Ergosterol

The diene of ergosterol is very sensitive to oxidation. The 5a,8a-peroxide of ergosterol and a substantial number of other oxidation produets have been found as fungal metabolites. 

Although the yeast sterol ergosterol (I) is at the present time not so cheap as diosgenin and its side-chain degradation to pregnane derivatives is more involved, it exhibits the marked advantage over all other readily available ring C unsubstituted steroids in that it already possesses the A -diene system, which in the other instances has first to be introduced. 

Schoenewaldt et al. (1952) observed that when the sulfuric acid rearrangement conditions of the 9a, 1 la-oxide (VIII) are extended from a few minutes (leading to the unsaturated did VII) to several hours, the chief product is A -2 -ergostadien-3 8-ol-7-one. It appears very likely that the procedure of Djerassi et al. (1951c, 1952c) developed for the conversion of such A -7-ketones to 11-ketones in the pregnane series would also prove applicable to these ergostadiene derivatives. 

The further degradation of A -ergosten-3/3-ol-ll-one acetate (XII) to allopregnan-3/3-ol-ll,20-dione acetate (XV) has been reported by Chamberlin et al. (1951-1953). It involves ozonization of XII to 3 -acetoxy-ll-ketobisnorallocholanic acid (XIV) and Barbier-Wieland degradation to the requisite allopregnan-3j8-ol-ll,20-dione acetate (XV), the conversion of which to cortisone has already been outlined in Fig. 12. 

---

Irradiation of steroidal 3,7-dienes with ultraviolet light may result in ring opening and formation of various trienes. The most important reaction of this type is the conversion of ergosterol to previtamin Dj. 

See also Vitamin D2 Ergosterol. [VITAMINS - VITAMIN D] (Vol 25) Ergoloid mesylate [8067-24-1]... 

In 1919, Huldschinski (8) realized that uv light cured rickets and impacted on its etiology. The uv light and codHver oil were found to be usehil in the treatment of the disease, and irradiation of food produced the same effect as irradiation of the animal. The link between irradiation and plant materials led to the conclusion that ergosterol was an antirachitic substance, and an extensive effort was made to characterize the chemistry of irradiated ergosterol. 

Perbenzoic acid gave a doubly unsaturated triol monobenzoate. Only two hydroxyl groups could be acetylated, and one was tertiary. The saturated triol reacted with lead tetracetate to give an a glycol. When reacted with chromic acid, it gave a hydroxy lactone. From these observations, Windaus and Gmndmann (11) described the correct stmcture for ergosterol (1). 

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... 

P-Hydroxy steroids which contain the 5,7-diene system and can be activated with uv light to produce vitamin D compounds are called provitamins. The two most important provitamins are ergosterol (1) and 7-dehydrocholesterol (3). They are produced in plants and animals, respectively, and 7-dehydrocholesterol is produced synthetically on a commercial scale. Small amounts of hydroxylated detivatives of the provitamins have been synthesized in efforts to prepare the metaboHtes of vitamin D, but these products do not occur naturally. The provitamins do not possess physiological activities, with the exception that provitamin D is found in the skin of animals and acts as a precursor to vitamin D, and synthetic dihydroxalated... 

Provitamin Ergosterol is isolated exclusively from plant sources. The commercial product is ca 90—100% pure and often contains up to 5... 

Properties 7-Dehydro-cholesterol Ergosterol Vitamin D2 Vitamin... 

Natamycin. Natamycin or pimaricin (2) is a polyene with only four conjugated double bonds. This tetraene is obtained from Streptomjces natalensis. Like the other polyenes, pimaricin induces release from cells with membranes containing 20—40 mol % ergosterol. This is also the ergosterol concentration in the membrane of Saccharomjces cerevisiae. 

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. 

Ketoconazole. For treatment of systemic mycoses with amphotericin B or miconazole, the patient must be admitted to a hospital. This is not always possible, particularly in areas where systemic mycoses occur frequently, nor is it always desirable, because of the expense. For these reasons, it was desirable to find an antimycotic that combined safety and broad-spectmm activity with oral adraiinistration. Ketoconazole (10), which is orally active, met most of these requirements. This inhibitor of the ergosterol biosynthesis is an A/-substituted imidazole, that differs from its precursors by the presence of a dioxolane ring (6,7). Ketoconazole is rapidly absorbed in the digestive system after oral adrninistration. Sufficient gastric acid is required to dissolve the compound and for absorption. Therefore, medication that affects gastric acidity (for example, cimetidine and antacids) should not be combined with ketoconazole. 

Plasma levels of 3—5 p.g/mL are obtained two hours after adraiinistration of 200 mg ketoconazole. No accumulation in the bloodstream was noted after a 30-wk treatment with this dose. The half-life is approximately eight hours. When ketoconazole is taken with meals, higher plasma levels are obtained. Distribution studies using radioactive ketoconazole in rats show radioactivity mainly in the Hver and the connective tissue. Radioactivity is also present in the subcutaneous tissue and the sebaceous glands. After one dose of 200 mg in humans, ketoconazole is found in urine, saUva, sebum, and cenimen. Like miconazole, the mode of action is based on inhibition of the cytochrome P-450 dependent biosynthesis of ergosterol. This results in disturbed membrane permeabiUty and membrane-bound enzymes (8,10,23,25). 

Ergosterol [57-87-4] M 396.7, m 165-166 , [a] 5 g-171 (in CHCI3). Crystd from ethyl acetate, then from ethylene dichloride. 

Another example of selective deuteration in homogeneous solution is saturation of the sterically more accessible A -double bond in ergosterol acetate (142 143). The a-configuration of the incorporated deuteriums... 

---