Abstract
Inhibition of CYP 17 is a promising strategy for the treatment of prostate cancer. Recently two non-steroidal compounds with high in vitro activity were synthesized in our group (BW19 and BW95). However, after a few hours they showed in vivo a strong decrease in their activity. This might be due to a fast biodegradation. Potential hydroxy and epoxy metabolites were synthesized and their inhibitory activities were tested by a new non-cellular assay using recombinant enzyme. As source, membrane fractions of E. coli pJL17/OR coexpressing human CYP 17 and rat NADPH-P450-reductase were, used. Showing a high and constant CYP 17 activity and a fast and easy isolation procedure the new method was advantageous compared with the microsomal assay. Interestingly, all the new synthesized hydroxy and epoxy compounds except one showed a lower inhibition of CYP 17 than the parent compounds. Thus, the loss of in vivo activity may be partly explained.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biodegradation, Environmental
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Cytochrome P-450 Enzyme System / metabolism
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Drug Evaluation, Preclinical / methods
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology
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Epoxy Compounds / chemistry
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Epoxy Compounds / pharmacology
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Escherichia coli / cytology
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Escherichia coli / drug effects
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Humans
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Hydroxylation
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Lethal Dose 50
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Male
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NADPH-Ferrihemoprotein Reductase / metabolism
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Progesterone / chemistry
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Progesterone / metabolism
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Rats
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Recombinant Proteins / metabolism
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Steroid 17-alpha-Hydroxylase / antagonists & inhibitors*
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Steroid 17-alpha-Hydroxylase / genetics
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Steroid 17-alpha-Hydroxylase / metabolism
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Testosterone / chemistry
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Testosterone / metabolism
Substances
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Enzyme Inhibitors
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Epoxy Compounds
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Recombinant Proteins
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Testosterone
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Progesterone
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Cytochrome P-450 Enzyme System
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Steroid 17-alpha-Hydroxylase
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NADPH-Ferrihemoprotein Reductase