Fundamental role of the fostriecin unsaturated lactone and implications for selective protein phosphatase inhibition.
Key derivatives and analogues of fostriecin were prepared and examined that revealed a fundamental role for the unsaturated lactone and confirmed the essential nature of the phosphate monoester. Thus, an identical 200-fold reduction in protein phosphatase 2A (PP2A) inhibition is observed with either the saturated lactone (7) or with an analogue that lacks the entire lactone (15). This 200-fold increase in PP2A inhibition attributable to the unsaturated lactone potentially may be due to reversible C269 alkylation within the PP beta12-beta13 active site loop accounting for PP2A/4 potency and selectivity.
Buck
Suzanne B
SB
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Hardouin
Christophe
C
Ichikawa
Satoshi
S
Soenen
Danielle R
DR
Gauss
C-M
CM
Hwang
Inkyu
I
Swingle
Mark R
MR
Bonness
Kathy M
KM
Honkanen
Richard E
RE
Boger
Dale L
DL
D000475:Alkenes / Q000737:chemistry / Q000494:pharmacology*; D000595:Amino Acid Sequence; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology; D008969:Molecular Sequence Data; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D011090:Polyenes; D011753:Pyrones; D013329:Structure-Activity Relationship
D000475:Alkenes; D004791:Enzyme Inhibitors; D007783:Lactones; D011090:Polyenes; D011753:Pyrones; D010749:Phosphoprotein Phosphatases; C040313:fostriecin