Design, Synthesis and Cardioprotection of Cryptotanshinone Derivatives

doi:10.6023/cjoc202110004

Chinese Journal of Organic Chemistry ›› 2022, Vol. 42 ›› Issue (6): 1735-1746.DOI: 10.6023/cjoc202110004 Previous Articles Next Articles

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隐丹参酮衍生物的设计、合成及心肌保护作用

孟方凤^a, 周佳慧^a, 程鑫涛^a, 许佳慧^a, 康磊^a, 李蝶^a, 王东浩^a, 毕跃峰^a^,^b^,^*()

a 郑州大学药学院郑州 450001
b 药物关键制备技术教育部重点实验室郑州 450001

收稿日期:2021-10-03 修回日期:2021-12-27 发布日期:2022-03-03
通讯作者: 毕跃峰
作者简介:
† 共同第一作者
基金资助:
河南省自然科学基金(182300410348)

Design, Synthesis and Cardioprotection of Cryptotanshinone Derivatives

Fangfeng Meng^a, Jiahui Zhou^a, Xintao Cheng^a, Jiahui Xu^a, Lei Kang^a, Die Li^a, Donghao Wang^a, Yuefeng Bi^a^,^b()

a School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001
b Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou 450001

Received:2021-10-03 Revised:2021-12-27 Published:2022-03-03
Contact: Yuefeng Bi
About author:
† These authors contributed equally to this work
Supported by:
Natural Science Foundation of Henan Province(182300410348)

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Abstract

Cryptotanshinone (CT) is the major lipid-soluble component of Salvia miltiorrhiza, which has myocardial protection and antioxidant effects. To improve its polarity, activity and targets, CT was hybridized with salvianolic acids, the water-soluble active component in salvia miltiorrhiza, and its analogues at its 1 site. A total of 42 derivatives were synthesized, all of which are new compounds. Compared with CT, the polarities of the derivatives were improved. The cardioprotective effects of derivatives were preliminarily evaluated by hypoxia/reoxygenation injury (HRI) model in vitro. The results showed that the activities of most derivatives were enhanced compared with CT, and 6 compounds showed significant effects. Sirtuin 1 (SIRT1) high-throughput activity screening platform and molecular docking technology were used to explore the possible mechanism preliminarily. Structure-activity relationship studies showed that the product activity of 1-position R configuration was better than that of S-configuration, and the activity of aromatic acid derivatives with electron-donating substituents was better than that of with electron-absorbing substituents.

Key words: cryptotanshinone, aromatic acid, hybridization, myocardial protection

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Fangfeng Meng, Jiahui Zhou, Xintao Cheng, Jiahui Xu, Lei Kang, Die Li, Donghao Wang, Yuefeng Bi. Design, Synthesis and Cardioprotection of Cryptotanshinone Derivatives[J]. Chinese Journal of Organic Chemistry, 2022, 42(6): 1735-1746.

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Fig. & Tab. 8

References 27

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Compound	Log P	Compound	Log P
CT	1.22	8R	1.12
1S	1.11	13S	0.91
1R	0.97	13R	0.49
2R	0.69	17S	0.85
3S	0.61	17R	1.03
3R	0.95	21S	1.11
4R	1.15	21R	0.74
6S	0.47	23S	0.66
6R	0.99	23R	0.78
8S	0.82

Compound	Log P	Compound	Log P
CT	1.22	8R	1.12
1S	1.11	13S	0.91
1R	0.97	13R	0.49
2R	0.69	17S	0.85
3S	0.61	17R	1.03
3R	0.95	21S	1.11
4R	1.15	21R	0.74
6S	0.47	23S	0.66
6R	0.99	23R	0.78
8S	0.82

Product	Yield^a/%	Product	Yield^a/%
1S, 1R	45.2	13S, 13R	79.9
2S, 2R	60.9	14S, 14R	53.2
3S, 3R	81.2	15S, 15R	63.0
4S, 4R	66.5	16S, 16R	46.0
5	68.3	17S, 17R	50.3
6S, 6R	41.1	18S, 18R	39.0
7S, 7R	54.0	19S, 19R	49.9
8S, 8R	52.0	20S, 20R	51.8
9S, 9R	42.7	21S, 21R	47.8
10S, 10R	47.0	22	22.5
11	48.3	23S, 23R	15.5
12	33.6

Product	Yield^a/%	Product	Yield^a/%
1S, 1R	45.2	13S, 13R	79.9
2S, 2R	60.9	14S, 14R	53.2
3S, 3R	81.2	15S, 15R	63.0
4S, 4R	66.5	16S, 16R	46.0
5	68.3	17S, 17R	50.3
6S, 6R	41.1	18S, 18R	39.0
7S, 7R	54.0	19S, 19R	49.9
8S, 8R	52.0	20S, 20R	51.8
9S, 9R	42.7	21S, 21R	47.8
10S, 10R	47.0	22	22.5
11	48.3	23S, 23R	15.5
12	33.6

Compd.	Relative cardiomyo- cyte viability	Compd.	Relative cardiomyo- cyte viability
Normal group	1.000±0.009	10R	0.748±0.040
Model group	0.641±0.034	13S	0.811±0.015##
CT	0.778±0.035#	13R	0.785±0.044#
1S	0.885±0.036#	14S	0.675±0.043
1R	0.879±0.014##	14R	0.690±0.022
2S	0.929±0.053#	15S	0.666±0.030
2R	0.947±0.060##	15R	0.664±0.036
3S	0.952±0.054##	16	0.774±0.028#
3R	0.874±0.043##	17S	0.750±0.022#
4S	0.894±0.072#	17R	0.830±0.039#
4R	0.943±0.061##	18S	0.798±0.040#
5	0.880±0.063#	18R	0.729±0.034
6S	0.791±0.044#	19S	0.632±0.047
6R	0.913±0.121#	19R	0.634±0.016
7S	0.871±0.057#	20S	0.607±0.106
7R	0.881±0.066#	20R	0.622±0.023
8S	0.838±0.064#	21S	0.663±0.029
8R	0.646±0.045	21R	0.721±0.051
9S	0.692±0.046	23S	0.735±0.032#
9R	0.610±0.035	23R	0.637±0.025
10S	0.657±0.030

隐丹参酮衍生物的设计、合成及心肌保护作用

Design, Synthesis and Cardioprotection of Cryptotanshinone Derivatives

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