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Novel Dehydroepiandrosterone Analogues with Enhanced Biological Activity and Reduced Side Effects in Mice and Rats¹

Fels Research Institute and Department of Microbiology, Temple University Medical School, Philadelphia 19140 [A. G. S., L. L. P.], and Steroid Laboratory, Crozer-Chester Medical Center, Chester, Pennsylvania 19013 [M. L. L.]

Treatment of laboratory mice and rats with the adrenal steroid, dehydroepiandrosterone (DHEA), produces antiobesity and broad spectrum tumor chemopreventive activity. Certain side effects are associated with DHEA administration which could limit its usefulness as a drug. DHEA can be metabolized into both testosterone and estrone and also increases liver weight and liver catalase activity. We have developed two synthetic steroids, 16-fluoro-5-androsten-17-one and 16-fluoro-5-androstan-17-one, which, unlike DHEA, do not stimulate uterine weight in sexually immature female rats or seminal vesicle weight in castrated male rats, nor stimulate liver weight and liver catalase activity in mice. 16-Fluoro-5-androsten-17-one is also about three times as potent as DHEA as an antiobesity agent and is more active when administered p.o. in inhibiting [³H]-7,12-dimethylbenz(a)-anthracene binding to skin DNA and tetradecanoylphorbol-13-acetate stimulation of epidermal [³H]thymidine incorporation in the mouse, two effects believed to be important in the tumor preventive action of DHEA. 16-Fluoro-5-androstan-17-one is as active as 16-fluoro-5-androsten-17-one in inhibiting [³H]-7,12-dimethylbenz(a)anthracene binding to skin DNA and tetradecanoylphorbol-13-acetate stimulation in epidermal [³H]thymidine incorporation but, on the contrary, is not more active than DHEA as an antiobesity drug. Compounds such as 16-fluoro-5-androsten-17-one and 16-fluoro-5-androstan-17-one, which lack specific side-effects of DHEA treatment and demonstrate greater potency, may have therapeutic application as drugs for humans.

¹ This work was supported by Grant CA-38574 from the National Cancer Institute, Cancer Prevention Grant SIG-6 from the American Cancer Society, the Advanced Technology Center of Southeastern Pennsylvania, and the Samuel S. Fels Fund.

² To whom requests for reprints should be addressed, at Fels Research Institute, Temple University Medical School, 3420 N. Broad St., Philadelphia, PA 19140.

Received 12/17/87. Revised 5/ 4/88. Accepted 5/25/88.

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