Nitrile hydratase from Rhodococcus erythropolis: metabolization of steroidal compounds with a nitrile group.
The progestin dienogest (17alpha-cyanomethyl-17beta-hydroxy-estra-4,9-dien-3-one) was metabolized by the nitrile hydratase-containing microorganism Rhodococcus erythropolis. An enzymatic hydrolysis of the nitrile group at the 17alpha-side chain was intended to obtain novel derivatives and to test them for progesterone receptor affinity. In contrast to the rapid enzymatic hydrolysis of nonsteroidal nitriles, the nitrile group of dienogest was cleaved very slowly. The dominant reaction was an aromatization of ring A. After prolonged fermentation, the 17alpha-acetamido derivatives of estradiol and of 9(11)-dehydroestradiol were formed. Three of the metabolites were also prepared synthetically. They were tested for hormonal activity by assessing their binding to progesterone and estrogen receptors in vitro. Neither the aromatized 17alpha-acetamido derivatives nor the dienogest derivative 17alpha-acetamido-17beta-hydroxy-estra-4,9-dien-3-one, which was prepared synthetically only, exhibited affinity for the progesterone receptor.
Kaufmann
G
G
Division of Research and Development, Jenapharm GmbH & Co. KG, Jena, Germany.
Dautzenberg
H
H
Henkel
H
H
Müller
G
G
Schäfer
T
T
Undeutsch
B
B
Oettel
M
M
D000818:Animals; D001711:Biotransformation; D004353:Drug Evaluation, Preclinical; D004958:Estradiol / Q000378:metabolism; D005285:Fermentation; D006836:Hydro-Lyases / Q000378:metabolism*; D006868:Hydrolysis; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism; D011817:Rabbits; D011960:Receptors, Estrogen / Q000378:metabolism; D012240:Rhodococcus / Q000378:metabolism*; D013329:Structure-Activity Relationship
D011725:Pyridines; D011960:Receptors, Estrogen; C023635:dienogest; D011374:Progesterone; D004958:Estradiol; D009277:Nandrolone; D006836:Hydro-Lyases; C048831:nitrile hydratase; C020729:3-cyanopyridine