Poligapolide, a PI3K/Akt Inhibitor in Immunodeficiency Virus Type 1 TAT-Transduced CHME5 Cells, Isolated from the Rhizome of Polygala tenuifolia

• Published in: Chemical & pharmaceutical bulletin Vol. 62; no. 5; pp. 467 - 471
• Main Authors: Yoo, Sul-Young, Le, Thi Kim Van, Jeong, Jin Ju, Kim, Dong-Hyun
• Format: Journal Article
• Language: English; Japanese
• Published: TOKYO The Pharmaceutical Society of Japan 2014; Pharmaceutical Society of Japan; Pharmaceutical Soc Japan; Japan Science and Technology Agency
• Subjects: Akt inhibitor; Cell Line; Cell Survival - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Cycloheximide - antagonists & inhibitors; Cycloheximide - pharmacology; Dose-Response Relationship, Drug; Human immunodeficiency virus 1; Humans; immunodeficiency virus type 1; Lactones - chemistry; Lactones - isolation & purification; Lactones - pharmacology; Life Sciences & Biomedicine; Lipopolysaccharides - antagonists & inhibitors; Lipopolysaccharides - pharmacology; Molecular Structure; Pharmacology & Pharmacy; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Physical Sciences; poligapolide; Polygala; Polygala - chemistry; Polygala tenuifolia; Polygalaceae; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - isolation & purification; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Rhizome - chemistry; Science & Technology; Signal Transduction - drug effects; Structure-Activity Relationship; tat Gene Products, Human Immunodeficiency Virus - genetics; tat Gene Products, Human Immunodeficiency Virus - metabolism; poligapolide; Polygalaceae; Akt inhibitor; MACROPHAGES; Polygala tenuifolia; immunodeficiency virus type 1; AKT
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c13-00958

The rhizome of Polygala tenuifolia WILLD (PT, family Polygalaceae) has been used in traditional Chinese medicine for inflammation, dementia, amnesia, neurasthenia and cancer. The phosphoinositide 3-kinase (PI3K)/Akt inhibitor(s) was isolated from PT by using the cytoprotective phenotype of human immunodeficiency virus type 1 (HIV-1) Tat-transduced CHME5 cells against lipopolysaccharide/cycloheximide. We isolated 9 constituents (1)–(9) from ethyl acetate fraction of PT, which potently showed anti-cytoprotective effect against HIV-1 TAT-transduced cells. Of them, (9R)-(−)-9-peptandecanolide (2), a new compound named poligapolide, most potently abolished the cytoprotective effect of HIV-1 Tat-transduced CHME5 cells. The compound (2) inhibited the phosphorylation of Akt and its downstream molecule, glycogen synthase kinase-3 beta (GSK3β) in PI3K/Akt cell survival signaling pathway, but did not suppress the phosphorylation of PI3K and pyruvate dehydrogenase lipoamide kinase isozyme 1. Based on these finding, poligapolide may abolish the cytoprotective phenotype of HIV-1 Tat-transduced CHME5 cells by inhibiting Akt phosphorylation in PI3K/Akt pathway.