Anti-juvenile Hormone Research Articles

Effects of three compounds with anti-juvenile hormone activity and a juvenile hormone analogue on endogenous juvenile hormone levels in the tobacco hornworm, Manduca sexta

The ability of three anti-juvenile hormones and one juvenile hormone analogue to reduce in vivo juvenile hormone levels in Manduca sexta has been investigated. Two compounds. FMev (tetrahydro-4-fluoromethyl-4-hydroxy-2 H-pyran-2-one) and ETB (ethyl-4-[2-( tert-butylcarbonyloxy)butoxy]-benzoate) reduced the titres of juvenile hormones I and II to near the levels of detection in topically treated larvae. Precocene III (7-ethoxy-6-methoxy-2,2-dimethylchromene) was inactive but the juvenile hormone analogue hydroprene was as effective as the two anti-juvenile hormones in reducing endogenous juvenile hormone titres in larvae. FMev was also shown to reduce the level of juvenile hormones II and III in pharate adults.

Studies on Biologically Active Heterocyclic Compounds

On the basis of the natural product models and biochemical designs, attempts were made to find leads for the development of new pesticide chemicals. Antilipidemic agents of several different chemical classes and cis-7-chloro-3a, 8b-dihydro-3a-methylfuro[3, 4-b]benzofuran-3 (1H)-one, which inhibited HMG-CoA reductase activity in rats in vivo, showed ovicidal activity against the eggs of azuki bean weevils, Callosobruchus chinensis, but failed to produce clear anti-juvenile hormone (JH) activity. A number of imidazole compounds possessing a JH-like terpene chain, designed to be potential inhibitors of JH biosynthesis, were synthesized and bioassayed on the silkworm, Bombyx mori larvae. New compounds, 1-geranyl-5-phenylimidazole (A-1) and the 1-citronellyl analog (A-2), showed remarkable anti-JH activity. When treated to the third instar larvae, miniature pupae were formed after molting to the fourth instar larvae. The fifth instars were also omitted by treatment of the fourth instar larvae. The presence of a phenyl group at the 5 position of the imidazole ring is essential for anti-JH activity. The introduction of a methoxy group in the 7 position of the terpene chain of A-1 and A-2 eliminated or decreased the activity. The anti-JH effects of A-1 and A-2 on B. mori larvae were completely blocked by simultaneous application of such a JH mimic as methoprene. Benzimidazoles having a terpenoid moiety, 1-(3, 7-dimethyl-7-methoxy-2-octenyl)-2-methylbenzimidazole (B-1) and the 7-ethoxy analog (B-2), showed high insecticidal activity against houseflies and green rice leafhoppers, Nephotettix cinticeps. They inhibited also larval molting of B. mori at low doses when applied topically to the larvae 1-2 days before erdysis. 8-Isopropyl-6-oxabicyclo[3.2.1]octan-7-one (trans-lactone) with a partial skeleton of picrotoxinin, which is an antagonist of γ-aminobutyric acid, and some related lactones were synthesized and their insecticidal activities were assayed on houseflies. In the insecticidal activity of the lactone compounds the configuration of the isopropyl group at C8-position played an important role. Thus trans-lactone had the highest activity. Ninety s-triazine derivatives were prepared by the reaction of amino acids and peptides with substituted biguanides and bioassayed on plant growth. Among the tested compounds the s-triazine derived from leucylleucine exhibited the highest growth inhibitory activity on rice.

Syntheses of the two optical isomers of the insect anti-juvenile hormone agent ethyl p-[2-(t-Butylcarbonyloxy)butoxy]benzoate (ETB) and their biological activities

The optical isomers (9) and (13) of the insect anti-juvenile hormone, (�)-ethyl p-[2-(t-butylcarbonyloxy)butoxy]benzoate (ETB) (14), have been synthesized and their biological activities examined in the tobacco hornworm Manduca sexta. It was found that the observed anti-juvenile hormone activity at low dose levels and juvenile hormone activity at higher levels in the Manduca sexta, after topical treatment with the racemic mixture (14) is due entirely to the (–)-enantiomer (9), the (+)-enantiomer (13) being completely inactive.

