Synthesis of 20S-protopanaxadiol β-D-galactopyranosides
20S-Protopanaxadiol (3β,12β,20S-trihydroxydammar-24-ene) 3-, 12-, and 20-O-β-D-galactopyranosides were synthesized for the first time. Condensation of 12β-acetoxy-3β,20S-dihydroxydammar-24-ene (1) and 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosylbromide (α-acetobromogalactose) (2) under Koenigs–Knorr conditions with subsequent removal of the protecting groups resulted in regio- and stereoselective formation of 20S-protopanaxadiol 3-O-β-D-galactopyranoside, an analog of the natural ginsenoside Rh2. Glycosylation of 12β,20S-dihydroxydammar-24-en-3-one (5) by 2 with subsequent treatment of the reaction products with NaBH4 in isopropanol and deacetylation with NaOMe gave 20S-protopanaxadiol 12- and 20-O-β-Dgalactopyranosides.
The ginsenoside metabolite compound K, a novel agonist of glucocorticoid receptor, induces tolerance to endotoxin-induced lethal shock
Compound K (C‐K), a protopanaxadiol ginsenoside metabolite, was previously shown to have immunomodulatory effects. Here, we describe a novel therapeutic role for C‐K in the treatment of lethal sepsis through the modulation of Toll‐like receptor (TLR) 4‐associated signalling via glucocorticoid receptor (GR) binding. In mononuclear phagocytes, C‐K significantly repressed the activation of TLR4/lipopolysaccharide (LPS)‐induced NF‐κB and mitogen‐activated protein kinases (MAPKs), as well as the secretion of pro‐inflammatory cytokines. However C‐K did not affect the TLR3‐mediated expression of interferon‐β or the nuclear translocation of IRF‐3. C‐K competed with the synthetic glucocorticoid dexamethasone for binding to GR and activated glucocorticoid responsive element (GRE)‐containing reporter plasmids in a dose‐dependent manner. In addition, the blockade of GR with either the GR antagonist RU486 or a siRNA against GR substantially reversed the anti‐inflammatory effects of C‐K. Furthermore, TLR4‐dependent repression of inflammatory response genes by C‐K was mediated through the disruption of p65/interferon regulatory factor complexes. Importantly, pre‐ or post‐treatment with C‐K significantly rescued mice from Gram‐negative bacterial LPS‐induced lethal shock by lowering their systemic inflammatory cytokine levels and by reversing the lethal sequelae of sepsis. Collectively, these results demonstrate that C‐K, as a functional ligand of GR, regulates distinct TLR4‐mediated inflammatory responses, and suggest a novel therapy for Gram‐negative septic shock.
Glucocorticoid action and novel mechanisms of steroid resistance: role of glucocorticoid receptor-interacting proteins for glucocorticoid responsiveness.
Glucocorticoids are widely used to treat inflammatory and malignant diseases. However, many individuals show a lack of therapeutic response and unwanted side-effects. Various known and unknown parameters determine glucocorticoid responsiveness, among them glucocorticoid receptor (GR)-interacting proteins. Several of the proteins interacting with GR also participate in other signal transduction pathways such as the AP-1 pathway and the nuclear factor-kappaB pathway. We suggest that a closer study of GR-interacting proteins may shed new light on mechanisms determining glucocorticoid sensitivity. In this commentary, the general mechanisms of GR action will be addressed and a proteomic-based method to study GR-interacting proteins will be described in brief.