Chemical synthesis of 15-ketosterols and their inhibitions of cholesteryl ester transfer protein Original Research Article

Described herein are the chemical syntheses of 3β-hydroxy-5α-cholest-8(14)-en-15-one and 3β-hydroxy-5α-cholest-8(14), 16-dien-15-one from diosgenin and the examinations of their ability to inhibit the cholesteryl ester transfer protein (CETP). Clemmensen reduction of diosgenin gave cholest-5-ene-3β,16β,26-triol. Tosylation of the latter compound gave cholest-5-ene-3β,16β,26-triol 26-tosylate which, upon reduction with LiAlH4, gave cholest-5-ene-3β,16β-diol. Hydrogenation-benzoylation of the latter to 5α-cholest-3β,16β-diol 3β-benzoate followed by mesylation-elimination gave 5α-cholest-16-ene-3β-ol 3β-benzoate. Controlled oxidation of the latter with CrO3-dimethylpyrazole gave 3β-hydroxy-5α,14α-cholest-16-en-15-one 3β-benzoate. Oxidation of Δ16-15-one with SeO2 gave 3β-hydroxy-5α-cholest-8(14),16-dien-15-one 3β-benzoate along with 3β-hydroxy-5α,14β-cholest-16-en-15-one 3β-benzoate. Selective hydrogenation of the Δ8(14).16-15-ketosteryl ester, followed by base hydrolysis gave 3β-hydroxy-5α-cholest-8(14)-en-15-one. Hydrolysis of 3β-hydroxy-5α-cholest-8(14),16-dien-15-one 3β-benzoate in basic media gave 3β-hydroxy-5α-cholest-8(14),16-dien-15-one. The effects of the 15-ketosterols on the CETP activity were studied in vitro by incubating cholesteryl ester donor (HDL), cholesteryl ester acceptor (LDL) and human plasma as a CETP source at 37 °C. 3β-Hydroxy-5α-cholest-8(14)-en-15-one was found to be active in supression of the levels of CETP activity in human plasma.