Lepidopteran anti-juvenile hormones: Effects on development of Apanteles congregatus in Manduca sexta

Parasitism by the braconid wasp Apanteles congregatus decreases the effectiveness of the anti-juvenile hormone agents ETB (ethyl 4-[2-{ittert-butyl carbonyloxy}bytoxy]benzoate) and fluoromevalonolactone (FMev) in inducing precocious metamorphosis of Manduca sexta larvae. Topical application of 1–200 μg ETB to parasitized third-instar larvae had no effect on either host or parasite development, whereas doses of 50μg or more ETB applied to unparasitized third-instar larvae caused formation of larval-pupal intermediates after the fourth instar. Parasitism also decreased the effectiveness of 100–200 μg FMev in causing metamorphosis at the moult following its application. In contrast to ETB, FMev disrupted development of the parasitoids. No wasps emerged when preterminal stage hosts were treated with FMev and the hosts formed larval-pupal intermediates. After treatment of terminal stage hosts with FMev, the number of emerging parasitoids was reduced by one-third. Precocene II (100 μg per larvae) had no effect on development of either M. sexta or A. congregatus.

Synthesis of crown‐ether precocenes

AbstractPreparation of potential insect antijuvenile hormone agents with 15‐crown‐5 and 18‐crown‐6 moieties connecting the C‐6 and C‐7 positions of the 2 H‐chromene ring of precocenes is described.

Natural and Synthetic Allatotoxins: Suicide Substrates for Juvenile Hormone Biosynthesis

Cytotoxic agents with antijuvenile hormone activity in insects have been discovered. Their mechanism of action may involve an oxidative bioactivation into a reactive quinone methide.

Metabolic fate of the hepatotoxic anti-juvenile hormone precocene II in the rat

The metabolic fate of precocene II (6,7-dimethoxy-2,2-dimethyl-2 H-benzo[ b]pyran), a potent anti-juvenile hormone, was examined in male Sprague-Dawley rats. When a single intraperitoneal dose of [ 3H] precocene II was administered, approximately 34% of the administered dose was excreted within the first 24 h. Examination of the various urinary metabolites indicated that precocene II is metabolized to a stereoisomeric cis/trans mixture of the 3,4-dihydroxy-3,4-dihydroprecocene II. In addition, a mercapturic acid derivative of precocene II was tentatively identified. Thus, it is postulated that a highly reactive 3,4-epoxide intermediate is generated in vivo by the rat during oxidative metabolite.

Synthesis of tritium labelled precocenes

AbstractRegiospecific syntheses of tritium labelled precocene I (5a) and precocene II (5b), the antijuvenile hormones, have been accomplished. The syntheses involved condensations between 2‐hydroxyacetophenones (1) with acetone‐T to give cross condensation products 2 which on cyclodehydration furnished 2,2‐dimethyl‐4‐chromanones‐(2‐gem dimethyl‐T) (3). Reduction of 3 with lithium aluminium hydride gave chroman‐4‐ols (2‐gem dimethyl‐T) (4). Dehydration of 4 furnished 2,2‐dimethyl‐ chromenes‐ (2‐gem dimethyl‐T) (5). Starting with appropriate acetophenones and acetone‐T, precocene I (7‐methoxy‐2,2‐dimethylchromene) and precocene II (6, 7‐dimethoxy‐2, 2‐dimethylchromene) labelled with tritium in the 2‐gem dimethyl positions, have been synthesised in high chemical as well as radiochemical yields.

Hepatotoxicity of the anti-juvenile hormone precocene II and the generation of dihydrodiol metabolites

Precocene II (6,7-dimethoxy-2,2-dimethylchromene), the most active anti-juvenile hormone isolated from Ageratum houstonianum, has been shown to be hepatotoxic in male Sprague-Dawley rats. A single 300-mg/kg dose of precocene II administered via i.p. injection caused extensive necrosis of parenchymal cells in the hepatic centrolobular areas. Liver functions were markedly affected as shown by the significant increases of glutamic-oxalacetic transaminase and glutamic-pyruvic transaminase in the serum. By means of reversed-phase high pressure liquid chromatography (HPLC), [ 3H]precocene II was found to be rapidly metabolized in vitro by rat liver microsomes in an NADPH-generating system. Approximately 5% (3.4 nmol/mg protein) of the radioactivity from the [ 3H]precocene II substrate was covalently bound to the macromolecular pellet at the end of a 15-min incubation period when phenobarbital (PB)-induced microsomes were used. Results obtained from experiments using different incubation systems indicated the involvement of the cytochrome P-450-dependent monooxygenases in the metabolism of precocene II and the concurrent covalent binding. The most predominent metabolite was isolated and accounted for >90% of the radioactivity associated with the ethylacetate-extractable metabolites. Further analysis by mass spectrometry and proton nuclear magnetic resonance (NMR) spectroscopy identified it as a 37 : 63 stereoisomeric mixture of the cis and trans 3,4-dihydrodiols of precocene II. A highly reactive (3,4-epoxy-6,7-dimethyl-2,2-dimethylchromane (precocene-3,4-epoxide) was thus suggested as a crucial metabolic intermediate which may be responsible for the histopathological changes seen in rat liver.

