Development and structure-activity relationships of tanshinones as selective 11β-hydroxysteroid dehydrogenase 1 inhibitors

doi:10.1007/s13659-022-00358-9

Natural Products and Bioprospecting ›› 2022, Vol. 12 ›› Issue (6): 36-36.DOI: 10.1007/s13659-022-00358-9

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Development and structure-activity relationships of tanshinones as selective 11β-hydroxysteroid dehydrogenase 1 inhibitors

Xu Deng^1,2, Su-Ling Huang³, Jian Ren¹, Zheng-Hong Pan^1,4, Yu Shen³, Hao-Feng Zhou¹, Zhi-Li Zuo¹, Ying Leng³, Qin-Shi Zhao¹

1 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China;
2 Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China;
3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
4 Guangxi Key Laboratory of Functional Phytochemicals Research and Utilization, Guangxi Institute of Botany, Chinese Academy of Sciences, Guilin 541006, China

Received:2022-07-20 Online:2022-12-23 Published:2022-12-24
Contact: Zhi-Li Zuo, E-mail: zuozhili@mail.kib.ac.cn;Ying Leng, E-mail: yleng@simm.ac.cn;Qin-Shi Zhao, E-mail: qinshizhao@mail.kib.ac.cn
Supported by:
We also thanked the National Natural Science Foundation of China (No. U1502223), Hunan Provincial Key Research and Development Project (Grant No. 2021WK2005 to X. Deng), Natural Science Foundation of Hunan Province (Grant No. 2021JJ30894 to X. Deng) and the open fund of State Key Laboratory of Phytochemistry and Plant Resource in West China (Grant No. P2020-KF03).

Development and structure-activity relationships of tanshinones as selective 11β-hydroxysteroid dehydrogenase 1 inhibitors

Xu Deng^1,2, Su-Ling Huang³, Jian Ren¹, Zheng-Hong Pan^1,4, Yu Shen³, Hao-Feng Zhou¹, Zhi-Li Zuo¹, Ying Leng³, Qin-Shi Zhao¹

1 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China;
2 Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China;
3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
4 Guangxi Key Laboratory of Functional Phytochemicals Research and Utilization, Guangxi Institute of Botany, Chinese Academy of Sciences, Guilin 541006, China

通讯作者: Zhi-Li Zuo, E-mail: zuozhili@mail.kib.ac.cn;Ying Leng, E-mail: yleng@simm.ac.cn;Qin-Shi Zhao, E-mail: qinshizhao@mail.kib.ac.cn
基金资助:
We also thanked the National Natural Science Foundation of China (No. U1502223), Hunan Provincial Key Research and Development Project (Grant No. 2021WK2005 to X. Deng), Natural Science Foundation of Hunan Province (Grant No. 2021JJ30894 to X. Deng) and the open fund of State Key Laboratory of Phytochemistry and Plant Resource in West China (Grant No. P2020-KF03).

Abstract

Abstract: 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) represents a promising drug target for metabolic syndrome, including obesity and type 2 diabetes. Our initial screen of a collection of natural products from Danshen led to the identification of tanshinones as the potent and selective 11β-HSD1 inhibitors. To improve the druggability and explore the structure-activity relationships (SARs), more than 40 derivatives have been designed and synthesized using tanshinone IIA and cryptotanshinone as the starting materials. More than 10 derivatives exhibited potent in vitro 11β-HSD1 inhibitory activity and good selectivity over 11β-HSD2 across human and mouse species. Based on the biological results, SARs were further discussed, which was also partially rationalized by a molecular docking model of 1 bound to the 11β-HSD1. Remarkably, compounds 1, 17 and 30 signifcantly inhibited 11β-HSD1 in 3T3-L1 adipocyte and in livers of ob/ob mice, which merits further investigations as anti-diabetic agents. This study not only provides a series of novel selective 11β-HSD1 inhibitors with promising therapeutic potentials in metabolic syndromes, but also expands the boundaries of the chemical and biological spaces of tanshinones.

Key words: Metabolic syndrome, Tanshinones, Selective 11β-HSD1 inhibitors, Structure-activity relationships

摘要： 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) represents a promising drug target for metabolic syndrome, including obesity and type 2 diabetes. Our initial screen of a collection of natural products from Danshen led to the identification of tanshinones as the potent and selective 11β-HSD1 inhibitors. To improve the druggability and explore the structure-activity relationships (SARs), more than 40 derivatives have been designed and synthesized using tanshinone IIA and cryptotanshinone as the starting materials. More than 10 derivatives exhibited potent in vitro 11β-HSD1 inhibitory activity and good selectivity over 11β-HSD2 across human and mouse species. Based on the biological results, SARs were further discussed, which was also partially rationalized by a molecular docking model of 1 bound to the 11β-HSD1. Remarkably, compounds 1, 17 and 30 signifcantly inhibited 11β-HSD1 in 3T3-L1 adipocyte and in livers of ob/ob mice, which merits further investigations as anti-diabetic agents. This study not only provides a series of novel selective 11β-HSD1 inhibitors with promising therapeutic potentials in metabolic syndromes, but also expands the boundaries of the chemical and biological spaces of tanshinones.

关键词: Metabolic syndrome, Tanshinones, Selective 11β-HSD1 inhibitors, Structure-activity relationships

Xu Deng, Su-Ling Huang, Jian Ren, Zheng-Hong Pan, Yu Shen, Hao-Feng Zhou, Zhi-Li Zuo, Ying Leng, Qin-Shi Zhao. Development and structure-activity relationships of tanshinones as selective 11β-hydroxysteroid dehydrogenase 1 inhibitors[J]. Natural Products and Bioprospecting, 2022, 12(6): 36-36.

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Development and structure-activity relationships of tanshinones as selective 11β-hydroxysteroid dehydrogenase 1 inhibitors

Development and structure-activity relationships of tanshinones as selective 11β-hydroxysteroid dehydrogenase 1 inhibitors

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