Microbial transformation and butyrylcholinesterase inhibitory activity of (-)-caryophyllene oxide and its derivatives

Microbial transformation of the sesquiterpene (-)-caryophyllene oxide ( 1) [(1R, 4R, 5R, 9S)-4,5-epoxycaryophyllan-8( 13)ene] by a number of fungi, using a standard two-stage fermentation technique, has afforded as products ( 1R, 4R, 5R, 9S)4,5- dihydroxycaryophyllan- 8( 13)- ene ( 2), (1S, 4R, 5R, 8S, 9S)-clovane-5,9-diol ( 3), ( 1R, 4R, 5R, 9S, 11R)- 4,5- epoxycaryophyllan-8( 13)-en-15-ol ( 4), ( 1R, 4R, 5R, 9S, 11S)- 4,5-epoxycaryophyllan-8( 13)-en-14-ol ( 5), (1R,2S,4R, 5R, 9S)- 4,5- epoxy-13-norcaryophyllan- 8-one ( 6), ( 1R, 4R, 5R, 8S, 9S)- 4,5- epoxycaryophyllan-13-ol ( 7), ( 1R, 4R, 5R, 8S, 9S, 13S)-caryolane-5,8,13-triol ( 8), ( 1R, 3R, 4R, 5R, 8S, 9S)-4,5-epoxycaryophyllan-3,13-diol ( 9), and ( 1S, 4R, 5R, 8S, 9S)- clovane-5,9,12-triol (10). Metabolites 6 and 8-10 were found to be new compounds, as deduced on the basis of spectroscopic techniques. Compounds 1-10 were evaluated for butyrylcholinesterase inhibitory activity, and compound 5 exhibited an IC50 value of 10.9 +/- 0.2 mu M.