Structure assignment, total synthesis, and evaluation of the phosphatase modulating activity of glucolipsin A.
The previously unknown stereostructure of glucolipsin A (1), a complex glycolipid endowed with glucokinase-activating properties, was unambiguously elucidated as (2R,2'R,3S,3'S) by comparison of its spectroscopic and analytical data with those of all conceivable C(2)-symmetric stereoisomers. This set of macrodiolides was prepared by a sequence comprising auxiliary guided aldol reactions, glycosidation of the resulting beta-hydroxy acid derivatives with trichloroacetimidate 7, followed by hydrolytic cleavage of the auxiliaries used. The hydroxy acids thus formed were subjected to a macrodilactonization reaction mediated by 2-chloro-1,3-dimethylimidazolinium chloride (22) as the activating agent; this transformation is highly productive only in the presence of admixed potassium cations which likely serve as templates to preorganize two substrate molecules in a favorable head-to-tail arrangement. Glucolipsin and analogues were subjected to enzymatic assays that revealed that glycoconjugates of this type effectively inhibit the activity of the dual specific phosphatase Cdc25A with IC(50) values in the low micromolar range, while being hardly active against the tyrosine phosphatase PTP1B in vitro. This activity profile was compared to that of other glycolipids previously prepared in this laboratory, including cycloviracin B(1) (2), caloporoside (38), woodrosin I (39), sophorolipid lactone (40), and tricolorin G (41).
Fürstner
Alois
A
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mülheim/Ruhr, Germany. fuerstner@mpi-muelheim.mpg.de
Ruiz-Caro
Juliana
J
Prinz
Heino
H
Waldmann
Herbert
H
D004187:Disaccharides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*
D004187:Disaccharides; D004791:Enzyme Inhibitors; C119399:glucolipsin-A; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases