TY - JOUR
T1 - Norcantharidin analogues : synthesis, anticancer activity and protein phosphatase 1 and 2A inhibition
AU - Hill, Timothy A.
AU - Stewart, Scott G.
AU - Gordon, Christopher P.
AU - Ackland, Stephen P.
AU - Gilbert, Jayne
AU - Sauer, Benjamin
AU - Sakoff, Jennette A.
AU - McCluskey, Adam
PY - 2008
Y1 - 2008
N2 - Cantharidin (1) and its derivatives are of significant interest as serine/threonine protein phosphatase 1 and 2A inhibitors. Additionally, compounds of this type have displayed growth inhibition of various tumour cell lines. To further explore both of these inhibition pathways, a number of amide-acid norcantharidin analogues (15-26) were prepared. Compounds 23 and 24, containing two carboxylic acid residues, showed good PP1 and PP2A activity, with IC 50 values of ∼15 and ∼3 μm, respectively. Substituted aromatic amide analogues 45, 48, 49, 52, 53, and 54 also displayed good PP1 and PP2A inhibition, with IC 50 values in the range of 15-10 μm (PP1) and 11-5 μm (PP2A). However, bulky ortho substituents on the aromatic ring caused the aromatic ring to be skewed from the NCO planarity, leading to a decrease in PP1 and PP2A inhibition. A number of analogues, 20, 22, 25 and 46, showed excellent tumour growth inhibition, with 46 in particular being more potent than the lead, norcantharidin 2.
AB - Cantharidin (1) and its derivatives are of significant interest as serine/threonine protein phosphatase 1 and 2A inhibitors. Additionally, compounds of this type have displayed growth inhibition of various tumour cell lines. To further explore both of these inhibition pathways, a number of amide-acid norcantharidin analogues (15-26) were prepared. Compounds 23 and 24, containing two carboxylic acid residues, showed good PP1 and PP2A activity, with IC 50 values of ∼15 and ∼3 μm, respectively. Substituted aromatic amide analogues 45, 48, 49, 52, 53, and 54 also displayed good PP1 and PP2A inhibition, with IC 50 values in the range of 15-10 μm (PP1) and 11-5 μm (PP2A). However, bulky ortho substituents on the aromatic ring caused the aromatic ring to be skewed from the NCO planarity, leading to a decrease in PP1 and PP2A inhibition. A number of analogues, 20, 22, 25 and 46, showed excellent tumour growth inhibition, with 46 in particular being more potent than the lead, norcantharidin 2.
UR - http://handle.uws.edu.au:8081/1959.7/546940
U2 - 10.1002/cmdc.200800192
DO - 10.1002/cmdc.200800192
M3 - Article
SN - 1860-7179
VL - 3
SP - 1878
EP - 1892
JO - ChemMedChem
JF - ChemMedChem
IS - 12
ER -
