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Development and structure-activity relationships of tanshinones as selective 11β-hydroxysteroid dehydrogenase 1 inhibitors |
| Xu Deng1,2, Su-Ling Huang3, Jian Ren1, Zheng-Hong Pan1,4, 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 |
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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.
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Metabolic syndrome, Tanshinones, Selective 11β-HSD1 inhibitors, Structure-activity relationships
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| Fund: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). |
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Corresponding Authors:
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
E-mail: zuozhili@mail.kib.ac.cn; yleng@simm.ac.cn; qinshizhao@mail.kib.ac.cn
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Issue Date: 23 December 2022
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