Design, Synthesis and Biological Evaluation of Novel Thiazole-Fused Glaucocalyxin A Derivatives

doi:10.6023/cjoc202101058

Chinese Journal of Organic Chemistry ›› 2021, Vol. 41 ›› Issue (6): 2393-2400.DOI: 10.6023/cjoc202101058 Previous Articles Next Articles

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新型蓝萼甲素-噻唑类衍生物的设计、合成与生物学评价

张涛^a, 李念先^a, 周楠茜^b, 马雯^a, 卫海沅^a, 张冰欣^a, 陈亮辉^a, 海广范^a, 段迎超^a, 白素平^a^,^*()

a 新乡医学院药学院河南新乡 453003
b 河南省人民医院超声科郑州 453003

收稿日期:2021-01-31 修回日期:2021-02-26 发布日期:2021-03-04
通讯作者: 白素平
基金资助:
国家自然科学基金(21672182); 河南省科技攻关(212102311026); 国家大学生创新创业训练计划(202010472018)

Design, Synthesis and Biological Evaluation of Novel Thiazole-Fused Glaucocalyxin A Derivatives

Tao Zhang^a, Nianxian Li^a, Nanqian Zhou^b, Wen Ma^a, Haiyuan Wei^a, Bingxin Zhang^a, Lianghui Chen^a, Guangfan Hai^a, Yingchao Duan^a, Suping Bai^a()

a School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003
b Department of Ultrasonography, Henan Provincial Peopleʼs Hospital, Zhengzhou 450003

Received:2021-01-31 Revised:2021-02-26 Published:2021-03-04
Contact: Suping Bai
Supported by:
National Natural Science Foundation of China(21672182); Science and Technology Tackling Key Project of Henan Province(212102311026); National Undergraduate Training Program for Innovation and Entrepreneurship(202010472018)

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Abstract

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

Cite this article

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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References 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

新型蓝萼甲素-噻唑类衍生物的设计、合成与生物学评价

Design, Synthesis and Biological Evaluation of Novel Thiazole-Fused Glaucocalyxin A Derivatives

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