STEROL SYNTHESIS, SYNTHESIS OF 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 oxystero l 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-heptafluoro- cholest-5-en-7-one (VI), with the antic ipation that the F-7 substitution would block major metabolism of the 7-ketosterol, and thereby enhance its potential in vivo effects on ser um cholesterol levels and other parameters. Chromium trioxide/dimethyl pyrazole oxidation of the acetate derivative of the previously descri bed 25,26,26,26,27,27,27-heptafluorocholest-5-en-3 beta-ol (Swaminatha n et al., 1993. J. Lipid Res. 34, 1805-1823) followed by mild alkaline hydro lysis 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) activ ity in rat jejunal microsomes, and on serum cholesterol levels and oth er parameters in male Sprague-Dawley rats were determined and compared with those obtained with I and with another alpha,beta-unsaturated ke tosterol, 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 tha t of II? in lowering the levels of HMG-CoA reductase activity in CHO-K 1 cells. Whereas addition of LT to rat jejunal microsomes inhibited AC AT activity (IC50 similar to 3 mu M), I and VI had no effect under the conditions studied (from 1 to 16 mu M). 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 cholestero l levels (relative to ad libitum but not pair-fed control animals). Th e F-7-7-ketosterol VII at 0.26'% in diet (the molar equivalent of 0.2% I), had no effect on food consumption, body weight, or serum choleste rol levels. Administration of I (0.1. 0.15 or 0.2% in diet) caused inc reases in the weight of small intestine. In contrast? no effect of VI (0.26% in diet) on small intestinal weight was observed. (C) 1998 Else vier Science ireland Ltd. All rights reserved.