Methyl farnesoate

The epoxidase catalyzing the 10,11-epoxidation of methyl farnesoate in homogenates of corpora allata from Locusta miqratoria has been studied in detail and has been shown to be a cytochrome P-450-mediated monooxygenase associated with the microsomal fraction. The enzyme is strictly dependent on NADPH and requires oxygen (36). It is sensitive to inhibition by carbon monoxide (36) and to offier compounds such as methyl enedioxyphenyl compounds and imidazoles that are well established inhibitors of the cytochrome P-450-mediated monooxygenases involved in xenobiotic metabolism (37-39). 

Two of the better known "anti-juvenile "Hormone" agents, preco-cenes (9) and fluoromevalonate (10) are inhibitors of JH biosynthesis. The mode of action of fluoromevalonate at the molecular level is unknown. Elucidation of the mode of action of precocenes indicates that these plant chromene derivatives reach the site of JH biosynthesis, the corpora allata (CA), where they undergo a lethal epoxidation leading to extensive macromolecular alkylation and ultimately cause cell death (11, 12). Bioactivation of precocenes to the highly reactive precocene epoxide (13) in the corpora allata is almost certainly catalyzed by methyl farnesoate (MF) epoxidase (14), a cytochrome P-450 sonooxygenase (15) tdtich is the last enzyme of the JH biosynthetic pathway (at least in locusts and cockroaches). 

Precocenes may not provide the new approach to insect control originally expected ("4th generation" insecticides, 9) because they are not active in some major groups of agricultural pests (Lepidoptera) and because their mode of action (cytotoxicity) is not compatible with environmental concerns. Indeed, precocene II has been shown to be hepatotoxic and nephrotoxic in rats (16, 17). However, research on precocenes has led to (at least) two Important conclusions (1) compounds structurally unrelated to the JH biosynthetic pathway can reach critical sites (e.g. epoxidase) within the CA, and (2) such compounds can be catalytically processed (e.g. epoxidlzed) by enzymes of JH biosynthesis. The lax substrate specificity of methyl farnesoate epoxidase in the corpora allata and its catalytic competence might be exploited in the design of irreversible Inhibitors of JH biosynthesis (Figure 1). 

A number of inhibitors of methyl farnesoate epoxidase of Blaberus glganteus corpora allata have been described (18). They include typical cytochrome P-450 monooxygenase inhibitors such as methylenedloxyphenyl compounds and substituted imidazoles. In assays of JH III biosynthesis by Perlplaneta amerlcana CA in vitro some methylenedloxyphenyl compounds were shown to inhibit hormone production at moderate to high concentrations (19). Both methylenedloxyphenyl compounds and terpenoid imidazoles have also some anti-juvenile hormone activity in Lepidoptera (7, 20). 

Figure 1. Three reactions catalyzed by methyl farnesoate epoxidase (a cytochrome P-450 monooxygenase) in the corpora allata.

Three acetylenic compounds (Figure 3) were compared to precocene II (1) for their ability to Inhibit JH biosynthesis in vitro, to inhibit oocyte growth in vivo, and to inhibit midgut microsomal (I.e. extra-allatal) cytochrome P-450 monooxygenases. The compounds were chosen to represent an analog of the substrate of the allatal monooxygenase, methyl farnesoate, with the... 

In Perlplaneta amerlcana CA, no accumulation of methyl farnesoate was noted with acetylenic Inhibitors of JH III biosynthesis, although this effect was observed with methylenedioxyphenyl Inhibitors (19). 

Figure 5. Accumulation of methyl farnesoate in corpora allata inhibited by the acetylenic insecticide synergist (4).

RPCH and PDH are reported to have stimulatory and inhibitory roles, respectively, in the secretion of methyl farnesoate from crustacean mandibular glands (70). 

A number of bicyclofarnesyl hydroquinones have already been isolated from the brown seaweed Dictyopteris undulata. The parent acyclic compound (11) has now been found in the fresh alga. Two papers on the terminal functionalization of farnesyl derivatives have been published. These include the use of 2,4,4,6-tetrabromocyclohexadienone as an alternative to N-bromosuccinimide for the formation of the bromohydrin of the terminal double bond of methyl farnesoate... 

In the search for chemicals inhibiting the enzymes O-methyl transferase and methyl farnesoate epoxidase, responsible for the methyl ester formation and for the terminal epoxidation in juvenile hormone biosynthesis. Brooks and co-workers (1984) prepared a number of acetylenic esters and 1,3-benzodioxole derivatives. These groupings are of particular interest in the context of JH biosynthesis inhibition. The acetylenic derivative 79 showed the strongest inhibitory action on both enzymes. 

Methyl Farnesoate methyl 3,7,11 -trlmethyl trans-2, trans 6.10-dodecatrlenoate (C16H26O2)... 

Borst DW, Laufer H, Landau M, Chang ES, Hertz WA, Baker FC, Schooley DA (1987) Methyl farnesoate and its role in crustacean reproduction and development. Insect Biochem 17 1123-1127 Browdy CL, Fainzilber M, Tom M, Loya Y, Lubzens E (1990) Vitellin synthesis in relation to oogenesis in in vitro incubated ovaries of Penaeus semisulatus (Crustacea Decapoda, Penaeidae). J Exp Zool (in press)... 

C7 Diploptera punctata Farnesol, farnesal, famesoic acid, methyl farneso- [251] ... 

A1 Musca domestica Farnesal, methyl farnesoate, JHI, JHIII, steroid [272] ... 

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