Fundamental Role of the Fostriecin Unsaturated Lactone and Implications for Selective Protein Phosphatase Inhibition

• Published in: Journal of the American Chemical Society 2003-12, Vol.125 (51), p.15694-15695
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Alkenes - chemistry; Alkenes - pharmacology; Amino Acid Sequence; Antineoplastic agents; Biological and medical sciences; Chemistry; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Exact sciences and technology; General aspects; Lactones - chemistry; Lactones - pharmacology; Medical sciences; Molecular Sequence Data; Organic chemistry; Organometalloidal and organometallic compounds; P derivatives; Pharmacology. Drug treatments; Phosphoprotein Phosphatases - antagonists & inhibitors; Polyenes; Preparations and properties; Pyrones; Structure-Activity Relationship
• ISSN: 0002-7863; 1520-5126
• 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 β12−β13 active site loop accounting for PP2A/4 potency and selectivity.