Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

4Alpha-(2-propenyl)-5alpha-cholestan-3alpha-ol (LY295427) was previously identified from a Chinese hamster ovary (CHO) cell-based low density lipoprotein receptor/luciferase (LDLR/Luc) assay to be a potent transcriptional activator of the LDL receptor promoter in the presence of 25-hydroxycholesterol. To investigate the effect of the 24,25-unsaturation in the D-ring side chain (desmosterol D-ring side chain) on antagonizing the repressing effect of 25-hydroxycholesterol, 4alpha-(2-propenyl)-5alpha-cholest-24-en-3alpha-ol (17), a 24,25-dehydro analog of LY295427, was thus synthesized from lithocholic acid via the formation of 3alpha-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4alpha- (2-propenyl)-5alpha-cholan-24-al (15). Test results showed that 17 had an EC30 value of 2.6 microM, comparable to 2.9 microM of LY295427, in the CHO cell-based LDLR/Luc assay in the presence of 25-hydroxycholesterol. Apparently, the built-in 24,25-unsaturation in the D-ring side chain of 17 had added little effect to antagonizing the repressing effect of 25-hydroxycholesterol. In the [1-14C-acetate]cholesterol biosynthesis inhibition assay, 17 at 10 microg/ml (23 microM) has been shown to inhibit the cholesterol biosynthesis in CHO cells by 38% relative to the vehicle control; whereas LY295427 showed no inhibition in the same assay in our previous studies. In contrast to LY295427, the built-in 24,25-unsaturation in the D-ring side chain of 17 has conferred an inhibitory effect on cholesterol biosynthesis in CHO cells. In summary, the observed LDL receptor promoter activity of 17 is related to its ability to prevent 25-hydroxycholesterol from exerting the repressing effect via an undetermined mechanism and, in part, to inhibit the cholesterol biosynthesis.
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PMID:Synthesis and in vitro biological activity of 4alpha-(2-propenyl)-5alpha-cholest-24-en-3alpha-ol: a 24,25-dehydro analog of the hypocholesterolemic agent 4alpha-(2-propenyl)-5alpha-cholestan-3alpha-ol. 1040 Mar 83

4alpha-(2-Propenyl)-5alpha-cholest-24-en-3alpha-ol (3) was shown recently in a Chinese hamster ovary (CHO) cell-based low-density lipoprotein receptor/luciferase (LDLR/Luc) assay to be a potent transcriptional activator of the LDL receptor promoter in the presence of 25-hydroxycholesterol. Because of the involvement of 12alpha-hydroxylation in the metabolism of cholesterol, we are interested in investigating the effect of introducing a 12alpha-hydroxyl group to 3 on the transcriptional activity of the LDL receptor promoter. Thus 4alpha-(2-propenyl)-5alpha-cholest-24-en-3alpha,12a lpha-diol (14), a 12alpha-hydroxyl analog of 3, was synthesized from deoxycholic acid via the formation of 12alpha-[[(tertbutyl)dimethylsilyl]oxy]-4alpha-( 2-propenyl)-5alpha-cholest-24-en-3-one (11). Test results show that 14 is inactive at concentrations of up to 20 microg/ml, compared to 3 with an EC30 value of 2.6 microM, in the CHO cell-based LDLR/Luc assay. Apparently introduction of a 12alpha-hydroxyl group abolishes the capability of 3alpha-sterol 14 to activate the transcription of the LDL receptor promoter. However, in the [1-14C-acetate]cholesterol biosynthesis inhibition assay in CHO cells, 14 at 10 microg/ml (23 microM) is shown to inhibit the cholesterol biosynthesis by 51% relative to the control cells. Our previous studies indicated that 3 showed a 38% inhibition, but 4alpha-(2-propenyl)-5alpha-cholestan-3alpha-ol (1) exhibited no inhibition in the same assay at 10 microg/ml. In summary the results indicate that, in addition to the 24,25-unsaturation, the 12alpha-hydroxyl group in 14 has also conferred an inhibitory effect on cholesterol biosynthesis in CHO cells; however, the inhibition of cholesterol biosynthesis by 14 does not lead to the transcriptional activation of the LDL receptor promoter.
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PMID:Synthesis and in vitro biological activity of 4alpha-(2-propenyl)-5alpha-cholest-24-en-3alpha,12 alpha-diol, a 12alpha-hydroxyl analog of 4alpha-(2-propenyl)-5alpha-cholest-24-en-3alpha-ol: the latter is a potent activator of the low-density lipoprotein receptor promoter. 1049 32