福司曲星不饱和内酯的基本作用及其对选择性蛋白磷酸酶抑制的影响。
Fundamental role of the fostriecin unsaturated lactone and implications for selective protein phosphatase inhibition.
作者信息
Buck Suzanne B, Hardouin Christophe, Ichikawa Satoshi, Soenen Danielle R, Gauss C-M, Hwang Inkyu, Swingle Mark R, Bonness Kathy M, Honkanen Richard E, Boger Dale L
机构信息
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
出版信息
J Am Chem Soc. 2003 Dec 24;125(51):15694-5. doi: 10.1021/ja038672n.
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.
制备并检测了福司曲星的关键衍生物和类似物，结果揭示了不饱和内酯的重要作用，并证实了磷酸单酯的本质特性。因此，无论是饱和内酯（7）还是缺乏整个内酯的类似物（15），对蛋白磷酸酶2A（PP2A）的抑制作用都出现了相同的200倍降低。归因于不饱和内酯的PP2A抑制作用增加200倍，这可能是由于PPβ12-β13活性位点环内的可逆C269烷基化，这解释了PP2A/4的效力和选择性。
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