Chlorocyclinones A-D, chlorinated angucyclinones from Streptomyces sp. strongly antagonizing rosiglitazone-induced PPAR-gamma activation.
In the course of our screening to identify novel PPAR-gamma modulators for the potential treatment of type 2 diabetes, four new chlorinated angucyclinones, chlorocyclinones A-D ( 1- 4), were isolated from the mycelium of Streptomyces sp. strain DSM 17045. Their structures were established by spectroscopic methods. Chlorocyclinones antagonize rosiglitazone-induced peroxisome proliferator-activated receptor gamma (PPAR-gamma) activation with IC 50's < 0.4 microM in vitro using an AlphaScreen assay and are able to displace rosiglitazone from the PPAR-gamma ligand-binding domain (LBD) in a scintillation proximity assay (SPA). The compounds proved to be active in a cell-based reporter gene assay as well, antagonizing rosiglitazone-induced PPAR-gamma activity with IC 50 values between 0.60 and 7.0 microM. Chlorocyclinone C ( 3) exhibited the most potent activity in all assays.
Potterat
Olivier
O
Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, D-88397, Biberach an der Riss, Germany. olivier.potterat@unibas.ch
Puder
Carsten
C
Wagner
Klaus
K
Bolek
Walter
W
Vettermann
Regine
R
Kauschke
Stefan G
SG
D000880:Anthraquinones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D047495:PPAR gamma / Q000187:drug effects*; D000077154:Rosiglitazone; D013302:Streptomyces / Q000737:chemistry*; D045162:Thiazolidinediones / Q000493:pharmacokinetics / Q000494:pharmacology*
D000880:Anthraquinones; D006843:Hydrocarbons, Chlorinated; D047495:PPAR gamma; D045162:Thiazolidinediones; C510997:angucyclinone; C526825:chlorocyclinone C; D000077154:Rosiglitazone; D008156:Luciferases