TAN-931, a novel nonsteroidal aromatase inhibitor produced by Penicillium funiculosum No. 8974. I. Taxonomy, fermentation, isolation,characterization and biological activities.
A novel nonsteroidal aromatase inhibitor, TAN-931, was isolated from the culture filtrate of a soil isolate fungus, No. 8974. The strain was identified as Penicillium funiculosum No. 8974. TAN-931 inhibited human placental and rat ovarian aromatase activity, and the IC50 value was 17.2 and 162 microM, respectively. The inhibition of human placental aromatase was uncompetitive with respect to androstenedione conversion with a Ki value of 40 microM. When TAN-931 was subcutaneously administered at doses of 25, 50 and 100 mg/kg (once/day, x4) to 20-day-old female Sprague-Dawley rats treated with gonadotropin, the plasma estradiol-17 beta level and the weight of ovaries and uterus were markedly reduced in a dose-dependent manner. The in vivo inhibitory activity of TAN-931 was more potent than that of 4-hydroxyandrostenedione. Consecutive administration of TAN-931 (100 mg/kg, sc, twice/day, x 7) to 9-week-old male Sprague-Dawley rats did not induce any adrenal hypertrophy even though administration of aminoglutethimide caused 2-fold enlargement of the adrenal under the same conditions. Specific binding of TAN-931 to the estrogen receptor from a human breast cancer cell line, MCF-7, was not detected.
Ishii
T
T
Microbiology Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan.
Hida
T
T
Ishimaru
T
T
Iinuma
S
S
Sudo
K
K
Muroi
M
M
Kanamaru
T
T
Okazaki
H
H
D000311:Adrenal Glands / Q000187:drug effects; D000818:Animals; D047072:Aromatase Inhibitors; D001667:Binding, Competitive; D001943:Breast Neoplasms; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000097:blood; D004965:Estrogen Antagonists / Q000378:metabolism; D005260:Female; D005285:Fermentation; D006064:Gonadotropins, Equine / Q000494:pharmacology; D006801:Humans; D062385:Hydroxybenzoates / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D006984:Hypertrophy; D008297:Male; D013058:Mass Spectrometry; D008855:Microscopy, Electron, Scanning; D015394:Molecular Structure; D009929:Organ Size / Q000187:drug effects; D010053:Ovary / Q000187:drug effects / Q000201:enzymology; D010407:Penicillium / Q000145:classification / Q000378:metabolism* / Q000648:ultrastructure; D010920:Placenta / Q000201:enzymology; D051381:Rats; D011919:Rats, Inbred Strains; D011960:Receptors, Estrogen / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014599:Uterus / Q000187:drug effects
C069914:4-(2,6-dihydroxybenzoyl)-3-formyl-5-hydroxybenzoic acid; D047072:Aromatase Inhibitors; D004965:Estrogen Antagonists; D006064:Gonadotropins, Equine; D062385:Hydroxybenzoates; D011960:Receptors, Estrogen; D004958:Estradiol