Biomaterial Database

Oxolanosterol oximes: dual-action inhibitors of cholesterol biosynthesis. 1994

L L Frye, and K P Cusack, and D A Leonard, and J A Anderson

Department of Chemistry, Rensselaer Polytechnic Institute, Troy, NY 12180-3590.

A series of oxolanosterol oximes and oxime ethers have been prepared as potential dual-action inhibitors of cholesterol biosynthesis. The synthesis of these oximes along with the evaluation of their ability to inhibit lanosterol 14 alpha-methyl demethylase (P450DM) and to suppress 3-hydroxy-3-methylglutaryl coenzyme. A reductase (HMGR) activity is presented. 3 beta-Hydroxylanost-7-en-15-one 15-oxime XIX was found to be an effective inhibitor of P450DM in rat liver microsomal preparations. In [14C]acetate incorporation studies using Chinese hamster ovary (CHO) cells, compound XIX was found to cause a dramatic reduction in the incorporation of acetate into C27 sterols with a concomitant increase in radiolabeled C30 sterols which is consistent with the inhibition of P450DM. In addition, 15-oxime XIX was shown to suppress HMGR activity in both wild-type CHO and P450DM-deficient (AR45) cells, indicating that suppression of HMGR is independent of any effects of this oxime on P450DM. In both cell lines, parallel declines in HMGR activity and HMGR protein levels were observed suggesting that compound XIX suppresses HMGR activity by regulation of gene expression. These results demonstrate that, as predicted, 15-oxime XIX is indeed a dual-action inhibitor of cholesterol biosynthesis which causes both the inhibition of P450DM and a reduction in HMGR activity.

UI	MeSH Term	Description	Entries
D007810	Lanosterol	A triterpene that derives from the chair-boat-chair-boat folding of 2,3-oxidosqualene. It is metabolized to CHOLESTEROL and CUCURBITACINS.	Kryptosterol,4,4,14 alpha-trimethyl-5 alpha-cholesta-8,24-dien-3 beta-ol
D008862	Microsomes, Liver	Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough.	Liver Microsomes,Liver Microsome,Microsome, Liver
D010088	Oxidoreductases	The class of all enzymes catalyzing oxidoreduction reactions. The substrate that is oxidized is regarded as a hydrogen donor. The systematic name is based on donor:acceptor oxidoreductase. The recommended name will be dehydrogenase, wherever this is possible; as an alternative, reductase can be used. Oxidase is only used in cases where O2 is the acceptor. (Enzyme Nomenclature, 1992, p9)	Dehydrogenases,Oxidases,Oxidoreductase,Reductases,Dehydrogenase,Oxidase,Reductase
D010091	Oximes	Compounds that contain the radical R2C	Aldoximes,Hydroxyimino Compounds,Ketoxime,Ketoximes,Oxime,Compounds, Hydroxyimino
D002784	Cholesterol	The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.	Epicholesterol
D006224	Cricetinae	A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.	Cricetus,Hamsters,Hamster
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D016466	CHO Cells	CELL LINE derived from the ovary of the Chinese hamster, Cricetulus griseus (CRICETULUS). The species is a favorite for cytogenetic studies because of its small chromosome number. The cell line has provided model systems for the study of genetic alterations in cultured mammalian cells.	CHO Cell,Cell, CHO,Cells, CHO
D058886	Sterol 14-Demethylase	An NADPH-dependent P450 enzyme that plays an essential role in the sterol biosynthetic pathway by catalyzing the demethylation of 14-methyl sterols such as lanosterol. The enzyme acts via the repeated hydroxylation of the 14-methyl group, resulting in its stepwise conversion into an alcohol, an aldehyde and then a carboxylate, which is removed as formic acid. Sterol 14-demethylase is an unusual cytochrome P450 enzyme in that it is found in a broad variety of organisms including ANIMALS; PLANTS; FUNGI; and protozoa.	Sterol 14-Demethylases,CYP51 Cytochrome P-450,Cytochrome P-450 CYP51,Eburicol 14 alpha-Demethylase,Eburicol 14alpha-Demethylase,Lanosterol 14 alpha-Demethylase,Obtusifoliol 14alpha-Demethylase,Sterol 14-alpha-Demethylase,14 alpha-Demethylase, Eburicol,14 alpha-Demethylase, Lanosterol,14-Demethylase, Sterol,14-Demethylases, Sterol,14-alpha-Demethylase, Sterol,14alpha-Demethylase, Eburicol,14alpha-Demethylase, Obtusifoliol,CYP51 Cytochrome P 450,CYP51, Cytochrome P-450,Cytochrome P 450 CYP51,Cytochrome P-450, CYP51,Eburicol 14 alpha Demethylase,Eburicol 14alpha Demethylase,Lanosterol 14 alpha Demethylase,Obtusifoliol 14alpha Demethylase,P-450 CYP51, Cytochrome,P-450, CYP51 Cytochrome,Sterol 14 Demethylase,Sterol 14 Demethylases,Sterol 14 alpha Demethylase
D019161	Hydroxymethylglutaryl-CoA Reductase Inhibitors	Compounds that inhibit HYDROXYMETHYLGLUTARYL COA REDUCTASES. They have been shown to directly lower CHOLESTEROL synthesis.	HMG-CoA Reductase Inhibitor,HMG-CoA Reductase Inhibitors,Hydroxymethylglutaryl-CoA Reductase Inhibitor,Statin,Statins, HMG-CoA,Inhibitors, HMG-CoA Reductase,Inhibitors, Hydroxymethylglutaryl-CoA,Inhibitors, Hydroxymethylglutaryl-Coenzyme A,Statins,HMG CoA Reductase Inhibitor,HMG CoA Reductase Inhibitors,HMG-CoA Statins,Hydroxymethylglutaryl CoA Reductase Inhibitor,Hydroxymethylglutaryl CoA Reductase Inhibitors,Hydroxymethylglutaryl-CoA Inhibitors,Hydroxymethylglutaryl-Coenzyme A Inhibitors,Inhibitors, HMG CoA Reductase,Inhibitors, Hydroxymethylglutaryl CoA,Inhibitors, Hydroxymethylglutaryl Coenzyme A,Inhibitors, Hydroxymethylglutaryl-CoA Reductase,Reductase Inhibitor, Hydroxymethylglutaryl-CoA,Reductase Inhibitors, HMG-CoA,Reductase Inhibitors, Hydroxymethylglutaryl-CoA,Statins, HMG CoA