Amidrazone and Amidoxime Inhibitors of Squalene Hopene Cyclase

The cyclization of squalene catalyzed by the enzyme squalene-hopene cyclase (SHC) leads to the hopanoid family of pentacyclic triterpenes, which are widely found in bacteria as membrane constituents. SHC mediates a cascade of regio- and stereoselective cyclizations that has triggered considerable interest in understanding the enzyme's mechanism of action. This paper reports synthetic studies leading to the preparation of trienylamidrazone 8, trienylamidoxime 9, and tetraenylamidoxime 10 corresponding to a partially cyclized squalene chain. All three compounds displayed significant levels of inhibition when assayed against SHC, with 9 being more active than 8, and amidoxime 10 being the most potent. Detailed profiles of their inhibition kinetics are also presented.