14-a-methylsterols

As a result of azole treatment as shown in figure 3, two 14-a-methylsterols accumulated, namely the dimethylsterol, obtusifoliol, and the trimethylsterol 24-methylenedihydrolanosterol, with a concomitant reduction in A5>24(28) rgostacjienoi>... 

Ergosterol synthesis inhibition has been found to coincide with an accumulation of 14 a-methylsterols in yeast cells. The corresponding inhibition in rat liver cells could only be achieved at a sixfold increase in ketoconazole concentration. The enzyme initiating the oxidation of the 14a-CH3 function is lanosterol- 14a-methyldemethylase. It has been... 

Azoles inhibit 14-a-sterol demethylase, a microsomal CYP that is essential for ergosterol biosynthesis (Figure 48-1). This results in the accumulation of 14-a-methylsterols that disrupt the packing of acyl chains of phospholipids and impair the functions of membrane-bound enzymes such as ATPase and those of the electron transport system, resulting in inhibited fungal growth. 

A -sterols are major intermediateT in tne . elegans pathway for sitosterol dealkylation. In addition, the predominance of A -4o-methylsterols revealed that the azasterold inhibits the isomerase that converts A - to A8(14)-4a-methylsterols. 

The effect of Voriconazole (10) is exerted within the fungal cell membrane. In particular, cytochrome P450-dependent 14-a-lanosterol demethylase is inhibited, which prevents the conversion of lanosterol (217) to ergosterol (218) - an important component of yeast and fungal cell membranes which does not occur in mammalians (Scheme 51). This mechanism results in the accumulation of toxic methylsterols and inhibition of fungal cell growth and replication [174]. 

Methylation at C-4 of sterol nucleus was one of the other factors affecting activity enhancement. Thus, in general, 4-methylsterols (14,15) and 4,4-dimethylsterols (8,13) exhibited higher activity than 4-desmethylsterols. A similar structure-activity relationship was observed also in the HHPA-induced inflammation on mouse ear [35]. Whereas cholesterol (7) did not show inhibitory activity, several 4,4-dimethylcholestane derivatives, 0-12, exhibited activity. 4,4-Dimethylcholestane-3a,5a-diol (12) was the most potent inhibitor its activity was comparable to that of ursolic acid (210) [35]. Compound 12 reduced also the inflammation induced by teleocidin B (3), one of the indole alkaloid-type of tumor promoters [53]. 

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