TY - JOUR
T1 - Aromatase inhibition by 4-thiosubstituted-4-androstene-3,17-dione derivatives
AU - Abul-Hajj, Yusuf J.
PY - 1990/1
Y1 - 1990/1
N2 - The synthesis and evaluation of 4-thiosubstituted-4-androstenedione analogs as inhibitors of estrogen synthetase (aromatase) is described. All compounds were prepared by the addition of various thiol reagents to 4β,5β-epoxyandrostanedione. Inhibitory activity of synthesized compounds was assessed using 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 Ki values. Several compounds were effective competitive inhibitors, and have apparent Ki values ranging from 34 to 52 nM, with the apparent Km for androstenedione being 54 nM. The results of these studies demonstrate a tightly fitted enzyme pocket that can accommodate bulky substituents at the C-4 position of androstenedione not to exceed 4.3 Å in width and 5.5 Å in length.
AB - The synthesis and evaluation of 4-thiosubstituted-4-androstenedione analogs as inhibitors of estrogen synthetase (aromatase) is described. All compounds were prepared by the addition of various thiol reagents to 4β,5β-epoxyandrostanedione. Inhibitory activity of synthesized compounds was assessed using 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 Ki values. Several compounds were effective competitive inhibitors, and have apparent Ki values ranging from 34 to 52 nM, with the apparent Km for androstenedione being 54 nM. The results of these studies demonstrate a tightly fitted enzyme pocket that can accommodate bulky substituents at the C-4 position of androstenedione not to exceed 4.3 Å in width and 5.5 Å in length.
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U2 - 10.1016/0022-4731(90)90158-O
DO - 10.1016/0022-4731(90)90158-O
M3 - Article
C2 - 2308324
AN - SCOPUS:0025089852
SN - 0960-0760
VL - 35
SP - 139
EP - 143
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
IS - 1
ER -