Squalene inhibitors

Dioxolane derivatives, which are obtained from methoxybutenone and glycols and used as antifungicides, and squalene synthetase inhibitors have been described (94MI1). The reactions of mono- and oligosaccharides with... 

The search for inhibitors of this pathway began with the first key regulatory enzyme, HMG CoA reductase. Several clinically useful inhibitors of HMG CoA reductase are now known. One of the most successful, Mevacor, produced by Merck, is one of the pharmaceutical industry s best selling products. However, the problem with inhibiting a branched biosynthetic pathway at an early point is that the biosynthesis of other crucial biomolecules may also be inhibited. Indeed, there is some evidence that levels of ubiquinone and the dolichols are affected by some HMG CoA reductase inhibitors. Consequently, efforts have recently been directed towards finding inhibitors of squalene synthase, the enzyme controlling the first step on the route to cholesterol after the FPP branch point. 

Terbinafme (Fig. 5.171), a member ofthe allylamine class ofantimycotics, is an inhibitor of the enzyme squalene epoxidase in fungal ergosterol biosynthesis. Terbinafme is orally active, is fungicidal and is effective against a broad range of dermatophytes and yeasts. It can also be used topically as a cream. 

The design of FTase inhibitors based on the structure of farnesyl pyrophosphate has been pursued with less intensity due to the possible nonselective effects of competing with other enzymes such as squalene synthetase that also accept farnesylpyrophosphate as substrate [3,4,9,10-12]. 

CATTEL, L., CERUTI, M., 2,3-Oxidosqualene cyclase and squalene epoxidase Enzymology, mechanism and inhibitors. In Physiology and Biochemistry of Sterols (G.W. Patterson and W.D. Nes, eds,), American Oil Chemists Society, Champaign. 1992, pp. 50-82. 

Organotellurium compounds such as dimethyltellurium dichloride and dimethyltelluride have been reported as potential inhibitors of squalene monooxygenase, causing a dramatic reduction in the rate of cholesterol biosynthesis and leading to degradation of the myelin sheath. 

Georgopapadakou, N.H. and Bertasso, A. (1992) Effects of squalene epoxidase inhibitors on Candida albicans. Antimicrobial Agents and Chemotherapy, 36, 1779-1781. 

Trifluoromethyl ketones and alcohol derivatives of squalene have been prepared in order to inhibit squalene epoxycyclase. This important enzyme regulates the biosynthesis of cholesterol. It bears a cysteine in its active site. Although these compounds have been shown to be good inhibitors, the involved mechanism is different from what was expected. Indeed, they do not inhibit squalene epoxycyclase, but they are substrates of this enzyme and are transformed into fluorohydroxysterols. The repression of the expression of HMG-CoA reductase is responsible for the observed inhibition of cholesterol biosynthesis. This repression comes from the back-regulation that is exerted by fluorohydroxysterols. Indeed, these compounds induce an important diminution of the cell activity of HMG-CoA reductase (Figure 7.66). °... 

Zaragozic acid or the squalastatins were discovered as fungal metabolites and have been identified as potent inhibitors of squalene synthase. These compounds have presented themselves as potential cholesterol lowering agents. 

H. S. Olcott (University of California, Berkeley, Calif.) We have studied the effects of aliphatic amines on the autoxidation of a fish oil and squalene in air at moderate temperatures. There was little protection unless phenolic-type inhibitors were also added, in which case secondary amines were more effective than primary or secondary amines. However, at 70 °C. trioctylamine alone protected the fish oil, whereas at lower temperatures it did not (2). Further study revealed that peroxides react with trioctylamine to yield some dioctylhydroxylamine which has antioxidant properties (1). These and other observations (3) indicate that... 

More recently it has been shown (6, 7) that zinc dialkyl dithiophosphates also act as chain-breaking inhibitors. Colclough and Cunneen (7) reported that zinc isopropyl xanthate, zinc dibutyl dithiocarbamate, and zinc diisopropyl dithiophosphate all substantially lowered the rate of azobisisobutyronitrile-initiated oxidation of squalene at 60°C. Under these conditions, hydroperoxide chain initiation is negligible, and it was therefore concluded that inhibition resulted from removal of chain-propagating peroxy radicals. Also, consideration of the structure of these zinc dithioates led to the conclusion that no suitably activated hydrogen atom was available, and it was suggested that inhibition could be accounted for by an electron-transfer process as follows ... 

Ergosterol biosynthesis inhibitors via squalene epoxidase enzyme inhibition... 

Toward the synthesis of zaragozic acids, a novel family of fungal metabolites that has been shown to be picomolar competitive inhibitors of squalene synthease, Hodgson s group and Hashimoto s group have used cyclic carbonyl ylide formation/[3 + 2]-cycloaddition approach. " In Hashimoto s synthesis, the 2,8-dioxabicyclo[3,2,l]octane core... 

Scheme 7.6 Stereoselective acetylation of the hydroxyl diethyl ester (9) to the (S)-acetate as an intermediate for the synthesis of a squalene synthase inhibitor ( ) of cholesterol synthesis.

One of the best therapeutic approaches may be to prevent absorption of cholesterol from the intestines by inclusion of a higher fiber content in the diet.66 Supplementation with a cholesterol-binding resin may provide additional protection. Plant sterols also interfere with cholesterol absorption. Incorporation of esters of sitostanol into margarine provides an easy method of administration. Supplemental vitamin E may also be of value.q Another effective approach is to decrease the rate of cholesterol synthesis by administration of drugs that inhibit the synthesis of cholesterol. Inhibitors of HMG-CoA reductase,s hh (e.g., vaLostatin) iso-pentenyl-PP isomerase, squalene synthase (e.g.,... 

Zaragozic Acids The zaragozic acids (squalestatins) are a class of competitive inhibitors of mouse, rat, and HepG2 squalene synthases, which also display antifungal activity [104]. The characteristic structural feature of this family of natural products is its highly oxygenated core. 

Bergstrom JD, Dufresne C, Bills GF, Nallin-Omstead M and Byrne K (1995) Discovery, biosynthesis and mechanism of action of the zaragozic acids potent inhibitors of squalene synthase. Annu Rev Microbiol 49, 607-639. 

Watson NS and Procopiou PA (1996) Squalene synthase inhibitors their potential as hypocholesterolaemic agents. Prog Med Chem 33, 331-378. 

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