Hydrogen bonding in steroidogenesis: studies on new heterocyclic analogs of estrone that inhibit human estradiol 17 beta-dehydrogenase.
New heterocyclic analogs of estrone are reported that inhibit estradiol 17 beta-dehydrogenase (E2-17 beta DH) from human placenta. The inhibitors are efficiently synthesized in two steps from estrone (or its 3-O-methyl ether), giving fully characterized analogs with pyrazole or isoxazole fused to the 16,17-position on the D ring. Dixon plots of enzyme kinetic data show the heterocyclic steroids are competitive inhibitors of E2-17 beta DH. Correlating molecular structures of the inhibitors with their Ki-values yields a pattern suggesting intermolecular hydrogen bonding stabilizes the [(pyrazole)inhibitor-E2-17 beta DH] complexes. A free energy difference of 2.74 Kcal/mol calculated from Ki-value differences between hydrogen bonded (4.08 microM) and non-bonded (425 microM) [inhibitor-E2-17 beta DH] complexes is in the range for intermolecular hydrogen bonding. We conclude that specific intermolecular hydrogen bonds stabilize [hydroxysteroid-enzyme] complexes, thereby making important contributions to the affinity between hydroxysteroids and steroid-specific enzymes of steroidogenesis.
Sweet
F
F
Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110.
Boyd
J
J
Medina
O
O
Konderski
L
L
Murdock
G L
GL
D000595:Amino Acid Sequence; D001665:Binding Sites; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D004970:Estrone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006860:Hydrogen Bonding; D007555:Isoxazoles / Q000494:pharmacology*; D007700:Kinetics; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy; D011487:Protein Conformation; D011720:Pyrazoles / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D007555:Isoxazoles; D011720:Pyrazoles; D004970:Estrone; D004960:Estradiol Dehydrogenases