1999 Volume 22 Issue 11 Pages 1207-1211
The time-dependent inactivation of aromatase by epoxy analogs of the good aromatase inhibitors, androst-4-ene-6, 17-dione (3) and androst-5-ene-4, 17-dione (7), 4β, 5β-epoxy and 5β, 6β-epoxy compounds 10 and 13 and their 19-oxo derivatives 11 and 14, was examined in either the presence or absence of NADPH. The 4β, 5β-epoxy-19-oxo steroid 11 along with the 19-methyl-5β, 6β-epoxide 13 inactivated human placental aromatase in a mechanism-based manner, in the presence of NADPH, with rate constants for inactivation (kinact) of 0.133 min-1 for steroid 11 and 0.100 min-1 for steroid 13, whereas the two other steroids, 10 and 14, did not. On the other hand, none of four epoxides studied caused time-dependent inactivation of aromatase in an affinity-labeling manner in the absence of NADPH. These results are the first report showing that inhibitors 11 and 13 are suicide substrates having an epoxyketone structural featue.
