Swaminathan S, Siddiqui A U, Gerst N, Pinkerton F D, Kisic A, Kim L J, Wilson W K, Schroepfer G J
Department of Biochemistry, Rice University, Houston, TX 77251, USA.
J Lipid Res. 1995 Apr;36(4):767-86.
3 beta-Hydroxy-5 alpha-cholest-8(14)-en-15-one (I) is a potent regulator of cholesterol metabolism. In the present study, the 7 alpha-methyl-25,26,26,26,27,27,27-heptafluoro analog (X) of I has been synthesized with the goal of blocking not only the side chain oxidation of I but also its conversion to cholesterol. X was prepared in seven steps from the known 7 alpha-methyl analog (IX) of I. Treatment of the acetate of IX with a mixture of trifluoroacetic anhydride, hydrogen peroxide, and sulfuric acid gave 3 beta-acetoxy-7 alpha-methyl-24-hydroxy-5 alpha-chol-8(14)-en-15-one (XII) in remarkably high (68%) yield. Dehydration of XII via the orthonitrophenylselenide to the 23-ene, followed by addition of (CF3)2CFI gave (23R)-3 beta-acetoxy-7 alpha-methyl-23-iodo-25,26,26,26,27,27,27-heptafluoro-5 alpha-cholest-8(14)-en-15-one (XV). Reductive deiodination of XV with tributyltin hydride, followed by hydrolysis of the acetate gave 3 beta-hydroxy-7 alpha-methyl-25,26,26,26,27,27,27-heptafluoro-5 alpha-cholest-8(14)-en-15-one (X). The F7-7 alpha-methyl-15-ketosterol X lowered the levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in CHO-K1 cells with a potency equivalent to that of I. X showed significant hypocholesterolemic action upon oral administration to rats, with a potency far in excess of the 7 alpha-methyl-15-ketosterol IX lacking the F7 substitution. In marked contrast to I, X showed little or no suppression of food consumption in rats. Upon oral administration of X to rats, low levels of X (relative to cholesterol), characterized by chromatographic and gas chromatography-mass spectrometric methodologies, were observed in serum, liver, and small intestine. No material was observed with the expected properties of F7-7-methylcholesterol (or potential intermediates in its possible formation from X). In contrast to I, X lowered serum cholesterol levels at dosages at which no effect on food consumption was observed.
3β-羟基-5α-胆甾-8(14)-烯-15-酮（I）是胆固醇代谢的有效调节剂。在本研究中，已合成了I的7α-甲基-25,26,26,26,27,27,27-七氟类似物（X），目的不仅是阻断I的侧链氧化，还阻断其向胆固醇的转化。X由I的已知7α-甲基类似物（IX）经七步制备。用三氟乙酸酐、过氧化氢和硫酸的混合物处理IX的乙酸酯，以极高的产率（68%）得到3β-乙酰氧基-7α-甲基-24-羟基-5α-胆甾-8(14)-烯-15-酮（XII）。XII通过邻硝基苯基硒化物脱水生成23-烯，然后加入(CF3)2CFI得到(23R)-3β-乙酰氧基-7α-甲基-23-碘-25,26,26,26,27,27,27-七氟-5α-胆甾-8(14)-烯-15-酮（XV）。用三丁基氢化锡对XV进行还原脱碘，然后水解乙酸酯，得到3β-羟基-7α-甲基-25,26,26,26,27,27,27-七氟-5α-胆甾-8(14)-烯-15-酮（X）。F7-7α-甲基-15-酮甾醇X降低了CHO-K1细胞中3-羟基-3-甲基戊二酰辅酶A还原酶的活性，其效力与I相当。X对大鼠口服给药后显示出显著的降胆固醇作用，效力远远超过缺乏F7取代的7α-甲基-15-酮甾醇IX。与I形成鲜明对比的是，X对大鼠的食物消耗几乎没有抑制作用。给大鼠口服X后，通过色谱和气相色谱-质谱法在血清、肝脏和小肠中观察到低水平的X（相对于胆固醇）。未观察到具有F7-7-甲基胆固醇预期性质的物质（或其由X可能形成过程中的潜在中间体）。与I不同，X在未观察到对食物消耗有影响的剂量下降低了血清胆固醇水平。
