Inhibitors of sterol synthesis. Chemical synthesis of 7 alpha-ethyl and 16 alpha-ethyl derivatives of delta 8(14)-15-oxygenated sterols and their effects on 3-hydroxy-3-methylglutaryl coenzyme A reductase in CHO-K1 cells.
The enolate of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one (II), formed upon treatment of II with potassium tert-butoxide in tert-butanol, was alkylated with ethyl iodide. In addition to the major products, 3 beta-hydroxy-14 alpha-ethyl-5 alpha-cholest-7-en-15-one and its 3 beta-ethyl ether, small amounts of 3 beta-hydroxy-7 alpha-ethyl-5 alpha-cholest-8(14)-en-15-one (V), 3 beta-hydroxy-16 alpha-ethyl-5 alpha-cholest-8(14)-en-15-one (VI) and the 3 beta-ethyl ether of VI were isolated. When the enolate of II was formed by treatment with lithium diisopropylamide in tetrahydrofuran, the same alkylation furnished VI as the major product. Reduction of VI with lithium aluminum hydride gave 16 alpha-ethyl-5 alpha-cholest-8(14)-ene-3 beta, 15 alpha-diol (IX) and its 15 beta epimer X, which were separated by column chromatography. Full 1H and 13C nuclear magnetic resonance (NMR) assignments, augmented by nuclear Overhauser effect difference spectra for VI, established the stereochemistry of these diols at C-15 and C-16. The NMR results indicate that the 16 alpha-ethyl group affects the side-chain conformation. The effects of II, V, VI, IX and X on the levels of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity were studied in CHO-K1 cells. With the exception of IX, each of the compounds reduced the levels of HMG-CoA reductase activity. The order of potency with respect to suppression of the elevated levels of HMG-CoA reductase activity induced by transfer of the cells to lipid-deficient medium, was II greater than V greater than VI greater than X.
Kim
H S
HS
Department of Biochemistry and Cell Biology, Rice University, Houston, TX 77251-1892.
Wilson
W K
WK
Kirkpatrick
N D
ND
Pinkerton
F D
FD
Swaminathan
S
S
Hylarides
M D
MD
Schroepfer
G J
GJ
D000478:Alkylation; D000818:Animals; D000924:Anticholesteremic Agents / Q000737:chemistry*; D000440:Butanols / Q000737:chemistry; D016466:CHO Cells / Q000201:enzymology; D002783:Cholestenones / Q000737:chemistry*; D006224:Cricetinae; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects*; D008094:Lithium / Q000737:chemistry; D000432:Methanol; D010100:Oxygen / Q000737:chemistry*; D011188:Potassium / Q000737:chemistry; D011437:Propylamines / Q000737:chemistry; D013261:Sterols / Q000138:chemical synthesis*
D000924:Anticholesteremic Agents; D000440:Butanols; D002783:Cholestenones; D011437:Propylamines; D013261:Sterols; C015073:cholest-8(14)-en-3-ol-15-one; C077664:tert-butoxide, potassium; D008094:Lithium; C007442:diisopropylamine; D006903:Hydroxymethylglutaryl CoA Reductases; D011188:Potassium; D010100:Oxygen; D000432:Methanol