Please use this identifier to cite or link to this item: http://hdl.handle.net/1959.13/33630

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Title
Synthesis and biological evaluation of norcantharidin analogues: towards PP1 selectivity
Author/Creator
Stewart, Scott G.;  Hill, Timothy A.;  Gilbert, Jayne;  Ackland, Stephen P.;  Sakoff, Jennette A.;  McCluskey, Adam
Institution
The University of Newcastle. Faculty of Science & Information Technology, School of Environmental and Life Science
Description
Simple modifications to the anhydride moiety of norcantharidin have lead to the development of a series of analogues displaying modest PP1 inhibition (low μM IC₅₀s) comparable to that of norcantharidin (PP1 IC₅₀ = 10.3 ± 1.37 μM). However, unlike norcantharidin, which is a potent inhibitor of PP2A (IC₅₀ = 2.69 ± 1.37 μM), these analogues show reduced PP2A inhibitory action resulting in the development of selective PP1 inhibitory compounds. Data indicates that the introduction of two ortho-disposed substituents on an aromatic ring, or para-substituent favours PP1 inhibition over PP2A inhibition. Introduction of a p-morphilinoaniline substituent, 35, affords an inhibitor displaying PP1 IC₅₀ = 6.5 ± 2.3 μM; and PP2A IC₅₀ = 7.9 ± 0.82 μM (PP1/PP2A = 0.82); and a 2,4,6-trimethylaniline, 23, displaying PP1 IC₅₀ = 48 ± 9; and PP2A IC₅ 85 ± 3 μM (PP1/PP2A = 0.56). The latter shows a 7-fold improvement in PP1 versus PP2A selectivity when compared with norcantharidin. Subsequent analysis of 23 and 35 as potential PP2B inhibitors revealed modest inhibition with IC₅₀s of 89 ± 6 and 42 ± 3 μM, respectively, and returned with PP1/PP2B selectivities of 0.54 and 0.15. Thus, these analogues are the simplest and most selective PP1 inhibitors retaining potency reported to date.
Relation
Bioorganic and Medicinal Chemistry Vol. 15, Issue 23, p. 7301-7310
Publisher Link
http://dx.doi.org/10.1016/j.bmc.2007.08.028
Date
2007
Publisher
Pergamon
Keyword(s)
cantharidin;  norcantharidin;  small molecule protein phosphatase inhibitors;  PP1;  PP2A;  PP2B
Resource Type
journal article
Identifier
http://hdl.handle.net/1959.13/33630
Identifier
ISSN:0968-0896
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Subject
"Bioorganic and Medicinal Chemistry"
 
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