ChemInform Abstract: Inhibitors of Sterol Biosynthesis and Growth in Plants and Fungi

Abstract

Abstract Sterols and their derivatives promote and maintain growth and development in plants and fungi by acting as membrane constituents and probably also as hormones, engaged in control of metabolism. Inhibitors of sterol biosynthesis, operating at various stages in the pathway, are useful probes for investigating these functions. Some of the inhibitors have assumed considerable commercial importance as agricultural fungicides and antimycotic drugs in medicine. There is also potential for using similar compounds to regulate plant growth. The work reviewed here, much of it done within the last few years, points unmistakably to a fundamental role for sterols in promoting growth and development in both plants and fungi. A clear target enzyme in the biosynthetic pathway for growth inhibition in both plants and fungi is the 14α-methylsterol demethylase. Work with triazoles, particularly with closely related analogues and separated enantiomers, has provided an insight into the affinity of these inhibitors for the different forms of cytochrome P-450 which catalyse fungal sterol 14α-demethylation, plant sterol 14α-demethylation and plant ent -kaurene oxidation. It may become increasingly necessary to evaluate the relative contribution of these processes to optimise performance of fungicides, herbicides and PGRs, both with regard to their activity at the primary site of action and with a view to controlling side effects. There is clear scope here for extending and improving in vitro enzyme assay methods. The effectiveness of the morpholines as agricultural fungicides contrasts with the high tolerance of plants to cyclopropyl and Δ 8 -sterols which are readily induced by application of these compounds. Further study of the basic reason for morpholine toxicity is, therefore, an area well worthy of further investigation. Inhibition of squalene epoxidase by allylamines has proved successful in the development of medical antimycotics but no agricultural fungicides, based on this mode of action, have been forthcoming. Other enzymes of the pathway have yet to be commercially exploited but the C-24 alkylation process seems clearly linked to growth in both plants and fungi and hence would appear to be a particularly promising site for new inhibitors. The pre-squalene enzyme HMG-CoA reductase seems to offer potential for regulating or stopping plant growth. Above all there is a need to evaluate precisely how sterols and their derivatives control growth and developmental processes. The judicious use of inhibitors of the type described here may help in this undertaking which, in turn, could generate new ideas for the design and discovery of more active and specific compounds.