Sterol synthesis. Synthesis of 3 beta-hydroxy-25,26,26,26,27,27,27-heptafluorocholest-5-en-7-one and its effects on HMG-CoA reductase activity in Chinese hamster ovary cells, on ACAT activity in rat jejunal microsomes, and serum cholesterol levels in rats.
3 beta-Hydroxycholest-5-en-7-one (I; 7-ketocholesterol) is an oxysterol of continuing interest in biology and medicine. In the present study, we have prepared a side-chain fluorinated analog, 3 beta-hydroxy-25,26,26,26,27,27,27-heptafluorocholest-5-en-7-one (VI), with the anticipation that the F7 substitution would block major metabolism of the 7-ketosterol, and thereby enhance its potential in vivo effects on serum cholesterol levels and other parameters. Chromium trioxide/dimethyl pyrazole oxidation of the acetate derivative of the previously described 25,26,26,26,27,27,27-heptafluorocholest-5-en-3 beta-ol (Swaminathan et al., 1993. J. Lipid Res. 34, 1805-1823) followed by mild alkaline hydrolysis gave VI. The effects of VI on 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity in Chinese hamster ovary (CHO-K1) cells, on acyl coenzyme A-cholesterol acyltransferase (ACAT) activity in rat jejunal microsomes, and on serum cholesterol levels and other parameters in male Sprague-Dawley rats were determined and compared with those obtained with I and with another alpha, beta-unsaturated ketosterol, i.e. 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one (II). I and VI showed essentially the same potency, considerably less than that of II, in lowering the levels of HMG-CoA reductase activity in CHO-K1 cells. Whereas addition of II to rat jejunal microsomes inhibited ACAT activity (IC50 approximately 3 microM), I and VI had no effect under the conditions studied (from 1 to 16 microM). Dietary administration of I, at levels of 0.1 and 0.15%, had no effect on food consumption, gain in body weight, or serum cholesterol levels. At 0.2%, I caused a modest decrease in body weight gain and a slight decrease in serum cholesterol levels (relative to ad libitum but not pair-fed control animals). The F7-7-ketosterol VI, at 0.26% in diet (the molar equivalent of 0.2% I), had no effect on food consumption, body weight, or serum cholesterol levels. Administration of I (0.1, 0.15 or 0.2% in diet) caused increases in the weight of small intestine. In contrast, no effect of VI (0.26% in diet) on small intestinal weight was observed.
Carroll
J N
JN
Department of Chemistry, Rice University, Houston, TX 77251-1892, USA.
Pinkerton
F D
FD
Su
X
X
Gerst
N
N
Wilson
W K
WK
Schroepfer
G J
GJ
D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000097:blood* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005247:Feeding Behavior / Q000187:drug effects; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D007583:Jejunum / Q000187:drug effects* / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D015394:Molecular Structure; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D002785:Sterol O-Acyltransferase / Q000378:metabolism*; D005466:Fluorocarbons
D000924:Anticholesteremic Agents; D002784:Cholesterol; D004791:Enzyme Inhibitors; D006903:Hydroxymethylglutaryl CoA Reductases; D002785:Sterol O-Acyltransferase; C115760:3-beta-hydroxy-25,26,26,26,27,27,27-heptafluorocholest-5-en-7-one; D005466:Fluorocarbons