2. Academic Validation
  3. Synthesis of selective 11β-HSD1 inhibitors based on dammarane scaffold

Synthesis of selective 11β-HSD1 inhibitors based on dammarane scaffold

  • Eur J Med Chem. 2017 Jul 28:135:324-338. doi: 10.1016/j.ejmech.2017.04.059.
Li-Dong Shao 1,  Ying Bao 2,  Yu Shen 3,  Jia Su 1,  Ying Leng 4,  Qin-Shi Zhao 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China.
  • 2 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China; University of Chinese Academy of Science, Beijing 100049, China.
  • 3 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: yleng@simm.ac.cn.
  • 5 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China. Electronic address: qinshizhao@mail.kib.ac.cn.
PMID: 28458137 DOI: 10.1016/j.ejmech.2017.04.059
Abstract

Inspired by natural 11β-HSD1 inhibitors hupehenols A - E, a ring-focused strategy was applied for the synthesis of 35 structurally diverse dammarane-type derivatives. These derivatives were effectively prepared from protopanaxadiol based on the modification of rings A and D. Among these compounds, ten were identified as selective 11β-HSD1 inhibitors (IC50 range: 101-1047 nM, SI range: 8-169) which exhibited inhibitory activities against human or mouse 11β-HSD1. Otherwise, we found 23a could selectively inhibit both human and mouse 11β-HSD1 with IC50 value of 994 and 213 nM (SI > 10 and > 47), respectively. Additionally, the molecular modelling results of 23a docking into the human and mouse 11β-HSD1 were in good agreement with the results from the enzyme inhibitory experiment. Moreover, valuable structural-activity relationship (SAR) information of dammarane-type 11β-HSD1 inhibitor was summarized.

Keywords

11β-HSD1 inhibitor; Dammarane; Hupehenols; SAR.

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