Cantharimides: A new class of modified cantharidin analogues inhibiting protein phosphatases 1 and 2A

• Published in: Bioorganic & medicinal chemistry letters 2001-11, Vol.11 (22), p.2941-2946
• Main Authors: McCluskey, Adam, Walkom, Cecilia, Bowyer, Michael C, Ackland, Stephen P, Gardiner, Emma, Sakoff, Jennette A
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Biological and medical sciences; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Cantharidin - analogs & derivatives; Cantharidin - chemical synthesis; Cantharidin - pharmacology; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Histidine - chemistry; Hydrolases; Medical sciences; Miscellaneous; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Phosphoprotein Phosphatases - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(01)00594-7

Cantharidin and its analogues have been of considerable interest as potent inhibitors of the serine/threonine protein phosphatases 1 and 2A (PP1 and PP2A). However, limited modifications to the parent compounds is tolerated. As part of an on-going study we have developed a new series of cantharidin analogues, the cantharimides. Inhibition studies indicate that cantharimides possessing a d- or l-histidine, are more potent inhibitors of PP1 and PP2A (PP1 IC 50=3.22±0.7 μM; PP2A IC 50=0.81±0.1 μM and PP1 IC 50=2.82±0.6 μM; PP2A IC 50=1.35±0.3 μM, respectively) than norcantharidin (PP1 IC 50=5.31±0.76 μM; PP2A IC 50=2.9±1.04 μM) and essentially equipotent with cantharidin (PP1 IC 50=3.6±0.42 μM; PP2A IC 50=0.36±0.08 μM). Cantharimides with non-polar or acidic amino acid residues are only poor inhibitors of PP1 and PP2A. A new series of cantharidin analogues, the cantharidiimides has been synthesised. Inhibition studies indicate that cantharidiimides possessing a d- or l-histidine, are more potent inhibitors of PP1 and PP2A (PP1 IC 50=3.22±0.7 μM; PP2A IC 50=0.81 μM and PP1 IC 50=2.82±0.6 μM; PP2A IC 50=1.35±0.3 μM, respectively) than norcantharidin (PP1 IC 50=5.31±0.76 μM; PP2A IC 50=2.9±1.04 μM) and essentially equipotent with cantharidin (PP1 IC 50=3.6±0.42 μM; PP2A IC 50=0.36±0.08 μM).