromide
|
X=C, Y=O
|
2
|
3.59+0.270
|
0.688+0.062
|
-
|
NMR, HRMS
|
61
|
9-O-2-(4-(3-Propoxy)phenyl)benzofuran-berberine
bromide
|
X=C, Y=NH
|
3
|
1.92+0.058
|
0.990+0.028
|
84.6
|
NMR, HRMS
|
62
|
9-O-2-(4-(3-Ethoxy)phenyl)-1H-indole-berberine
bromide
|
X=C, Y=S
|
2
|
1.07+0.005
|
0.421+0.001
|
-
|
NMR, HRMS
|
63
|
9-O-2-(4-(3-Propoxy)phenyl)-1H-indole-berberine
bromide
|
X=C, Y=NH
|
3
|
0.774+0.013
|
0.711+0.048
|
-
|
NMR, HRMS
|
64
|
9-O-2-(4-(3-Ethoxy) phenyl)benzo [d]thiazole-berberine
bromide
|
X=N, Y=S
|
2
|
1.64+0.015
|
0.175+0.013
|
-
|
NMR, HRMS
|
65
|
9-O-2-(4-(3-Opropoxy)phenyl) benzo
[d]thiazole-berberine bromide
|
X=N, Y=S
|
3
|
1.48+0.091
|
0.587+0.031
|
79.2
|
NMR, HRMS
|
66
|
9-O-2-(4-(3-Ethoxy)phenyl)benzo
[d]oxazole-berberine bromide
|
X=N, Y=O
|
2
|
3.30+0.018
|
0.346+0.007
|
-
|
NMR, HRMS
|
67
|
9-O-2-(4-(3-Propoxy)phenyl)benzo
[d]oxazole-berberine bromide
|
X=N, Y=O
|
3
|
2.12+0.021
|
0.639+0.011
|
-
|
NMR, HRMS
|
68
|
9-O-[(2-Pyridinium)bromide ethyl]-berberine
bromide
|
R3=H
|
2
|
0.196+0.013
|
2.82+0.183
|
-
|
NMR, LC/MS
|
69
|
9-O-[(3-Pyridinium
bromide)propyl]-berberine dibromide
|
R3=H
|
3
|
0.359+0.044
|
13.3+0.749
|
-
|
NMR, LC/MS
|
70
|
9-O-[(2-(3-Methyl)pyridinium
bromide)ethyl]-berberine bromide
|
R3=CH3
|
2
|
0.048+0.003
|
2.46+0.141
|
-
|
NMR, LC/MS
|
71
|
9-O-[3-(3-Methyl pyridinium bromide)propyl]-berberine
bromide
|
R3=CH3
|
3
|
0.152+0.016
|
15.8+0.986
|
-
|
NMR, LC/MS
|
72
|
1,2-Di(berberine-9-O-yl)ethane dibromide
|
-
|
2
|
0.320+0.022
|
1.11+0.050
|
-
|
NMR, LC/MS
|
73
|
1,3-Di(berberine-9-O-yl)ethane dibromide
|
-
|
3
|
0.226+0.006
|
0.531+0.026
|
-
|
NMR, LC/MS
|
74
|
1,4-Di(berberine-9-O-yl)ethane dibromide
|
-
|
4
|
0.176+0.014
|
0.231+0.023
|
-
|
NMR, LC/MS
|
75
|
9-O-{3-{4-[(2-Methoxycarbonyl-pyrrolidin-1-yl)methyl]1H-1,2,3-triazol-1-yl}propyl}berberine
bromide
|
Proline methyl ester
|
3
|
0.785+0.023
|
5.30+0.106
|
-
|
NMR, LC/MS
|
76
|
9-O-{3-{4-[(2-Methoxycarbonyl-pyrrolidin-1-yl)methyl]1H-1,2,3-triazol-1-yl}butyl}berberine
bromide
|
Proline methyl ester
|
4
|
0.903+0.047
|
5.27+0.378
|
63.5
|
NMR, LC/MS, HRMS
|
77
|
9-O-{3-{4-[(2-Ethoxycarbonyl-pyrrolidin-1-yl)methyl]1H-1,2,3-triazol-1-yl}propyl}berberine
