Kaurenoic acid

Most of the GA-synthesis inhibitors characterized so far affect two segments of the compHcated pathway from MVA to the many different GAs identified. The cycHzation reactions that produce / Akaurene are inhibited by the onium growth retardants, and the oxidations of /-kaurene to /-kaurenoic acid are sensitive to heterocycHc triazoles such as paclobutrazol and similar compounds. Other enzymes in the pathway are points for pathway dismption by as yet undeveloped GA biosynthesis inhibitors (236). 

C. M. Compadre, et al. Characterization of bacterial mutagenicity mediated by 13-hydroxy-ent-kaurenoic acid CA142 (steviol) and several structurally related derivatives and evaluation of potential to induce glutathione-S-transferase in mice. Mutat Res 1986 169 93-103. 

Microbiological Methods. The low substrate specificity of many of the enzymes involved in GA biosynthesis in Gibberella fujikuroi has been utilized for the preparation of higher plant GAs. Suitable analogs of the natural GA-precursors are converted by the fungus to the corresponding GA analogs. It is usual to prevent the synthesis of the natural GAs in order to facilitate purification of the unnatural products. A mutant strain, Bl- la, in which GA biosynthesis is blocked early in the pathway (67) (between ent-kaurenal and ent-kaurenoic acid) has been used. 

The Bl-tla mutant was found also to metabolize ent-lfo-hydroxy-kaurenoic acid to a number of 150-hydroxylated GAs (J.R. Bearder K. Kybird, unpublished information), one of which, 58-hydroxy GAg., was subsequently identified as a new GA, GAl, in seeds of Pyrus communis (39) ... 

Figure 4. Metabolites from feeds of steviol (ent-13-hydroxykaurenoic acid) and ent-kaurenoic acid to the GA mutant Bl-41a of G. fujikuroi. Steviol is found as a glucoside in the higher plant Stevia rebaudiana it is not found in the fungus.

Murphy, G.J.P., Briggs, p-E. "Metabolism of ent-kaurenpl-17 l C, ent-kaurenal-17- and ent-kaurenoic acid-17- C by germinating Hordeum distichon grains." Phytochemistry,... 

U. Bearder, J.R., MacMillan, J., Phinney, B.O. "Fungal products. Part XIV. Metabolic pathways from ent-kaurenoic acid to the fungal gibberellins in mutant Bl-J+la of Gibberella fujikuroi." J. . . Perkin Trans. 1975, 1, 721-726. 

VALENCIA, A., WENS, A., PONCE-MONTER, H PEDR6N, N., GALLEGOS, A.J., QUIJANO, L CALDERON, J., GOMEZ, F, RIOS, T., Zoapatle. XII. In vitro effect of kaurenoic acid isolated from Montanoa frutescens and two derivatives upon human spermatozoa., J. Ethnopharmacol., 1986,1,89-94. 

TIRAPELLIB, C.R., AMBROSIO, S.R., DA COSTA, F.B., DE OLIVEIRA, A.M., Inhibitory action of kaurenoic acid from Viguiera robusta (Asteraceae) on phenylephrine-induced rat carotid contraction., Fitoterapia, 2002,73,56-62. 

The retardation effect of all these substances can be reversed by gibberellins. Furthermore, it has been possible, in the case of some of these substances, to detect precisely the point of attack or site of action in the gibberellin biosynthesis sequence. As can be seen from Figure 3, it is assumed that the onium compounds inhibit the cyclization of geranylgeranyl pyrophosphate to copalyl pyrophosphate (7), whereas it has been demonstrated in cell-free systems that pyrimidines, norbornenodiazetines, and triazoles inhibit the sequential oxidation of ent-kaurene to ent-kaurenoic acid (fj, 9). 

This plant growth regulatory activity is due to inhibition of the biosynthesis of gibberellins (j>), at the three oxidation steps between ent-kaurene and ent-kaurenoic acid (Figure 2). 

The kaurenolides and fujenal that are formed by Gibberella fujikuroi are side products from the major biosynthetic pathway. Ent-kaurenoic acid is dehydrogenated to form ent-kaur-6,16-dienoic acid. Epoxidation on the p-face and hydrolysis afforded 7-hydroxykaurenolide (5.117), which was then hydroxylated at C-3 or C-18 to form the dihydroxykaurenolides. The unusual aldehyde anhydride fujenal (5.119) was formed via the 6p,7p-diol. Amongst the metabolites of Gibberella fujikuroi there are several compounds in which the 16-ene is hydrated to give a 16p-tertiary alcohol. These compounds are not metabolized further and represent a dumping mechanism . 

Rearrangements have been widely used for angular alkylation reactions, as demonstrated by the synthesis of 3 240 or 5. a precursor of steviol (a compound with gibberellin-like activity) or kaurenoic acid (C-13 hydrogen instead of OH)421. 

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