Synthesis of optically pure norcantharidin analogue NCA-01, a highly selective protein phosphatase 2B inhibitor, and its derivatives

• Published in: Chemistry, an Asian journal Vol. 7; no. 6; p. 1221
• Main Authors: Shimizu, Tadashi, Iizuka, Masato, Matsukura, Hiroko, Hashizume, Daisuke, Sodeoka, Mikiko
• Format: Journal Article
• Language: English
• Published: Germany 01.06.2012
• Subjects: Binding Sites; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Calcineurin - metabolism; Calcineurin Inhibitors; Cell Survival - drug effects; Crystallography, X-Ray; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Interleukin-2 - metabolism; Jurkat Cells; Protein Structure, Tertiary; Stereoisomerism
• ISSN: 1861-471X
• DOI: 10.1002/asia.201200077

An efficient synthetic route to optically pure norcantharidin analogue NCA-01, a highly selective inhibitor of protein phosphatase 2B (PP2B; calcineurin), has been developed. The absolute stereochemistry of the enantiomers was determined by X-ray crystallographic analysis. Optically pure NCA derivatives that had various substituents at the C1 position were synthesized in a similar manner. The PP2B-inhibitory activities of NCA-01 and its derivatives were independent of the enantiomeric form. NCA-01 dimethyl ester potently inhibited IL-2 production in Jurkat cells.