TY - JOUR
T1 - 10β-Propynyl-substituted steroids. Mechanism-based enzyme-activated irreversible inhibitors to estrogen biosynthesis
AU - Covey, D. F.
AU - Hood, W. F.
AU - Parikh, V. D.
PY - 1981
Y1 - 1981
N2 - A series of 10β-propynyl-substituted steroids are reported as mechanism-based enzyme-activated irreversible inhibitors of the human placental aromatase which converts 4-androstene-3,17-dione to 1,3,5(10)-estratrien-3-ol-17-one. Thus 10-propargylestr-4-ene-3,17-dione binds to the enzyme with an apparent K(i) of 23 nM and causes time-dependent inactivation (pseudo-first order k(inact) = 1.11 x 10-3 5-1). The 10-[(1S)-1-hydroxy-2-propynyl]estr-4-ene-3,17-dione analog of the known enzyme-generated intermediate, 4-androsten-19-ol-3,17-dione, behaved similary and had an apparent K(i) of 27 μM and a psuedo-first order k(inact) of 2.91 x 10-35-1. The stereoisomeric 10-[(1R)-1-hydroxy-2-propynyl]estr-4-ene-3,17-dione did not cause time-dependent inactivation, but bound in a competitive manner with an apparent K(i) of 2.5μM. Finally, 10-(1-oxo-2-propynyl)-estr-4-ene-3,17-dione, the proposed enzyme-generated affinity label and analog of the second intermediate (3,17-dioxoandrost-4-en-19-al) in the enzymatic reaction, bound to the enzyme with an apparent K(i) of 12 μM and caused time-dependent inactivation with a pseudo-first order k(inact) of 5.35 x 10-45-1.
AB - A series of 10β-propynyl-substituted steroids are reported as mechanism-based enzyme-activated irreversible inhibitors of the human placental aromatase which converts 4-androstene-3,17-dione to 1,3,5(10)-estratrien-3-ol-17-one. Thus 10-propargylestr-4-ene-3,17-dione binds to the enzyme with an apparent K(i) of 23 nM and causes time-dependent inactivation (pseudo-first order k(inact) = 1.11 x 10-3 5-1). The 10-[(1S)-1-hydroxy-2-propynyl]estr-4-ene-3,17-dione analog of the known enzyme-generated intermediate, 4-androsten-19-ol-3,17-dione, behaved similary and had an apparent K(i) of 27 μM and a psuedo-first order k(inact) of 2.91 x 10-35-1. The stereoisomeric 10-[(1R)-1-hydroxy-2-propynyl]estr-4-ene-3,17-dione did not cause time-dependent inactivation, but bound in a competitive manner with an apparent K(i) of 2.5μM. Finally, 10-(1-oxo-2-propynyl)-estr-4-ene-3,17-dione, the proposed enzyme-generated affinity label and analog of the second intermediate (3,17-dioxoandrost-4-en-19-al) in the enzymatic reaction, bound to the enzyme with an apparent K(i) of 12 μM and caused time-dependent inactivation with a pseudo-first order k(inact) of 5.35 x 10-45-1.
UR - http://www.scopus.com/inward/record.url?scp=0019829686&partnerID=8YFLogxK
M3 - Article
C2 - 7451489
AN - SCOPUS:0019829686
SN - 0021-9258
VL - 256
SP - 1076
EP - 1079
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 3
ER -