Synthesis and biological testings as inhibitors of HMGCoA reductase of the seco-acid of tuckolide and its C-7 epimer.
The seco-acid of the natural macrolactone, tuckolide (decarestrictin D) and the C-7 epimer have been prepared in enantiomerically pure form from D-gluconolactone and poly(3-hydroxy butyric acid). The key steps are Horner Emmons olefination and stereoselective reduction of the resulting enone to provide both epimers at C-7. None of the seco-acids inhibit microsomal HMGCoA reductase of pea or rat liver. It may be concluded that the cholesterol biosynthesis inhibiting effect of tuckolide is unlikely to proceed via HMGCoA reductase inhibition.
Colle
S
S
Groupe SUCRES, UMR 7565 CNRS-Université Henri Poincaré-Nancy I, Nancy-Vandoeuvre, France.
Taillefumier
C
C
Chapleur
Y
Y
Liebl
R
R
Schmidt
A
A
D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology; D019684:Magnoliopsida / Q000166:cytology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D063065:Organophosphonates / Q000737:chemistry; D010944:Plants; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000447:Aldehydes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones; D063065:Organophosphonates; C073577:decarestrictine D; D006903:Hydroxymethylglutaryl CoA Reductases