Design and synthesis of seco-oxysterol analogs as potential inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase gene transcription.
The synthesis and biological activity of a series of seco-oxysterol analogs designed to be inhibitors of transcription of the gene for 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGR) are described. The compound possessing the most significant activity, [1 alpha (E),4 beta]-3-[2-(4- hydroxy-1-methylcyclohexyl)ethenyl]-alpha,alpha-dimethylbenzenepentan ol (4, U-88156), inhibited (IC50 = 10 microM) the expression of beta-galactosidase (beta-gal) in a transfected human HepG2 cell line wherein the beta-gal gene was driven by a 5 kB segment of the promoter for hamster HMGR. Furthermore, using wild-type HepG2 cells, it was shown that 10 microM 4 reduced HMGR mRNA levels by 73% while stimulating LDL-receptor activity by 47%. In the same system, the related oxysterol, 25-hydroxycholesterol (1), at 10 microM lowered both HMGR mRNA levels and LDL-receptor activity by 58% and 64%, respectively. Overall HMGR activity in wild-type HepG2 cells was inhibited 30% by 4 at 10 microM. These findings collectively demonstrate that a seco-oxysterol analog is capable of regulating HMGR gene expression and that this regulation can occur without a concomitant attenuation of the level of LDL-receptor activity.
Larsen
S D
SD
Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001.
Spilman
C H
CH
Yagi
Y
Y
Dinh
D M
DM
Hart
K L
KL
Hess
G F
GF
D000818:Animals; D006224:Cricetinae; D015195:Drug Design; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics*; D010100:Oxygen / Q000737:chemistry; D011401:Promoter Regions, Genetic; D011973:Receptors, LDL / Q000378:metabolism; D013261:Sterols / Q000138:chemical synthesis / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D011973:Receptors, LDL; D013261:Sterols; D006903:Hydroxymethylglutaryl CoA Reductases; D010100:Oxygen