Ergosterol derivative

The highly oxygenated ergosterol derivatives, ergokonin A and B (165, 166), are produced by T. koningii and T. viride isolates [232]. Ergokonin A is characterised by esterification at the 3-hydroxyl with the unusual 3-hydroxy-leucine-3-O-sulphate moiety [231] and has been shown cause... 

Miller illustrated the use of a nitroso dienophile in his synthesis of Diels-Alder product 24 from ergosterol (22) and nitroso 23. Subsequent cleavage of the N-O bond in 24 furnished an ergosterol derivative with significant anticancer activity. ... 

Irradiated ergosterol was found not to be as antirachitic in the chick as in the rat, whereas the chick could be protected by direct kradiation. The provitamin in cholesterol was shown not to be ergosterol. Rygh (14) in 1935 found that 1 rat unit of cod Hver oil was 100 times more potent in chicks than 1 rat unit of vitamin D2. Brockmann (15) in 1936, prepared the pure crystalline 3,5-dinitrobenzoate derivative of vitamin D obtained from tuna Hver oil... 

Clotrimazole and other azole derivatives have a different mode of action than the polyenes, eg, amphotericin B. The latter biad to the ergosterol present ia the membranes of yeasts and fungi, but azole derivatives inhibit the cytochrome P-450 dependent biosynthesis of ergosterol (8—11). This inhibition not only results in a reduction of ergosterol, but also in an accumulation of C-14 methyl sterols. They disturb membrane permeabiUty, inhibit cell rephcation, and are basically responsible, in combination with the reduction of ergosterol levels, for the antifungal action. 

Miconazole. Miconazole nitrate [22832-87-7] (Fig. 2), the 1-phenethyl-imidazole derivative first described in 1969, interferes at low doses with the cytochrome P-450 dependent ergosterol biosynthesis in yeasts and fungi. The result is accumulation of C-14 methylated sterols on the one hand and reduction of the ergosterol levels in the membranes on the other hand (12). Analogous to clotrimazole, this leads to a disturbance in the membranes it results in inhibition of ceU repHcation, mycelium development (in C. albicans) and finally, ceU death. High concentrations of miconazole, which may be achieved with topical use, disturb the orientation of phosphoHpids in the membranes, which produces leaks (13). 

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. 

A. Molecular Ion Because of low volatility, most steriods are derivatized before analysis by GC/MS. Molecular ions are usually observed for steriods sufficiently volatile to be analyzed underivatized by GC/MS (see Figure 31.1) Some important steroids in urine include estrone, estradiol, estriol, pregnanediol, and 17-ketosteroids. which can be analyzed by GC/MS as the TMS or the MO-TMS derivatives. The plant steroids, such as camposterol, ergosterol. stigmasterol, cholestanol, and sitosterol, are generally analyzed as the TMS derivatives. 

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. 

We have already reported that the use of cyclohexanol at 140°C in the hydrogenation of ergosterol over Cu/A1203 gives the 5(5 derivative with an 81% selectivity owing to an intramolecular hydrogen transfer reaction, whereas direct H2 addition over the same catalyst gives the 5a isomer with 89% selectivity (10) (Scheme 1). 

Ergosterol CjgH OH, a trebly unsaturated alcohol, is derived from the same ring system. It is produced in relatively large amounts by fungi, in particular by yeast, and on irradiation it is isomerised to the anti-rachitic vitamin, vitamin-D (Windaus). 

Plant sterols such as stigmasterol typically contain an extra ethyl group when compared with cholesterol. Now this is not introduced by an electrophilic ethylation process instead, two successive electrophilic methylation processes occur, both involving SAM as methyl donor. Indeed, it is a methylene derivative like that just seen in ergosterol formation that can act as the alkene for further electrophilic alkylation. After proton loss, the product has a side-chain with an ethylidene substituent the side-chains of the common plant sterols stigmasterol and sitosterol are then related by repeats of the reduction and dehydrogenation processes already seen in ergosterol formation. 

Fluconazole and itraconazole are newer, orally effective triazole derivatives. The topically active allylamine naftidine and the morpholine amorolfine also inhibit ergosterol synthesis, albeit at another step. 

Peroxy derivatives of steroids have been isolated from both marine and terrestrial sources. They are most commonly 5a, 8a-endoperoxides with variations in the side-chains. The ergosterol peroxide 102 is the most ubiquitous endoperoxide-containing natural product and is isolated from a large number of sources. Ergosterol peroxide 102 was found to have antitumour activity against breast cancer and carcinosarcoma cell lines. A number of other steroidal endoperoxides have been reported which differ in the nature of the side-chain. Compound 103 was found to be an inhibitor of tumour promotion in mouse studies . 

In addition to the endogenous metabolites, some exogenous sterols possess biological activity similar to that of D3. Ergocalciferol (vitamin D2) is derived from the plant sterol ergosterol and may act as a substrate for both the 25-hydroxylase and the 1-hydroxylase enzyme systems of the liver and kidney to form 25-(OH)D2 and 1,25-(0H)2 D2, respectively. Ergocalciferol (vitamin D2) is the form used in commercial vitamins and supplemented dairy products. Dihydrotachysterol, another sterol that is used as a therapeutic agent, also functions as a substrate for the hydroxylase enzymes in the liver and kidney. 

Cholecalciferol is pure vitamin D3 derived from the ultraviolet conversion of 7-dehydrocholesterol to cholecalciferol. Ergocalciferol vitamin D2) is a sterol derived from yeast and fungal ergosterol. Calcitriol [Rocaltrol, 1,25-(0H)2D3] is the metabolically active vitamin D3 compound. Dihydrotachysterol is a synthetic compound that may act somewhat more quickly than either vitamin D2 or D3. 

The 5-fluorocytosine (flucytosine) is an inhibitor of sterol C-14 demethylase, an enzyme involved in the biosynthesis of ergosterol, an element of fungal wall. It is marketed as an anti-fungal agent, whereas nucleoside derivatives of the... 

Mecfianism of Action An imidazole derivative that inhibits synthesis of ergosterol (vital component of fungal cell formation), damaging cell membrane. TAerapeMtIc Effect Fungistatic may be fungicidal, depending on concentration. 

Mechanism of Action A triazole derivative that inhibits the synthesis of ergosterol, a vital component of fungal cell wall formation. Therapeutic Effect Damages fungal cell wall membrane. 

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. 

The photochemistry of all these compounds is of interest with respect to the well-known photochemistry of cyclohexadiene (1.3) derivatives, for instance, the photochemical reactions of 2.4.6-triaryl-cyclohexadien(2.4)-on-ol(2) series of Perst and Dimroth or in a more comprehensive context the photochemical transformation of ergosterol, luniisterol, isopyrocalciferol and pyrocalciferol which were first studied by Windaus and Dimroth and fully investigated by Veluz, Havinga and Dauben... 

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