INHIBITORS OF STEROL SYNTHESIS - A HIGHLY EFFICIENT AND SPECIFIC SIDE-CHAIN OXIDATION OF 3-BETA-ACETOXY-5-ALPHA-CHOLEST-8(14)-EN-15-ONE FOR CONSTRUCTION OF METABOLITES AND ANALOGS OF THE 15-KETOSTEROL
Herz, JE; Swaminathan, S; Pinkerton, FD; Wilson, WK; Schroepfer, GJ
| HERO ID | 1206098 |
|---|---|
| In Press | No |
| Year | 1992 |
| Title | INHIBITORS OF STEROL SYNTHESIS - A HIGHLY EFFICIENT AND SPECIFIC SIDE-CHAIN OXIDATION OF 3-BETA-ACETOXY-5-ALPHA-CHOLEST-8(14)-EN-15-ONE FOR CONSTRUCTION OF METABOLITES AND ANALOGS OF THE 15-KETOSTEROL |
| Authors | Herz, JE; Swaminathan, S; Pinkerton, FD; Wilson, WK; Schroepfer, GJ |
| Journal | Journal of Lipid Research |
| Volume | 33 |
| Issue | 4 |
| Page Numbers | 579-598 |
| Abstract | As part of a program directed towards the chemical syntheses of potential metabolites and analogs of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one (I), a potent regulator of cholesterol metabolism, several routes have been explored for the preparation of 3 beta-hydroxy-15-keto-5 alpha-chol-8(14)-en-24-oic acid (IV). These investigations led to a remarkably specific and efficient side-chain oxidation of I. For example, treatment of the acetate of I with a mixture of trifluoroacetic anhydride, hydrogen peroxide, and sulfuric acid for 3.5 h at -2 degrees C gave a crude product consisting of 3 beta-acetoxy-24-trifluoroacetoxy-5 alpha-chol-8(14)-en-15-one (XI), 3 beta-acetoxy-24-hydroxy-5 alpha-chol-8(14)-en-15-one (XII), and 3 beta, 24-diacetoxy-5 alpha-chol-8(14)-en-15-one (XIII) in yields of 58%, 8%, and 3%, respectively, by HPLC analysis. XI was readily hydrolyzed to XII upon treatment with triethylamine in methanol at room temperature. Oxidation of XII with Jones reagent gave 3 beta-acetoxy-15-keto-5 alpha-chol-8(14)-en-24-oic acid (XVIII) from which its methyl ester (IX) was prepared by treatment with diazomethane. Mild alkaline hydrolysis of XVIII gave the 3 beta-hydroxy-delta 8(14)-15-keto C24 acid (IV). Hydrolysis of the crude product of the side-chain oxidation with K2CO3 in methanol gave 3 beta,24-dihydroxy-5 alpha-chol-8(14)-en-15-one (XIV) which was oxidized with Jones reagent to yield 3,15-diketo-5 alpha-chol-8(14)-en-24-oic acid (XV). Treatment of XV with diazomethane gave its methyl ester (XVI) which, upon controlled reduction with NaBH4, yielded methyl 3 beta-hydroxy-15-keto-5 alpha-chol-8(14)-en-24-oate (XVII). Compound IX was also prepared by an independent route. Full 1H and 13C NMR assignments are presented for 12 new compounds. IV caused a approximately 56% reduction of the level of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in CHO-K1 cells at a concentration of 2.5 microM. In contrast, the corresponding 3,15-diketo acid XV had no detectable effect on reductase activity under the same conditions. |
| Pmid | 1527481 |
| Wosid | WOS:A1992HR22400013 |
| Url | https://www.scopus.com/inward/record.uri?eid=2-s2.0-0026600785&partnerID=40&md5=4c89d7e29361b102ddaf83052e04261d |
| Is Certified Translation | No |
| Dupe Override | No |
| Comments | Source: Web of Science A1992HR22400013 |
| Is Public | Yes |
| Language Text | English |
| Keyword | H-1 AND C-13 NMR SPECTROSCOPY; MASS SPECTROMETRY; 15-OXYGENATED BILE ACID |
| Is Qa | No |