Synthesis and in vitro studies of radiolabeled and fluorescent aromatase inhibitors

Thesis/Dissertation · Fri Jan 01 04:00:00 EST 1988

OSTI ID:7068386

Chen, G G

7a-Substituted 4-androstene-3,17-diones are effective inhibitors of aromatase in vitro. One of the potent competitive inhibitors in the series, 7a-(4{prime}-iodo)phenylthio-4-androstene-3,17-dione (7a-IPTA) with an apparent K{sub i} of 12 nM, was prepared as a {sup 125}I-radiolabeled probe. Metabolism studies on human placental microsomes of {sup 125}I-7a-IPTA demonstrated that deiodination, cleavage of the 7a-thio substituent and metabolites No. 1, No. 2, and No. 3, and di-iodothiophenol are produced. MCF-7 cells metabolism of IPTA showed the metabolites No. 1 and No. 2 were the major metabolites. Comparing the retention time and by coelution, metabolite No. 1 was shown to be identical to 7a-(4{prime}iodo)phenylthio-17B-hydroxy-4-androsten-3-one. Synthetic analogs of a 7a-substituted 4-3n3-3,17-dione or 1,4-idene-3,17-diene-3,17-dione have been evaluated as inhibitors of human placental microsomal aromatase, with apparent K{sub i} ranges of 4.4-86.7 nM at apparent K{sub m} ranges of 53.3-74.8 nM, and V{sub max} ranges of 112.8-236.4 nmol/mg protein/min. Naphthylthio derivatives are about 3-4 fold more effective than dinitrophenyl derivatives. The 1,4-diene steroids have better aromatase inhibitory activity than 4-ene steroids. Particularly, IPTADD is the most potent inhibitor in the series.

• Research Organization: Ohio State Univ., Columbus, OH (USA)
• OSTI ID: 7068386
• Country of Publication: United States
• Language: English

Related Subjects

550501* -- Metabolism-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ANIMALS
BETA DECAY RADIOISOTOPES
CELL CONSTITUENTS
DAYS LIVING RADIOISOTOPES
ELECTRON CAPTURE RADIOISOTOPES
ENZYME INHIBITORS
ENZYMES
FETAL MEMBRANES
IN VITRO
INTERMEDIATE MASS NUCLEI
IODINE 125
IODINE ISOTOPES
ISOMERASES
ISOTOPES
MAMMALS
MAN
MEMBRANES
METABOLISM
METABOLITES
MICROSOMES
NUCLEI
ODD-EVEN NUCLEI
ORGANOIDS
PLACENTA
PRIMATES
RADIOISOTOPES
RIBOSOMES
VERTEBRATES