Ergosteroids V: preparation and biological activity of various D-ring derivatives in the 7-oxo-dehydroepiandrosterone series

• Published in: Steroids Vol. 67; no. 3; pp. 221 - 233
• Main Authors: Reich, Ieva L., Reich, Hans J., Kneer, Nancy, Lardy, Henry
• Format: Journal Article
• Language: English
• Published: NEW YORK Elsevier Inc 01.03.2002; Elsevier; Elsevier Science
• Subjects: 13C NMR of steroids; 5,15-Diene steroids; 7-Oxo-DHEA; 7-Oxygenated steroids; Androsterone - analogs & derivatives; Androsterone - chemistry; Androsterone - pharmacology; Animals; Biochemistry & Molecular Biology; Biological and medical sciences; Cytosol - enzymology; Dehydroepiandrosterone - chemistry; Dehydroepiandrosterone - metabolism; Dehydroepiandrosterone - pharmacology; Endocrinology & Metabolism; Enzyme Induction - drug effects; Ergosteroids; Glycerolphosphate Dehydrogenase - biosynthesis; Hydroxylation; Life Sciences & Biomedicine; Liver - ultrastructure; Magnetic Resonance Spectroscopy; Malate Dehydrogenase - biosynthesis; Mitochondria, Liver - enzymology; Rats; Science & Technology; Structure-Activity Relationship; 5,15-Diene steroids; Ergosteroids; 7-Oxo-DHEA; 13C NMR of steroids; 7-Oxygenated steroids; 5,15-diene steroids; STEROIDS; ergosteroids; RATS; MAGNETIC-RESONANCE SPECTRA; 7-oxygenated steroids; INDUCTION; 7-oxo-DHEA; DEHYDROEPIANDROSTERONE; ACETATE; C-13 NMR of steroids
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/S0039-128X(01)00155-6

Our previous finding that D-ring seco derivatives of dehydroepiandrosterone retained biologic activity (Reich et al., Steroids 1998;63:542–53) motivated us to synthesize and test a number of steroids in which the D-ring is retained but altered in various ways. Several new steroids were synthesized and characterized by 1H and 13C NMR spectroscopy. The availability of a number of closely related compounds allowed detailed 13C chemical shift correlations. Using the induction of two thermogenic enzymes in rats, liver mitochondrial glycerophosphate dehydrogenase (GPDH) and cytosolic malic enzyme, as criteria of biologic activity some 30 compounds were assayed. Hydroxylation of dehydroepiandrosterone (DHEA) at the 16α position was previously shown to diminish activity (Lardy et al., Steroids 1998;63:158–65); the corresponding 7-oxo compound is fully active. Hydroxylation at the 15β position of DHEA, 7-oxo-DHEA, or 16α-hydroxy-7-oxo-DHEA greatly diminished the induction of GPDH but induction of malic enzyme was retained. Most 5,15 diene steroids tested had 2 weak, or no, ability to enhance the formation of GPDH but did increase malic enzyme.