Chemical synthesis of 15-ketosterols and their inhibitions of cholesteryl ester transfer protein.
Described herein are the chemical syntheses of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one and 3 beta-hydroxy-5 alpha-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-3 beta, 16 beta,26-triol. Tosylation of the latter compound gave cholest-5-ene-3 beta,16 beta,26-triol 26-tosylate which, upon reduction with LiAIH4, gave cholest-5-ene-3 beta,16 beta-diol. Hydrogenation-benzoylation of the latter to 5 alpha-cholest-3 beta,16 beta-diol 3 beta-benzoate followed by mesylation-elimination gave 5 alpha-cholest-16-ene-3 beta-ol 3 beta-benzoate. Controlled oxidation of the latter with CrO3-dimethylpyrazole gave 3 beta-hydroxy-5 alpha, 14 alpha-cholest-16-en-15-one 3 beta-benzoate. Oxidation of delta 16-15-one with SeO2 gave 3 beta-hydroxy-5 alpha-cholest-8(14),16-dien-15-one 3 beta-benzoate along with 3 beta-hydroxy-5 alpha, 14 beta-cholest-16-en-15-one 3 beta-benzoate. Selective hydrogenation of the delta 8(14),16-15-ketosteryl ester, followed by base hydrolysis gave 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one. Hydrolysis of 3 beta-hydroxy-5 alpha-cholest-8(14),16-dien-15-one 3 beta-benzoate in basic media gave 3 beta-hydroxy-5 alpha-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 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)
Kim
H S
HS
Department of Industrial Chemistry, Kyungpook National University, Taegu, Korea.
Oh
S H
SH
Kim
D I
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Kim
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Cho
K H
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Park
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YB
D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002783:Cholestenones / Q000138:chemical synthesis / Q000494:pharmacology; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters / Q000378:metabolism; D004144:Diosgenin / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006023:Glycoproteins; D006801:Humans; D006865:Hydrogenation; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013261:Sterols / Q000138:chemical synthesis* / Q000494:pharmacology*
C098205:3-hydroxycholest-8(14),16-dien-15-one; D000924:Anticholesteremic Agents; C506642:CETP protein, human; D002352:Carrier Proteins; D002783:Cholestenones; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D006023:Glycoproteins; D013261:Sterols; C015073:cholest-8(14)-en-3-ol-15-one; D004144:Diosgenin