Inhibitor of sterol biosynthesis

Scheme 18.34 Allenic steroids as inhibitors of sterol biosynthesis.

Boguslawski, W. and Wrobel, J. 1974. An inhibitor of sterol biosynthesis present in cow s milk. Nature 247, 210-211. 

In Chlorella species triparanol inhibited the removal of the 14a-methyl group, the second alkylation of the side-chain, and, in one species, the A8- A7-isomerase.149 This drug and AY9944 showed a lack of specificity in Chlorella, and it may be that primitive plants like these might be valuable as test organisms to establish the activities of potential inhibitors of sterol biosynthesis. 

Inhibitors of sterol biosynthesis provide many, useful, broad spectrum, fungicides, and it is essential that their effectiveness is retained as long as possible. Of the two major groups of SBI fungicides, only.the morpholines, which inhibit A reductase and/or A -A isomerase depending on their... 

Imazalil resistance appeared to be a stable character of the Isolates—no change in resistance level was observed after six weekly transfers on imazalil-free culture medium or six disease cycles in untreated lemon fruits. Six imazalil-resistant Isolates tested were cross-resistant to propiconazole, fenarimol, flusila-zole, penconazole, myclobutanil, prochloraz, diclobutrazol, and bltertanol, all of which inhibit the C-14 demethylation reaction in fungal sterol biosynthesis (27,28). However, the imazalil-resistant Isolates were sensitive to tridemorph and fenpropimorph, also inhibitors of sterol biosynthesis but of the A -A7 isomerization reaction (29). Imazalil-resistant mutants of P. italicum have shown the same pattern of cross-resistance (20,30). 

The identity of the sites responsible for regulating the distribution of intermediates between branches is presently unknown. Interpretation of available evidence is complicated by our incomplete understanding of the late steps of sterol biosynthesis (see Chapter 1). Experiments using various inhibitors of sterol biosynthesis have implicated the following as potential regulatory sites ... 

Oximes of certain sterols were examined as inhibitors of cholesterol biosynthesis, by suppressing two enzymes that are involved in the biochemical pathway of cholesterol biosynthesis. This dual activity indicates a promising series of biologically reactive oximes (and oxime ethers) capable of reducing cholesterol levels . 

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... 

Well over 100 plant pathogens have become resistant to various fungicides under field conditions. Failure of the acyl alanines, benzimidazoles, thiophanates, carboxanilides, dicarboximides, hydroxypyrimidines, some organophosphates, and most of the antibiotics has occurred. In other cases, a moderate decrease in sensitivity without a rapid loss of disease control has been observed as in the case of sterol biosynthesis inhibitors (triazoles, pyrimidines, and imidazoles) and organophosphates. The most effective approach is to use fungicides having different modes of action in combination,... 

Sterol biosynthesis inhibiting insecticides. The earliest examples of sterol biosynthesis inhibitors were triadimefon, imazalil, and triarimol. These compounds act by blocking the C14 alpha demethylation step in ergosterol biosynthesis [54], Further work in this area has resulted in numerous fungicides, a number of them containing aromatic fluorine, perfluoroalkyl ethers, and the trifluoromethylphenyl group (Fig. 11). In this section, we will discuss the trifluoromethylphenyl sterol biosynthesis inhibitors, such as triflumizole and fluotrimazole. 

Fig. 11. Trifluoromethyl-containing generation of sterol biosynthesis inhibitors.

For obvious reasons, inhibitors of cholesterol biosynthesis have aroused intense interest. Studies on a variety of species (mostly rats) have been made using 1-alkylimidazoles," colchicine," and chenodeoxycholic acid, the last work being particularly interesting as the metabolite affected HMG-CoA reductase but not cholesterol 7a-hydroxylase, the steps believed to be rate-limiting for the biosynthesis of sterols and of bile acids respectively. Arsenite, /8-mercaptoethanol, dithiothreitol, and ethanethiol all inhibited the biosynthesis of cholesterol from MVA in rat liver homogenates. The accumulation of 4,4-dimethyl-5a-cholest-8-en-3/3-ol together with the corresponding A -diene supported the view that... 

Exploration of the area of imidazole-l-carboxamides has led to the discovery of prochloraz, a broad-spectrum fungicide for use on a variety of crops. Prochloraz and its analogues are inhibitors of ergosterol biosynthesis and structure-activity relationships in the area are discussed. In particular, the usefulness of an in vitro assay for sterol biosynthesis as a guide to the chemical effort is considered. Finally, the biological activity of prochloraz is briefly described. 

Svoboda and co-workers (Svoboda and Robbins, 1967 1968 Svoboda et al., 1967 1969) found that triparanol, 2-(4-chlorophenyl)-l-[4-(2-diethylamino-ethoxy)phenyl]-l-(4-tolyl) ethanol and 22,25-diazacholesterol (99) inhibit sterol reductase and also disrupt the normal growth and development of the larvae of tobacco homworm, Manduca sexta. Both compounds are known as inhibitors of steroid biosynthesis in vertebrates. 22,25-DiazacholesteroI is a hypocholeste-rolaemic agent acting as a competitive antagonist of cholesterol. A similar activity was found later for 25-azacholesterol (100). For the determination of the minimum structural requirements of activity, Svoboda and Robbins synthesised and tested... 

The resolution of synthetic presqualene and prephytoene alcohols via their etienic acid derivatives has been reported. This work confirmed that the active (-f-)-enantiomers in both series have the same absolute configuration [(li , 2/ , 3/ )]. It has been established, by use of Hn.m.r., that the proton (deuteron) introduced at C-3 during the cyclization of squalene to tetrahymanol by Tetrahymena pyriformis has the 3/8 configuration. Both antipodes of the trimethyldecalol (13) have been shown to be effective inhibitors of cholesterol biosynthesis in rat liver enzyme preparations and cultured mammalian cells. The accumulation of squalene 2,3-oxide and squalene 2,3 22,23-dioxide in the treated systems indicates that inhibition occurs at the cyclization stage. The inhibitor is metabolized to the diol (14). The results of other sterol inhibition... 

Covey, D.F. (1988), Aromatase inhibitors Specific inhibitors of oestrogen biosynthesis. In Berg and Plempel (eds). Sterol Biosynthesis Inhibitors. Ellis Horwood Ltd., Cambridge, pp. 534-571. 

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