Squalene inhibition

Like the a2ole derivatives, it inhibits the biosynthesis of ergosterol. However, naftifine [65472-88-0] does not inhibit the cytochrome P-450 dependent C-14-demethylase, but the epoxidation of squalene. Squalene epoxidase cataly2es the first step in the conversion of squalene via lanosterol to ergosterol in yeasts and fungi or to cholesterol in mammalian cells. The squalene epoxidase in C. albicans is 150 times more sensitive to naftifine, C2 H2 N, than the en2yme in rat fiver (15). Naftifine is available as a 1% cream. 

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. 

The synthetic thiocarbamates, of which tolnaftate (Fig. 5.20J) is an example, also inhibit squalene epoxidase. Tolnaftate inhibits this enzyme from C. albicans, but is inactive against whole cells, presumably because of its inability to penetrate the cell wall. Tolnaftate is used topically in the treatment or prophylaxis of tinea. 

This synthetic allylamine derivative inhibits the enzyme squalene epoxidase at an early stage in fungal sterol biosynthesis. Acting as a structural analogue of squalene, naffidine causes the accumulation of this unsaturated hydrocarbon, and a decrease in ergosterol in the fungal cell membrane. 

This is not discussed in detail since mechanisms of resistance have been carefully reviewed (Ghannoum and Rice 1999). It was pointed out that resistance has not been associated with modification of the structure. For the 1,2,4-triazoles that have been widely used, their effect is due to inhibition of the synthesis of ergosterol that is the dominant component of fungal cell membranes. Resistance is generally associated with modification of the target enzymes, for example, the epoxidation of squalene (Terbinafine) or 14a-demethylase (Fluconazole). Resistance of Candida albicans to the azole antifungal agent fluconazole demonstrated, however, the simultaneous occurrence of several types of mechanism for resistance (Perea et al. 2001) ... 

Synthesis of endogenic cholesterol is also controlled by exogenous cholesterol supplied in food the more dietary cholesterol is digested, the less endogenic cho-lesterol is produced in the liveV. Exogenous cholesterol inhibits the activity of hydroxymethylglutaryl-CoA reductase and the cyclization of squalene to lanosterol. 

Zaragozic acid A (which is also called squalestatin SI and has been shown to lower serum cholesterol levels in test animals by inhibition of squalene biosynthesis) by K. C. Nicolaou (University of California San Diego, Scripps Research Institute) ... 

Farnesylamine (123) (Fig. 20), a sesquiterpene alkaloid, was recently detected in whole extracts of Monomorium fieldi [129]. This compound had already be prepared by synthesis and found to display a whole range of biological activities. Among others, it inhibits arthropod molting, squalene synthesis, and the growth of malignant tumor cells, modulates human T cells and has anti-osteo-porosis activity [129]. 

Dimethyltelluride, dimethyltellurium dichloride and trimethyltelluronium chloride inhibit squalene monooxygenase in Schwann cells in culture. 

Tellurium-induced demyelination seems to be a result of squalene monooxygenase inhibition, and dimethyl tellurium dichloride may be the neurotoxic species presented to Schwann cells in vivo. 

Naftiflne is highly active against dermatophytes but less active against yeasts. Its mechanism of action is based on selective inhibition of squalene epoxidase, a key enzyme for the synthesis of ergos-terol. Side effects include local irritation and erythema. Contact with mucous membranes should be avoided. 

NT325 Reid, W. W. Accumulation of squalens-2,3-oxide during inhibition of phytosterol biosynthesis in Nicotiana tabacum. Phytochemistry 1968 7(3) NT338... 

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). °... 

Mechanism of Action A fungicidal antifungal that inhibits the enzyme squalene ep-oxidase, thereby interfering with fungal biosynthesis. Therapeutic Effect Results in death of fungal cells. 

In Tabernaemontana divaricata treatment of plant cell suspension cultures with an elicitor cause inhibition of CS activity [24,25]. This response is accompanied by stimulation of activity of constitutive enzyme activities of the isoprenoid pathway leading to 2,3-oxidosqualene (squalene synthase and squalene oxidase), and induction of enzymes required for biosynthesis of pentacyclic triterpenoid phytoalexins (/lAS and aAS). Thus inhibition of the branchpoint enzyme CS results in increased flux through the triterpenoid pathway. 

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... 

It is a synthetic allylamine derivative, which exerts its antifungal effect by inhibiting squalene epoxidase leading to deficiency of ergosterol and corresponding accumulation of squalene which causes fungal cell death. 

Terbinafine Inhibits epoxidation of squalene in fungi increased levels are toxic to them Reduces ergosterol prevents synthesis of fungal cell membrane Mucocutaneous fungal infections Oral t duration, days Toxicity Gastrointestinal upset, headache, hepatoxicity t Interactions None reported... 

Butenafine hydrochloride (Mentax) is a benzylamine that is structurally related to the allylamines. As with the allylamines, butenafine inhibits the epoxidation of squalene, thus blocking the synthesis of ergosterol, an essential component of fungal cell membranes. Butenafine is available as a 1% cream to be applied once daily for the treatment of superficial dermatophytosis. 

All results indicate that squalene makes a big contribution to enhance tumor growth inhibition and tumor suppression by anticancer treatments as well as by acting as a successful chemoprotective agent. 

Squalene supplementation is suggested to be accounted for tumor growth inhibition and prevention of normal cells to turn into tumor cells under oxidative stress. Although there is lack of evidence for human trials to show anticancer and antioxidant effects of squalene, animal models and in vitro experiments highlight a significant activity which urges for further exploration. 

Murakoshi, M., Nishino, H., Tokuda, H., Iwashima, A., Okuzumi, J., Kitano, H., and Iwasaki, R. (1992). Inhibition by squalene of the tumor promoting activity of 12 o-tetradecanoylphorbol-13 acetate in mouse skin carcinogenesis. Int. ]. Cancer 52,950-952. 

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