- Title
- Synthesis and biological evaluation of norcantharidin analogues: towards PP1 selectivity
- Creator
- Stewart, Scott G.; Hill, Timothy A.; Gilbert, Jayne; Ackland, Stephen P.; Sakoff, Jennette A.; McCluskey, Adam
- 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
- Publisher
- Pergamon
- Resource Type
- journal article
- Date
- 2007
- 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.
- Subject
- cantharidin; norcantharidin; small molecule protein phosphatase inhibitors; PP1; PP2A; PP2B
- Identifier
- http://hdl.handle.net/1959.13/33630
- Identifier
- uon:3263
- Identifier
- ISSN:0968-0896
- Language
- eng
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