Synthesis and Evaluation of 4-(Substituted thio)-4-androstene-3,17-dione Derivatives as Potential Aromatase Inhibitors

The synthesis and evaluation of 4-(substituted thio)-4-androstene-3,17-dione derivatives as inhibitors of estrogen synthetase (aromatase) are described. All compounds were prepared by the addition of various thiol reagents to 4β,5β-epoxyandrostanedione. Inhibitory activity of synthesized compounds was determined with use of a human placental microsomal preparation as the enzyme source and [1β-³H]-4-androstene-3,17-dione as substrate. Synthesized compounds exhibiting high inhibitory activity were further evaluated under initial velocity conditions to determine apparent K_i values. Several compounds were effective competitive inhibitors and have apparent K_i values ranging from 36 to 73 nM, with the apparent K_m for androstenedione being 53 nM. The results of these studies demonstrate a tightly fitted enzyme pocket that can accommodate bulk up to about 5.5 Å.