Search for Medicinal Leads Inhibiting Nuclear Export of NES-containing Protein

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1'-Acetoxychavicol acetate (ACA), a NES-antagonistic inhibitor against nuclear export of NES containing protein, was suggested to be readily hydrolyzed in vivo because of its two acetyl moieties. Thus, some carbamate and carbonate analogs were prepared to be analyzed for its activity and stability in the medium containing serum. This analysis clarified that the functional group, which is difficult to be hydrolyzed, on phenolic hydroxyl portion extremely reduced the inhibitory activity for nuclear export of NES containing protein. Additionally, reactants of ACA and N-acetyl-L-cyctein methyl ester established 1-acetoxy-2-ene moiety as the binding site of cystein-529 in CRM1 and presumed the hydrolysis of ester linkage at 4-OH followed by formation of p-quininemethide intermediate to be essential for potent activity. Under this circumstance, molecular orbital calculation for each energy barrier based on the plausible mechanism of action of ACA disclosed the hydrolysis energy of acetyl group at 4-OH in ACA to be a rate-determining step. Furthermore, 2,3-difluoro-ACA analog with lower E1 was shown to exhibit 50 fold more potent activity than that of ACA. On the other hand, homology model of human CRM1 was built by means of a fold recognition method. Through the docking study of the analogs and the constructed homology model, the correlation between interaction energy and biological activity was obserbed.