Anti-juvenile hormones

Larvae of the large milkweed bug, Oncopeltus fasciatus treated with precocene II undergo precocious metamorphosis and moult into diminutive forms with adult characters. Freshly hatched females treated with precocene II remain sterile and their corpora allata loose their ability to secrete juvenile hormone even when transplanted into an untreated body (Muller et al., 1979 Masner et al., 1979 Pener et al., 1978). 

The action of precocenes on the molecular level is not understood. Pratt and Bowers (1977) demonstrated the inhibition of the final steps in juvenile hormone biosynthesis, including epoxidation of farnesenic acid, following administration of precocene II to the test insects. Based on their experimental findings, members of the Bristol research group hypothesised that precocene and its derivatives are epoxidised to 3,4-epoxides having alkylating properties. The formation of these epoxides competes with the epoxidation step in JH biosynthesis, thus destroying the ability of corpora allata to synthesise JH. 

However, other authors concluded that the effect induced by precocenes is a consequence of their antifeeding or general toxic action (Slama, 1978 Kelly and Fuchs, 1978 Rembold et al., 1979). Arguments favouring this hypothesis are the growth disruption of insects caused by some antifeedants (Ruscoe, 1972), the observation that precocene had no effect on the development of insects that are resistant to some antifeedants due to adaptation (Slama, 1978), and by the lack of morphological abnormalities on honey bee following administration of precocene II (Rembold et al., 1979). 

Kelly and Fuchs (1978) found an inhibition of trypsin synthesis after treatment of insects with precocene II and concluded that the retarded ovarial maturation is but a consequence of a general toxic state. 

The principal metabolite of precocene II in the test insects was found to be 

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Other chemicals evaluated but not yet adopted commercially include organophosphorus compounds, triphenyltin compounds, quaternary ammonium salts, imidazoles, benzimidazoles, carbamates and the precocene anti-juvenile hormones [517]. Although none of the above has found use as an insect-resist agent, several have been used as antimicrobial agents for textiles. 

These inhibitors would be classified as anti-juvenile hormones and could be expected to show selective action on insects as a class. Such analogs are by no means just around the corner since at least two important properties that they should possess may be difficult to build into small organic molecules suitable for pest control. These properties are the ability to withstand general metabolic inactivation while retaining the ability to inhibit irreversibly the target enzymes of the corpus allatum and the property to accumulate selectively in corpora allata, a physically small target, so as to offset dilution in the general body cavity. 

Our strategy for an endocrinologic approach to insect control therefore was based upon the search for anti-juvenile hormones. 

We began to extract plants with apolar solvents and tested these extracts by contact and fumigation against the cotton stainer, Dysdercus cingulatus, and the milkweed bug, Oncopeltus fasciatus. Eventually we found that the extract of the bedding plant, Ageratum houstonianum, contained two potent anti-juvenile hormones. 

Figure 3. Anti-juvenile hormones from Ageratum houstoni-anum...

If the juvenile hormones and their analogs are representative of third-generation pesticides (18), the anti-juvenile hormones may be considered in a fourth-generation concept. 

The Control of Insect Growth" symposium, organized by Julius Menn, highlighted recent advances in the biochemistry of regulation of development by insect growth regulators, anti juvenile hormones, and behavior modification governed by antifeedants, pheromones, and defensive secretions. 

Anti-Juvenile Hormones. A plant defensive strategy targeted to disruption of the endocrine regulation of the early larval stages of metamorphosis was revealed with the discovery of anti-juvenile... 

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). 

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). 

Bioassay of Anti Juvenile Hormone Compounds An Alternative Approach... 

At the heart of any search for bioactive molecules is the need for effective bioassays. Several bioassays have been developed for the identification of compounds with anti-juvenile hormone (AJH) activity. The most common of these AJH bioassays involves the treatment of young larvae or nymphs with the potential AJH by incorporation into the diet or contact application, and then waiting for several days (or, in some cases, weeks) for precocious development (or other AJH response) to occur ( 1, ). Alternatively, AJH activity can be determined using jri vitro assays such as corpora allata cultures or epidermal cell cultures to monitor for inhibition of juvenile hormone (JH) biosynthesis (3-6) or blockage of the JH induced inhibition of pupal commitment (7), respectively. 

The 2.2-dimethyl-2H-benzpyran system Is the parent skeleton of a number of anti-juvenile hormone compounds this ring system has now been prepared by electron transfer sensitised irradiation of alkoxy-substituted cinnamyl alcohols. 

Reports are available on the discovery of insect anti-feeding substances and anti-juvenile hormones, on the homology of biosynthetic routes and its basis in chemotaxonomy, and on the role of terpenoids in chemical ecology. Further speculations have been made about the biosynthesis of various classes of sesquiterpenoid based on the results of a study of the quantitative co-occurrence of these in the genus Hymenaea. 

In addition. Connat and Ncpa (1990) examined various anti-juvenile hormone agents on the fecundity of the female tick Omithndoms mouhato and demonstrated that 500 pg of PBO applied topically induced rapid death. 

Matolcsy et al. (1980 1981) reported that 1,2-dimethoxy-4-isopropoxy-5-vinylbenzene (77) a compound derived formally by opening the dihydropyrane ring of precocene II, possesses a precocene type anti-juvenile hormone activity. This finding indicates that compounds lacking the chromene ring structure can also be active. 

No prediction can be made as yet on the future role of anti-juvenile hormones in insect control. However, the results obtained hitherto demonstrate the possibility of developing anti-insect agents acting to disrupt rather than mimic endocrine function. 

Compounds with anti-juvenile-hormone activity have been found in Ageratum houstonianum, Asteraceae (see Chapter 18). In this case, the insects molt precociously and produce adults one or two stages too early. The females produced usually are sterile. 

Frequently dimethylallyl residues are attached to compounds with other chemical structures (see above). They may form additional rings as in ageratochro-mene, a compound isolated from the plant Ageratum haustoniatum with anti-juvenile hormone activity in insects (E 5.5.3). Isovaleric acid and 3,3-dimethyl-acrylic acid, which have been found in higher plants, are thought to be products of leucine metabolism (D 14). 

Hemiterpenes Ageratochromene (D 6) Anti-juvenile hormone activity in insects... 

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