Open AccessLathyrane Diterpenoids as Novel hPXR Agonists: Isolation, Structural Modification, and Structure–Activity Relationships
Author(s) -
Dong Huang,
Ruimin Wang,
Wei Li,
Ying-Yuan Zhao,
Fang-Yu Yuan,
Xue-Long Yan,
Ye Chen,
GuiHua Tang,
Huichang Bi,
Sheng Yin
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00277
Subject(s) - isolation (microbiology) , computational biology , pharmacology , medicine , computer science , stereochemistry , chemistry , traditional medicine , bioinformatics , biology
Pregnane X receptor (PXR) that orchestrates the intricate network of xeno- and endobiotic metabolism is considered as a promising therapeutic target for cholestasis. In this study, the human PXR (hPXR) agonistic bioassay-guided isolation of Euphorbia lathyris followed by the structural modification led to the construction of a lathyrane diterpenoid library ( 1 - 34 ). Subsequent assay of this library led to the identification of a series of potent hPXR agonists, showing better efficacy than that of typical hPXR agonist, rifampicin. The most active compound, 8 , could dose-dependently activate hPXR at micromolar concentrations and significantly up-regulate the expressions of PXR downstream genes CYP3A4 , CYP2B6 , and MDR1 . The structure-activity relationships (SARs) studied in combination with molecular modeling suggested that acyloxy at C-7 and the presence of 14-carbonyl were essential to the activity. These findings suggested that lathyrane diterpenoids could serve as a new type of hPXR agonist for future anticholestasis drug development.