The long-term objective of this proposal is to develop selective inhibitors of aromatase, C17-20 lyase, and the cholesterol side chain cleavage enzyme for application to problems in endocrinology and oncology. Specific inhibitors of aromatase would block estrogen biosynthesis and thus provide potential agents for use in the management of estrogen-dependent mammary tumors. Specific inhibitors of C17-20 lyase would block androgen as well as estrogen biosynthesis and could thus be useful in the mangement of prostatic tumors. Specific inhibitors of the cholesterol side chain cleavage enzyme would block steroid hormone biosynthesis from cholesterol and could be useful in the management of cortisol hypersecretion due to autonomously functioning adrenal tumors. The types of inhibitors chosen for development are known as suicide substrates. Such compounds contain function groups which are in themselves not chemically reactive, but are capable of becoming chemically reactive after the target enzyme carries out its catalytic reaction.
The specific aims are: 1) to study the mechanism of action of known and newly prepared aromatase suicide substrates; 2) to demonstrate the feasibility of using a radiolabeled aromatase suicide substrate to localize tissue distribution of this enzyme; 3) to prepare a novel 14,15-secopregnene as a C17-20 lyase inhibitor and evaluate its effectiveness in microsomal preparations from rat testes; and 4) to prepare novel actylenic steroids as inhibitors of the cholesterol side chain cleavage enzyme and evaluate them using mitochondrial powders from bovine adrenal glands. The methodology involves organic synthesis, enzymology, analysis by gas chromatography-mass spectrometry, and autoradiography.
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