title: Cantharimides: a new class of modified cantharidin analogues inhibiting protein phosphatases 1 and 2A.
abstract: 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 microM; PP2A IC(50)=0.81+/-0.1 microM and PP1 IC(50)=2.82+/-0.6 microM; PP2A IC(50)=1.35+/-0.3 microM, respectively) than norcantharidin (PP1 IC(50)=5.31+/-0.76 microM; PP2A IC(50)=2.9+/-1.04 microM) and essentially equipotent with cantharidin (PP1 IC(50)=3.6+/-0.42 microM; PP2A IC(50)=0.36+/-0.08 microM). Cantharimides with non-polar or acidic amino acid residues are only poor inhibitors of PP1 and PP2A.
authors.affiliation: Medicinal Chemistry Group, School of Biological and Chemical Sciences, The University of Newcastle, Callaghan, NSW 2038, Australia. amcclusk@mail.newcastle.edu.au
authors.forename: A
authors.initials: A
authors.lastname: McCluskey
authors.forename: C
authors.initials: C
authors.lastname: Walkom
authors.forename: M C
authors.initials: MC
authors.lastname: Bowyer
authors.forename: S P
authors.initials: SP
authors.lastname: Ackland
authors.forename: E
authors.initials: E
authors.lastname: Gardiner
authors.forename: J A
authors.initials: JA
authors.lastname: Sakoff
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry; D002193:Cantharidin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006639:Histidine / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D006639:Histidine; C069741:norcantharidin; D010749:Phosphoprotein Phosphatases; D002193:Cantharidin