Synthesis of hydrophilic berberine derivatives modified with nitrogen heterocycles

doi:10.16085/j.issn.1000-6613.2019-0282

Abstract

Abstract:

In order to improve the water solubility of berberine and increase its absorption and transportation in vivo, a series of nitrogen heterocycle functionalized berberines (4—6) were synthesized via demethylation of berberine followed by bromoalkylation and bromo-substitutions with benzimidazole, 1,2,4-triazole and pyrazole. Except for 6a, all the other compounds were new and had been characterized by ¹H NMR, ¹³C NMR spectroscopy and ESI MS spectrometry. Their water solubilities analyzed by ultraviolet spectrophotometry showed that the introduction of odd-number carbon chains functionalized with 1,2,4-triazole led to significant increases of the hydrophilicity. Among them, the 1,3-propylene bridged one had the highest solubility of 13.87 mg/mL, which is 11 times higher than that of berberine, making it a promising prodrug with high bioavailability.

Key words: berberine, synthesis, nitrogen heterocyclic ring, ultraviolet spectrophotometry, organic compounds

摘要：

为了提高小檗碱的水溶性，增加其在体内的吸收和转运效率，以小檗碱为初始原料，经高温脱去C(9)位甲基，然后与二溴烷烃进行单边溴烷基化反应，再与苯并咪唑、1,2,4-三氮唑和吡唑经亲核取代反应制得了一系列氮杂环修饰的小檗碱衍生物（4～6）。除了化合物6a，所得衍生物均为新化合物，其结构经核磁氢谱/碳谱（¹H NMR/¹³C NMR）、电喷雾质谱[MS（ESI）]多重表征确认。随后，利用紫外分光光度法测定了部分衍生物在水中的溶解度，结果显示奇数链长烷基取代1,2,4-三氮唑的引入使小檗碱在水中的溶解度大幅度提升。其中，1,3-亚丙基桥连的1,2,4-三氮唑小檗碱衍生物的水溶性高达13.87mg/mL，是小檗碱的12倍，因此它是潜在的具有更高生物利用度的小檗碱药物前体。

关键词: 小檗碱, 合成, 氮杂环, 紫外分光光度法, 有机化合物

CLC Number:

O629.3

Qi MENG,Xinhui ZHU,Weihua JIANG,Qiaoqiao TENG. Synthesis of hydrophilic berberine derivatives modified with nitrogen heterocycles[J]. Chemical Industry and Engineering Progress, 2019, 38(11): 5066-5073.

孟启,朱信辉,蒋卫华,滕巧巧. 水溶性氮杂环修饰小檗碱衍生物的合成[J]. 化工进展, 2019, 38(11): 5066-5073.

Figures/Tables 8

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化合物	线性回归方程	R²
BBR	A=65.6919C-0.0213	0.9999
4a	A=47.4593C-0.0100	0.9999
4b	A=41.6400C+0.0090	0.9996
5a	A=44.7500C-0.0020	0.9998
5b	A=56.7317C-0.0084	0.9998
5c	A=48.4842C+0.0114	0.9990
5d	A=48.5794C-0.0333	0.9997
6a	A=62.4461C-0.0113	0.9996
6b	A=63.0220C+0.0050	0.9995

化合物	线性回归方程	R²
BBR	A=65.6919C-0.0213	0.9999
4a	A=47.4593C-0.0100	0.9999
4b	A=41.6400C+0.0090	0.9996
5a	A=44.7500C-0.0020	0.9998
5b	A=56.7317C-0.0084	0.9998
5c	A=48.4842C+0.0114	0.9990
5d	A=48.5794C-0.0333	0.9997
6a	A=62.4461C-0.0113	0.9996
6b	A=63.0220C+0.0050	0.9995

化合物	吸光度A	化合物	吸光度A
BBR	1.267	5c	0.994
4a	0.698	5d	1.909
4b	0.558	6a	1.498
5a	1.259	6b	0.984
5b	2.057	—	—

化合物	吸光度A	化合物	吸光度A
BBR	1.267	5c	0.994
4a	0.698	5d	1.909
4b	0.558	6a	1.498
5a	1.259	6b	0.984
5b	2.057	—	—

浓度 /mg?mL^-1	日内精密度		日间精密度
浓度 /mg?mL^-1	吸光度A	RSD/%	吸光度A	RSD/%
5	0.249	0.46	0.249	1.47
	0.242		0.231
	0.246		0.248
	0.240
	0.251
20	0.994	2.46	0.994	2.28
	0.969		0.953
	0.972		0.956
	0.976
	0.982
40	1.929	1.34	1.929	2.05
	1.907		1.909
	1.897		1.950
	1.910
	1.926