How Anti-Juvenile Hormones Work

SYNOPSIS. TWO compounds which possess anti-juvenile hormone activity in insects have been isolated and identified from the plant Ageratum houstonianum. These compounds, called precocenes, have been shown to inhibit the development of the insect corpus allatum (CA) and/or destroy the CA in sensitive species. The action of the precocenes can be seen to affect only those CA which are actively synthesizing and secreting the juvenile hormone. Structure-optimization studies of the precocenes reveal that the 3,4-double bond must be present and unsubstituted for biological activity to occur. In vivo and in vitro studies reveal that the precocenes are very probably converted into reactive epoxides which undergo facile reaction with nucleophiles since histological examination of precocene-inactivated CAs indicate a direct cytotoxic action of the precocenes on the parenchymal cells of the CA. The most likely mode of action would appear to involve the alkylation of macromolecular cellular elements by a reactive epoxide or similar activated precocene intermediate.

How Anti-Juvenile Hormones Work

Synopsis. Two compounds which possess anti-juvenile hormone activity in insects have been isolated and identified from the plant Ageratum houstonianum. These compounds, called precocenes, have been shown to inhibit the development ofthe insect corpus allatum (CA) and/or destroy the CA in sensitive species. The action of the precocenes can be seen to affect only those CA which are actively synthesizing and secreting the juvenile hormone. Structure-optimization studies of the precocenes reveal that the 3,4-double bond must be present and unsubstituted for biological activity to occur. In vivo and in vitro studies reveal that the precocenes are very probably converted into reactive epoxides which undergo facile reaction with nucleophiles since histological examination of precocene-inactivated CAs indicate a direct cytotoxic action of the precocenes on the parenchymal cells of the CA. The most likely mode of action would appear to involve the alkylation of macromolecular cellular elements by a reactive epoxide or similar activated precocene inter? mediate.

Fluoromevalonate acts as an inhibitor of insect juvenile hormone biosynthesis

The potential of analogues of insect juvenile hormones (JHs) for pest control has been demonstrated by the application of methoprene for the selective control of certain insects, including several mosquito species, the cigarette beetle and the hornfly1. Compounds that impede JH production could offer a potentially more attractive method of control because accelerated metamorphosis would shorten the lifetime of the larvae, the stage that usually does maximum damage to the host plant. Of the few anti-juvenile hormone (AJH) agents described2–5, only precocenes evoke all the required biological responses, but they affect a few insect taxa of minor economic importance. Their activity is thought to result from cytotoxicity6,7 in the corpora allata. In view of similarities between the biosynthesis of the carbon skeletons of insect JHs8,9 and farnesyl pyrophosphate (a precursor of steroids and other terpenoids10), compounds that inhibit the early steps in the biosynthesis of cholesterol might be expected to suppress JHs. Although this concept has already been explored without success11,12, we now report the inhibition of juvenile hormone biosynthesis (AJH activity, see Table 1 legend) by a fluorinated mevalonate tetrahydro-4-fluoromethyl-4-hydroxy-2H-pyran-2-one, FMev, Fig. 1) which until now was known only to be hypocholesterolaemic13–15.

Reversed Phase High Pressure Liquid Chromatographic Separation of Precocenes-I, -II, Antijuvenile Hormones and Their Derivatives

Abstract HPLC separation of precocene-I, precocene-II, dihydroprecocene-I, precocene-I dimer and precocene-II dimer has been carried out under varying conditions of eluent concentration for MeOH: H2O system. It is observed that the mixture of above compounds is adequately resolved using MeOH: H2O (3:1).

Synthesis of Precocene-I Dimer. A Potential Antijuvenile Hormone

Abstract Precocene-I (1) (7-methoxy-2, 2-dimethylchromene) and precocene-II (6,7-dimethoxy-2, 2-dimethylchromene) isolated from Ageratum houstonianum plants have been shown to exhibit novel antijuvenile hormone activity1. These compounds induce precocious metamorphosis in young nymphal stages of test insects resulting thereby into unviable miniature adults showing distinct cessation of juvenile hormone mediated functions. One of the views regarding the mode of action of these compounds suggests importance of the presence of unsubstituted 3,4 double bond in the molecule2 and possible formation of 3,4-epoxide3 of precocenes via the diol4,5 which might be the species responsible for the anti JH activity.

