Lipase-catalyzed preparation of optically active 1′-acetoxychavicol acetates and their structure–activity relationships in apoptotic activity against human leukemia HL-60 cells

Structure–activity relationships of 1′-acetoxychavicol acetate (ACA) for apoptotic activity against human leukemia HL-60 cells were investigated using optically active ACA and various racemic ACA analogues. Natural-type (or with different acyl group) ACA showed a high apoptotic activity, but the ortho or meta isomers, 4-deacetoxy analogue, and the 2′–3′ dehydrogenated derivative had no effect, or a weak activity. Optically active (R)- and (S)-ACA were prepared by a lipase-catalyzed esterification. Using a mixture of vinyl acetate–tetrahydrofuran (1:1 v/v) as a solvent at refluxing temperature, optically pure (R)- and (S)-ACA were obtained (99.7% ee and 99.1% ee, respectively). The apoptosis-inducing effects of both enantiomers were compared by means of an MTT assay and the detection of typical apoptotic phenomena (DNA fragmentation, caspase-3 activation, and PARP cleavage) and these two activities were almost equal. These results indicate that the essential moieties of ACA for apoptotic activity against HL-60 cells are both the presence of a 4-acetoxyl group and an unsaturated double bond between C-2′ and C-3′, and that the configuration at the 1′-position is unrelated to activity.

(1′S)-Acetoxychavicol acetate ((S)-ACA) and its enantiomer were prepared by a lipase-catalyzed esterification. Structure–activity relationships of ACA for apoptotic activity were investigated using these enantiomers and various racemic analogues.Figure optionsDownload as PowerPoint slide