16-nor Limonoids from Harrisonia perforata as promising selective 11β-HSD1 inhibitors.
Two new 16-nor limonoids, harperspinoids A and B (1 and 2), with a unique 7/5/5/6/5 ring system, have been isolated from the plant Harrisonia perforate together with a known one, Harperforin G (3). Their structures were elucidated by NMR spectroscopy, X-ray diffraction analysis and computational modelling. Compound 1 exists as polymorphic crystals. Conformations of 1 in solution were further discussed based on the computational results. These compounds exhibited notable inhibitory activity against the 11β-HSD1 enzyme. Compound 3 had potencies for the inhibition of human 11β-HSD1 with high selectivity against 11β-HSD2 (IC500.58 μM, SI > 174). Molecular docking and quantitative structure-activity relationship studies revealed a mixed regulatory mechanism.
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, P. R. China.|College of Forestry, Southwest Forestry University/Key Laboratory of Forest Disaster Warning and Control of Yunnan Province, Kunming 650224, P. R. China.
Xiao-Hui
XH
Yan
Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550002, P. R. China.
Ping
P
Yi
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, P. R. China.
Pei
P
Cao
Beijing Key Laboratory of Polymorphic Drugs, Institute of Materia Medica, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100050, P. R. China.
Shi-Ying
SY
Yang
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, P. R. China.
Xin
X
Fang
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, P. R. China.
Yu
Y
Zhang
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, P. R. China.
Bin Wu
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, P. R. China.
Ying
Y
Leng
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, P. R. China.
Ying-Tong
YT
Di
Beijing Key Laboratory of Polymorphic Drugs, Institute of Materia Medica, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100050, P. R. China.
Yang
Y
Lv
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, P. R. China.
Xiao-Jiang
XJ
Hao
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D036701:Limonins / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D029641:Simaroubaceae / Q000737:chemistry*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D036701:Limonins; D010936:Plant Extracts; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2