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

Li-Dong Shao; Ying Bao; Yu Shen; Jia Su; Ying Leng; Qin-Shi Zhao

doi:10.1016/j.ejmech.2017.04.059

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. Epub 2017 Apr 23.

Authors

Li-Dong Shao¹, Ying Bao², Yu Shen³, Jia Su¹, Ying Leng⁴, Qin-Shi Zhao⁵

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.

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
Animals
Dammaranes
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
HEK293 Cells
Humans
Mice
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Triterpenes / chemical synthesis
Triterpenes / chemistry
Triterpenes / pharmacology*

Substances

Enzyme Inhibitors
Triterpenes
11-beta-Hydroxysteroid Dehydrogenase Type 1