Synthesis and biological evaluation of norcantharidin analogues: Towards PP1 selectivity

Stewart, Scott G., Hill, Timothy A., Gilbert, Jayne, Ackland, Stephen P., Sakoff, Jennette A. and McCluskey, Adam (2007) Synthesis and biological evaluation of norcantharidin analogues: Towards PP1 selectivity. Bioorganic & Medicinal Chemistry, 15 23: 7301-7310. doi:10.1016/j.bmc.2007.08.028


Author Stewart, Scott G.
Hill, Timothy A.
Gilbert, Jayne
Ackland, Stephen P.
Sakoff, Jennette A.
McCluskey, Adam
Title Synthesis and biological evaluation of norcantharidin analogues: Towards PP1 selectivity
Journal name Bioorganic & Medicinal Chemistry   Check publisher's open access policy
ISSN 0968-0896
1464-3391
Publication date 2007-12-01
Year available 2007
Sub-type Article (original research)
DOI 10.1016/j.bmc.2007.08.028
Open Access Status Not yet assessed
Volume 15
Issue 23
Start page 7301
End page 7310
Total pages 10
Editor Chi-Huey Wong
H. Waldmann
Yuichi Hashimoto
Place of publication Oxford, U.K.
Publisher Pergamon/Elsevier
Language eng
Subject 0304 Medicinal and Biomolecular Chemistry
1115 Pharmacology and Pharmaceutical Sciences
Abstract Simple modi. cations to the anhydride moiety of norcantharidin have lead to the development of a series of analogues displaying modest PP1 inhibition (low mu M IC(50)s) comparable to that of norcantharidin (PP1 IC50 = 10.3 +/- 1.37 mu M). However, unlike norcantharidin, which is a potent inhibitor of PP2A (IC50 = 2.69 +/- 1.37 mu M), 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 mu M; and PP2A IC50 = 7.9 +/- 0.82 mu M (PP1/PP2A = 0.82); and a 2,4,6-trimethylaniline, 23, displaying PP1 IC50 = 48 +/- 9; and PP2A IC5 85 +/- 3 mu M (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 IC(50)s of 89 +/- 6 and 42 +/- 3 mu M, 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. Crown copyright (C) 2007 Published by Elsevier Ltd. All rights reserved.
Formatted abstract
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.
Crown copyright © 2007 Published by Elsevier Ltd. All rights reserved.
Keyword Cantharidin
Norcantharidin
Small molecule protein phosphatase inhibitors
PP1
PP2A
PP2B
Q-Index Code C1
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
Institute for Molecular Bioscience - Publications
 
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