新型蓝萼甲素-噻唑类衍生物的设计、合成与生物学评价

doi:10.6023/cjoc202101058

摘要/Abstract

蓝萼甲素(Glaucocalyxin A, GLA)是从蓝萼香茶菜中分离得到的四环二萜类活性天然产物. 设计并合成了一系列基于蓝萼甲素的噻唑类衍生物, 评估了它们对六种肿瘤细胞(HepG2, NCI-H460, JEG-3, K562, HL-60和Hela)的增殖抑制活性. 结果表明在GLA的A环上引入氨基噻唑结构可以显著提高其细胞增殖抑制活性, 尤其是N-烷基氨基噻唑类衍生物对六种肿瘤细胞都表现出较好的抑制活性. 其中, 化合物6和8对HL-60和Hela细胞的抑制活性都优于阳性药物阿霉素, IC₅₀低至0.51 µmol•L ^–1. 形态学和流式细胞仪的测定表明蓝萼甲素-噻唑类化合物可以诱导肿瘤细胞凋亡.

关键词: 蓝萼甲素, 噻唑衍生物, 抗肿瘤

Glaucocalyxin A (GLA) is an active natural tetracyclic diterpenoid isolated from the traditional Chinese herb Isodon glaucocalyx (maxin) Hara. In this work, a series of thiazole type derivatives based on GLA were designed and prepared. Their antiproliferative activities against six tumor cell lines (HepG2, NCI-H460, JEG-3, K562, HL-60 and Hela) were evaluated in-vitro. The results revealed that the introduction of aminothiazole substructures into A-ring of the GLA could improve their antiproliferative effects significantly. Among them,N-alkyl thiazole derivatives showed remarkably activities to the six tumor cell lines. Especially, compounds6and8presented significant antitumor activities against HL-60 and Hela cell lines with IC₅₀ as low as 0.51 µmol•L ^–1, which were better than the positive drug adriamycin. The apoptosis morphology and flow cytometry studies indicated that the thiazole-fused GLA derivatives could induce apoptosis of tumor cells.

Key words: glaucocalyxin A, thiazole, antitumor

引用此文

张涛, 李念先, 周楠茜, 马雯, 卫海沅, 张冰欣, 陈亮辉, 海广范, 段迎超, 白素平. 新型蓝萼甲素-噻唑类衍生物的设计、合成与生物学评价[J]. 有机化学, 2021, 41(6): 2393-2400.

Tao Zhang, Nianxian Li, Nanqian Zhou, Wen Ma, Haiyuan Wei, Bingxin Zhang, Lianghui Chen, Guangfan Hai, Yingchao Duan, Suping Bai. Design, Synthesis and Biological Evaluation of Novel Thiazole-Fused Glaucocalyxin A Derivatives[J]. Chinese Journal of Organic Chemistry, 2021, 41(6): 2393-2400.

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参考文献 26

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Entry	Compd.	Reaction conditions^a	Yield/%
1	1	PyHBr₃ (1.2 equiv.), THF, 0 ℃, 1 h	51
2	1	PyHBr₃ (1.2 equiv.), THF, –20 ℃, 12 h	36
3	1	PyHBr₃ (1.2 equiv.), THF, 20 ℃, 1 h	41
4	1	PyHBr₃(1.5 equiv.), THF, 0 ℃, 1 h	30
5	1	PyHBr₃ (1.1 equiv.), THF, 0 ℃, 0.5 h	56
6	1	NBS (1.2 equiv.), THF, 0 ℃, 12 h	<10
7	3	PyHBr₃ (1.1 equiv.), THF, 0 ℃, 12 h	40
8	3	NBS (1.2 equiv.), THF, 0 ℃, Et₃N, 12 h	<10
9	3	PyHBr₃ (1.0 equiv.), THF, 20 ℃, 6 h	32

