TY - JOUR
T1 - Synthesis and evaluation of 4-substituted-4-androstene-3,17-dione derivatives as aromatase inhibitors
AU - Abul-Hajj, Yusuf J
AU - Liu, Xing Ping
AU - Hedge, Matthew
PY - 1995/8
Y1 - 1995/8
N2 - The synthesis and biological evaluation of 4-amino-, 4-alkoxy-, 4-aryloxy-, 4-alkyl- and 4-aryl-4-androstenedione derivatives as inhibitors of estrogen synthetase (aromatase) are described. Inhibitory activity of synthesized compounds was assessed using a human placental microsomal preparation as the enzyme source and [1β-3H]androstenedione as substrate. Synthesized compounds exhibiting aromatase inhibitory activity were evaluated further under initial velocity conditions to determine apparent Ki values. Several compounds were effective competitive inhibitors and have apparent Ki values ranging from 38 to 1290 nM, with the apparent Km for androstenedione being 47 nM. Alkylation or arylation of 4-N, S, or O-substituted steroids results in compounds that are effective competitive inhibitors that are devoid of time-dependent inactivation and that the free pair of electrons on N, S, or O is not an essential requirement for 4-substituted androstenedione derivatives to be effective aromatase inhibitors. The results obtained from this investigation are consistent with our previous studies which show that aromatase has a hydrophobic pocket in the active site around the C-4α region of androstenedione.
AB - The synthesis and biological evaluation of 4-amino-, 4-alkoxy-, 4-aryloxy-, 4-alkyl- and 4-aryl-4-androstenedione derivatives as inhibitors of estrogen synthetase (aromatase) are described. Inhibitory activity of synthesized compounds was assessed using a human placental microsomal preparation as the enzyme source and [1β-3H]androstenedione as substrate. Synthesized compounds exhibiting aromatase inhibitory activity were evaluated further under initial velocity conditions to determine apparent Ki values. Several compounds were effective competitive inhibitors and have apparent Ki values ranging from 38 to 1290 nM, with the apparent Km for androstenedione being 47 nM. Alkylation or arylation of 4-N, S, or O-substituted steroids results in compounds that are effective competitive inhibitors that are devoid of time-dependent inactivation and that the free pair of electrons on N, S, or O is not an essential requirement for 4-substituted androstenedione derivatives to be effective aromatase inhibitors. The results obtained from this investigation are consistent with our previous studies which show that aromatase has a hydrophobic pocket in the active site around the C-4α region of androstenedione.
UR - http://www.scopus.com/inward/record.url?scp=0029148611&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029148611&partnerID=8YFLogxK
U2 - 10.1016/0960-0760(95)00130-R
DO - 10.1016/0960-0760(95)00130-R
M3 - Article
C2 - 7662584
AN - SCOPUS:0029148611
SN - 0960-0760
VL - 54
SP - 111
EP - 119
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
IS - 3-4
ER -