Optically active cantharidin analogues possessing selective inhibitory activity on Ser/Thr protein phosphatase 2B (calcineurin): implications for the binding mode.
Cantharidin is well known as a potent serine/threonine protein phosphatase 1 and 2A (PP1 and PP2A) inhibitor, with less potent inhibitory activity for PP2B, which regulates T-cell proliferation. We synthesized and evaluated four optically pure stereoisomers of 1-substituted norcantharidin analogues. The absolute stereochemistry of each stereoisomer was determined based on X-ray crystal structure analysis. Remarkably, optically active cantharidin analogues having (1S)-configuration showed selective inhibition of PP2B, without inhibiting PP1 or PP2A.
Baba
Yoshiyasu
Y
Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba, Sendai, Miyagi 980-8577, Japan.
Hirukawa
Nozomu
N
Sodeoka
Mikiko
M
D001665:Binding Sites; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002193:Cantharidin / Q000737:chemistry / Q000494:pharmacology*; D002942:Circular Dichroism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D054645:Protein Phosphatase 1; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism
D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D019703:Calcineurin; D054645:Protein Phosphatase 1; D002193:Cantharidin