Entry	Compd.	Reaction conditions^a	Yield/%
1	1	PyHBr₃ (1.2 equiv.), THF, 0 ℃, 1 h	51
2	1	PyHBr₃ (1.2 equiv.), THF, –20 ℃, 12 h	36
3	1	PyHBr₃ (1.2 equiv.), THF, 20 ℃, 1 h	41
4	1	PyHBr₃(1.5 equiv.), THF, 0 ℃, 1 h	30
5	1	PyHBr₃ (1.1 equiv.), THF, 0 ℃, 0.5 h	56
6	1	NBS (1.2 equiv.), THF, 0 ℃, 12 h	<10
7	3	PyHBr₃ (1.1 equiv.), THF, 0 ℃, 12 h	40
8	3	NBS (1.2 equiv.), THF, 0 ℃, Et₃N, 12 h	<10
9	3	PyHBr₃ (1.0 equiv.), THF, 20 ℃, 6 h	32

Compd.	IC₅₀^a (µmol•L^–1)
Compd.	Hep G2	NCI-H460	JEG-3	K562	HL-60	HeLa
5	3.97±0.09	5.27±0.21	5.19±0.06	10.12±0.20	2.40±0.15	2.33±0.11
6	3.08±0.06	4.07±0.15	1.13±0.14	5.63±0.48	0.82±0.03	0.56±0.02
7	3.20±0.30	3.31±0.24	2.13±0.37	4.00±0.21	0.84±0.06	2.17±0.06
8	1.81±0.01	2.47±0.25	3.04±0.09	3.25±0.09	0.90±0.06	0.51±0.05
9	2.53±0.13	3.35±0.18	3.70±0.12	4.08±0.29	1.19±0.04	2.19±0.04
10	4.14±0.37	3.95±0.16	6.03±0.67	7.33±0.72	1.50±0.10	2.02±0.08
11	6.66±0.53	8.07±0.34	18.81±1.92	6.54±0.41	3.31±0.15	4.47±0.03
12	3.15±0.08	3.18±0.26	4.97±0.46	6.03±0.30	2.02±0.09	2.12±0.11
13	10.70±0.29	9.69±0.40	9.71±0.21	9.72±0.54	3.09±0.19	5.28±0.03
14	5.17±0.34	4.83±0.04	6.28±0.10	22.49±0.75	2.42±0.11	2.49±0.05
GLA	3.94±0.07	8.99±0.18	4.25±0.08	7.20±0.17	6.46±0.05	8.19±1.96
Adriamycin	0.50±0.01	1.73±0.02	0.52±0.02	5.15±0.11	1.73±0.02	0.69±0.01

Compd.	IC₅₀^a (µmol•L^–1)
Compd.	Hep G2	NCI-H460	JEG-3	K562	HL-60	HeLa
5	3.97±0.09	5.27±0.21	5.19±0.06	10.12±0.20	2.40±0.15	2.33±0.11
6	3.08±0.06	4.07±0.15	1.13±0.14	5.63±0.48	0.82±0.03	0.56±0.02
7	3.20±0.30	3.31±0.24	2.13±0.37	4.00±0.21	0.84±0.06	2.17±0.06
8	1.81±0.01	2.47±0.25	3.04±0.09	3.25±0.09	0.90±0.06	0.51±0.05
9	2.53±0.13	3.35±0.18	3.70±0.12	4.08±0.29	1.19±0.04	2.19±0.04
10	4.14±0.37	3.95±0.16	6.03±0.67	7.33±0.72	1.50±0.10	2.02±0.08
11	6.66±0.53	8.07±0.34	18.81±1.92	6.54±0.41	3.31±0.15	4.47±0.03
12	3.15±0.08	3.18±0.26	4.97±0.46	6.03±0.30	2.02±0.09	2.12±0.11
13	10.70±0.29	9.69±0.40	9.71±0.21	9.72±0.54	3.09±0.19	5.28±0.03
14	5.17±0.34	4.83±0.04	6.28±0.10	22.49±0.75	2.42±0.11	2.49±0.05
GLA	3.94±0.07	8.99±0.18	4.25±0.08	7.20±0.17	6.46±0.05	8.19±1.96
Adriamycin	0.50±0.01	1.73±0.02	0.52±0.02	5.15±0.11	1.73±0.02	0.69±0.01