水溶性氮杂环修饰小檗碱衍生物的合成

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

摘要/Abstract

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

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

中图分类号:

O629.3

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.

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.

图/表 8

参考文献 18

1	杨庆珍, 郑司浩, 黄林芳. 小檗碱提取方法和药理活性研究进展[J]. 中国新药杂志, 2015, 24(5): 519-525.
	YANGQingzhen, ZHENGSihao, HUANGLinfang. Advance in extraction methods and pharmacological activities of berberine[J]. Chinese Journal of New Drugs, 2015, 24(5): 519-525.
2	韩谢, 邵开元, 胡文祥. 小檗碱结构修饰的研究进展[J]. 武汉工程大学学报, 2018, 40(1): 1-7.
	HANXie, SHAOKaiyuan, HUWenxiang. Advances in structural modification of berberine[J]. Journal of Wuhan Institute of Technology, 2018, 40(1): 1-7.
3	LO C Y, HSU L C, CHENM S, et al. Synthesis and anticancer activity of a novel series of 9-O-substituted berberine derivatives: a lipophilic substitute role[J]. Bioorganic & Medicinal Chemistry Letters, 2013, 23(1): 305-309.
4	TAOT, ZHAOY, WUJ, et al. Preparation and evaluation of itraconazole dihydrochloride for the solubility and dissolution rate enhancement[J]. International Journal of Pharmaceutics, 2009, 367(1): 109-114.
5	HANH K, CHOIH K. Improved absorption of meloxicam via salt formation with ethanolamines[J]. European Journal of Pharmaceutics & Biopharmaceutics, 2007, 65(1): 99-103.
6	陈竹, 曾雪, 张保顺, 等. 9-O-小檗碱葡萄糖苷在大鼠体内的药动学研究[J]. 中国药房, 2012, 23(27): 2501-2503.
	CHENZhu, ZENGXue, ZHANGBaoshun, et al. Pharmacokinetic study of 9-O-glucosyl-berberine in rats[J]. China Pharmacy, 2012, 23(27): 2501-2503.
7	CHENZ, YEX, YIJ, et al. Synthesis of 9-O-glycosyl-berberine derivatives and bioavailability evaluation[J]. Medicinal Chemistry Research, 2012, 21(8): 1641-1646.
8	ODAMEF, KRAUSEJ, HOSTENE C, et al. Synthesis, characterization and DPPH scavenging activity of some benzimidazole derivatives[J]. Bulletin of the Chemical Society of Ethiopia, 2018, 32(2): 271-284.
9	GOHERS S, GRIFFETTK, HEGAZYL, et al. Development of novel liver X receptor modulators based on a 1,2,4-triazole scaffold[J]. Bioorganic & Medicinal Chemistry Letters, 2019, 29: 449-453.
10	ZHANGW J, OU T M, LUY J, et al. 9-Substituted berberine derivatives as G-quadruplex stabilizing ligands in telomeric DNA[J]. Bioorganic & Medicinal Chemistry, 2007, 15(16): 5493-5501.
11	MAY, OU T M, TANJ H, et al. Synthesis and evaluation of 9-O-substituted berberine derivatives containing aza-aromatic terminal group as highly selective telomeric G-quadruplex stabilizing ligands[J]. Bioorganic & Medicinal Chemistry Letters, 2009, 19(13): 3414-3417.
12	HUANGM Y, LINJ, HUANGZ J, et al. Design, synthesis and anti-inflammatory effects of novel 9-O-substituted-berberine derivatives[J]. Medicinal Chemistry Communications, 2016, 7: 658-666.
13	PANGJ Y, QINY, CHENW H, et al. Synthesis and DNA-binding affinities of monomodified berberines[J]. Bioorganic & Medicinal Chemistry, 2005, 13(20): 5835-5840.
14	IWASAK, KAMIGAUCHIM, UEKIM, et al. Antibacterial activity and structure-activity relationships of berberine analogs[J]. European Journal of Medicinal Chemistry, 1996, 31(6): 469-478.
15	LONGY H, BAIL P, QINY, et al. Spacer length and attaching position-dependent binding of synthesized protoberberine dimers to double-stranded DNA[J]. Bioorganic & Medicinal Chemistry, 2006, 14(13): 4670-4676.
16	刘艳飞, 肖代鹏, 刘珍宝, 等. 一种小檗碱9-位吡唑衍生物及其制备和应用: CN108084177A[P]. 2018-05-29.
	LIUYanfei, XIAODaipeng, LIUZhenbao, et al. Berberine 9-site pyrazole derivative as well as preparation and application thereof: CN108084177A[P]. 2018-05-29.
17	张慧慧, 施洋, 张晓霞, 等. 安石榴苷平衡溶解度与油水分配系数的测定[J]. 新疆医科大学学报, 2018, 41(2): 225-228.
	ZHANGHuihui, SHIYang, ZHANGXiaoxia, et al. Determination of equilibrium solubility and apparent oil/water partition coefficient of punicalagin[J]. Journal of Xinjiang Medical University, 2018, 41(2): 225-228.
18	ZHANGH, XIEC, LIUZ, et al. Identification and molecular understanding of the odd-even effect of dicarboxylic acids aqueous solubility[J]. Industrial & Engineering Chemistry Research, 2013, 52(51): 18458-18465.

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