Inhibitors of sterol synthesis. Chemical synthesis of 7α-ethyl and 16α-ethyl derivatives of Δ8(14)-15-oxygenated sterols and their effects on 3-hydroxy-3-methylglutaryl coenzyme A reductase in CHO-K1 cells

✍ Scribed by Hong-Seok Kim; William K. Wilson; Nanda Duhé Kirkpatrick; Frederick D. Pinkerton; Shankar Swaminathan; Mark D. Hylarides; George J. Schroepfer Jr.

• Publisher: Elsevier Science
• Year: 1992
• Tongue: English
• Weight: 987 KB
• Volume: 62
• Category: Article
• ISSN: 0009-3084
• DOI: 10.1016/0009-3084(92)90054-s

✦ Synopsis

The enolate of 3B-hydroxy-Sa-cholest-8( )-en-15-one (H), formed upon treatment of H with potassium tert-butoxide in tertbutanol, was alkylated with ethyl iodide. In addition to the major products, 3#-hydroxy-14a-ethyl-5c~-cholest-7-en-15-one and its 38ethyl ether, small amounts of 3#-hydroxy-7c~-ethyl-5ct-cholest-8(l 4)-en-i 5-one (V), 3/~-hydroxy-16,-ethyl-5cc-cholest-8( )-en-15-one (VI) and the 3B-ethyl ether of VI were isolated. When the enolate of H 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~ethyl-5a-eholest-8( )-ene-3/~,15ct-diol (IX) and its 15/~ epimer X, which were separated by colunm chromatography. Full IH 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~-ethyl group affects the side-chain conformation. The effects of H, V, VI, IX and X on the levels of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity were studied in CHO-KI 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 > V > VI > X.