Fluorinated chromenes. III. Synthesis of 3‐fluoro‐2,2‐dimethyl‐2H‐chromenes

AbstractThe reaction of 2‐fluoro‐1,1‐dimethoxy‐3‐methylbut‐2‐ene (3) with phenols in dry pyridine leads to 3‐fluoro‐2,2‐dimethyl‐2H‐chromenes. 3‐Fluoro analogues of the natural insect antijuvenile hormones Precocene I (1a) and II (1b) have been prepared by this method.

Precocene Induction of Tick Sterility and Ecdysis Failure1

Argas persicus, Ornithodoros coriaceus and Rhipicephalus sanguineus were sterilized and their ecdysis inhibited by treatment with precocene, a reported anti-juvenile hormone. Precocious metamorphosis was not observed. When juvenile hormone was applied to precocene-treated nymphs, the percentage remaining in that instar increased and survival was higher. Juvenile hormone alone had no effect.

The hormonal regulation of the larval diapause in the codling moth, Laspeyresia pomonella (Lep. Tortricidae)

The hormonal control of the facultative diapause of the codling moth has been investigated. The diapause can be divided into 4 phases or periods: (1) diapause induction by short-day conditions ( SD) in young larvae, (2) initiation of the diapause in the early last larval instar by a high titre of juvenile hormone, (3) onset and maintenance of diapause with inactivity of the neuroendocrine system, as evidenced by the results of neck-ligation experiments, (4)termination of diapause by the production of ecdysteroid. Diapause-induced larvae pupated after spinning the cocoon, if the state of induction was changed by injection with the anti-juvenile hormone precocene II at the beginning of the last larval instar and subsequent results of neck-ligation experiments, (4) termination of diapause by the production of ecdysteroid. treated with juvenile hormone during the first 1.5 days after the last larval moult and subsequently reared under SD. Under LD, continuous application of juvenile hormone during the last larval instar and after spinning did not prevent the insects from moulting to either a supernumerary larva, a pupa or a larval-pupal intermediate. Termination of diapause, i.e. pupation, was achieved by injecting diapausing larvae with 20-hydroxyecdysone. Although juvenile hormone was found to have a prothoractropic effect in diapausing larvae, no pupal moult could be induced by the application of the hormone. Contrary to the hormonal situation before pupation of nondiapausing larvae, no juvenile hormone could be detected before or during the pupation of larvae after diapause.

Fluorinated chromenes 1: 2,2,2-trifluoroethoxy precocene analogs and their corresponding 3,4-epoxides

Preparation of potential insect antijuvenile hormone agents 2,2-dimethyl-7-(2,2,2-trifluoroethoxy)-2H-chromene ( 3a ), 6-methoxy-2,2-dimethyl-7-(2,2,2-trifluoroethoxy)-2 H -chromene ( 3b ) and 7-methoxy-2,2-dimethyl-6--(2,2,2-trifluoroethoxy)-2 H -chromene ( 3c ) and the corresponding 3,4-epoxides 5a and 5b is reported.

Fluorinated chromenes. Synthesis of 6,7‐dimethoxy‐2‐methyl‐2‐trifluoromethyl‐2H‐chromene

AbstractPreparation of the title compound, a trifluoromethyl analog of the natural insect antijuvenile hormone 6,7‐dimethoxy‐2,2‐dimethyl‐2H‐chromene (precocene II), from 3,4‐dimethoxyphenol and 1,1,1‐trifluoro‐4,4‐dimethoxy‐2‐methyl‐2‐butyl mesylate is described.

Precocene II is no Anti-Juvenile Hormone in the Honey Bee, Apis mellifera

The effect of precocene II on development of the honey bee, Apis mellifera, was studied in vitro. One- to two-day-old worker larvae (body weight 0.5 - 1.0 mg) were removed from the colonies, reared on royal jelly-yeast extract, and after 24 h were topically applied with different amounts (5 - 75 μg/larva) of precocene II. Toxicity was observed only with precocene doses of 50 μg/larva and more. The larval weight-gains declined with the increase of doses. The acetone-treated control had better survival and weight-gain as compared to the no-treatment control. The larval and pu­pal periods in the treated larvae remained unchanged as compared to the controls. The possibility of precocene acting as an antifeedant is discussed.