bromide
|
Proline ethyl ester
|
3
|
0.601+0.147
|
2.40+0.258
|
-
|
NMR, LC/MS, HRMS
|
78
|
9-O-{3-{4-[(2-Ethoxycarbonyl-pyrrolidin-1-yl)methyl]1H-1,2,3-triazol-1-yl}butyl}berberine
bromide
|
Proline ethyl ester
|
4
|
0.606+0.052
|
2.32+0.304
|
76.6
|
NMR, LC/MS, HRMS
|
79
|
9-O-{3-{4-[(Piperidin-1-yl)methyl]-1H-1,2,3-triazol-1yl}propyl}
berberine bromide
|
piperidine
|
3
|
0.108+0.001
|
4.24+0.071
|
-
|
NMR, LC/MS, HRMS
|
80
|
9-O-{3-{4-[(Piperidin-1-yl)methyl]-1H-1,2,3-triazol-1yl}butyl}
berberine bromide
|
piperidine
|
4
|
0.274+0.011
|
5.73+0.09
|
63.7
|
NMR, LC/MS, HRMS
|
81
|
9-O-{3-{4-[(N,N-Dibutyl-amino)methyl]-1H-1,2,3-triazol1-yl}propyl}berberine
bromide
|
N(n-Bu)2
|
3
|
0.243+0.006
|
2.06+0.106
|
-
|
NMR, LC/MS, HRMS
|
82
|
9-O-{3-{4-[(N,N-Dibutyl-amino)methyl]-1H-1,2,3-triazol1-yl}butyl}
berberine bromide
|
N(n-Bu)2
|
4
|
0.469+0.040
|
5.46+0.106
|
71.7
|
NMR, LC/MS, HRMS
|
83
|
9-O-{3-{4-[(N,N-Dipropyl-amino)methyl]1H-1,2,3-triazol1-yl}
propyl}berberine bromide
|
N(n-Pr)2
|
3
|
0.140+0.011
|
1.58+0.099
|
-
|
NMR, LC/MS, HRMS
|
84
|
9-O-{3-{4-[(N,N-Dipropyl-amino)methyl]-1H-1,2,3triazol-1-yl}butyl}berberine
bromide
|
N(n-Pr)2
|
4
|
0.270+0.018
|
4.77+0.148
|
62.5
|
NMR, LC/MS, HRMS
|
85
|
9-O-{3-{4-[(N,N-Di-isopropyl-amino)methyl]-1H-1,2,3triazol-1-yl}propyl}berberine
bromide
|
N(i-Pr)2
|
3
|
0.067+0.003
|
2.86+0.396
|
-
|
NMR, HRMS
|
86
|
9-O-{3-{4-[(N,N-Di-isopropyl-amino)methyl]-1H-1,2,3triazol-1-yl}butyl}berberine
bromide
|
N(i-Pr)2
|
4
|
0.044+0.001
|
6.21+0.127
|
52.8
|
NMR, HRMS
|
87
|
9-O-{3-[4-(Benzyl)-1H-1,2,3-triazol-1-yl]proyl}berberine
bromide
|
Phenyl
|
3
|
0.310+0.029
|
2.21+0.138
|
-
|
NMR, LC/MS, HRMS
|
88
|
9-O-{3-[4-(Benzyl)-1H-1,2,3-triazol-1-yl]butyl}berberine
bromide
|
Phenyl
|
4
|
1.32+0.196
|
1.50+0.131
|
60.6
|
NMR, LC/MS, HRMS
|
89
|
9-O-{3-[4-(Butyl)-1H-1,2,3-triazol-1-yl]propyl}berberine
bromide
|
(CH2)2CH3
|
3
|
0.165+0.015
|
4.06+0.250
|
-
|
NMR, LC/MS, HRMS
|
90
|
9-O-{3-[4-(Butyl)-1H-1,2,3-triazol-1-yl]butyl}berberine
bromide
|
(CH2)2CH3
|
4
|
0.201+0.017
|
2.02+0.500
|
77.9
|
NMR, LC/MS, HRMS
|
Reference by http://goo.gl/0LGThO
