A number of ethyl 4-(2-benzylalkyloxy)benzoates were prepared and their activity to induce precocious metamorphosis was evaluated in larvae of the silkworm, Bombyx mori, which was clearly recognized as a juvenile hormone (JH)-deficiency symptom. Ethyl 4-(2-benzylhexyloxy)benzoate (6) and its 2-benzylheptyloxy analog (7) were found to induce precocious metamorphosis at relatively low doses. Both enantiomers of 6 and 7 were prepared using a chiral auxiliary oxazolidinone. (S)-Enatiomers were more active than (R)-isomers at low doses of 0.1 and 1 mg, but at higher doses their activity was reversed. The activity of compound 6 could be fully counteracted by methoprene, a JH agonist, but not by the dietary administration of 20-hydroxyecdysone. The ester group was important in the ability to induce precocious metamorphosis. The (S)-enatiomer of 6 prolonged the duration of the instar and delayed the onset of cocoon spinning when applied to 5th instar larvae, suggesting that this compound might have JH-like activity as well as anti-JH activity.

A series of ethyl 4-(2-benzylalkyloxy)benzoates possessing precocious metamorphosis-inducing activity showed juvenile hormone (JH) activity when topically applied to allatectomized 4th instar larvae of Bombyx mori. Hexyl (KF-13) and heptyl analogs, which induced precocious metamorphosis at low doses, had relatively high JH activity. In both compounds, (S )-enantiomers were more active than (R)-enantiomers. A correlation was observed between JH activity and anti-JH activity in the ethyl 4-(2-benzylalkyloxy)benzoate series. Replacement of the 4-ethoxycarbonyl group with a 4-ethyl or 3,4-methylenedioxy group in KF-13 eliminated both JH and anti-JH activity.

A series of ethyl 4-(2-aryloxyhexyloxy)benzoates was prepared and tested for their activity to induce precocious metamorphosis in larvae of the silkworm. Phenyl analog 5 showed activity comparable to that of the 6-methyl-3-pyridyl analog reported as a novel anti-JH agent. The activity of 5 could be fully counteracted by methoprene, a JH agonist. The ethoxycarbonyl group of 5 was essential for its activity.Key words: anti-juvenile hormone; precocious metamorphosis; silkwormThe juvenile hormone (JH) is involved in a wide range of physiological processes in both developing and mature insects. 1) JH is critical for the regulation of metamorphosis and is required in the adult for such reproductive functions as pheromone biosynthesis, ovarian development, and maturation of eggs in females. Therefore, an anti-JH agent, which chemically blocks the functioning of the JH control system, could be an effective tool for studies on insect physiology as well as a potential insect growth regulator (IGR).2) Although some anti-JH agents have so far been found, including precocenes, fluoromevalonate, ethyl 4-[2-(tert-butylcarbonyloxy)butyloxy]benzoate (ETB) and 1,5-disubstituted imidazoles, their degree of activity is not sufficiently high for use as IGRs. 2)ETB is known to show both JH activity and anti-JH activity toward the tobacco hornworm, Manduca sexta, 3) and the silkworm, Bombyx mori, 4) depending on the dose applied: a low dose of ETB induced precocious metamorphosis, a clear sign of JH-deficiency, but at higher doses, the precocious metamorphosis-inducing activity disappeared and instead, JH-like activity was observed. Riddiford et al. have reported that ETB acted as a partial JH antagonist in the target tissue of the larval epidermis.5) By modifying the structure of ETB, we have recently found that ethyl 4-[2-(6-methyl-3-pyridyloxy)butyloxy]benzoate (1) induced precocious metamorphosis in 3rd instar larvae of B. mori at higher doses. 6) We have further synthesized analogs in which the ethyl side chain of 1 was modified, and found that butyl-substituted analog 2 was more potent than 1.7) In contrast to ETB, the activity of compounds 1 and 2 to induce precocious metamorphosis was correlated with the applied dose to some extent. In our continuing studies on this series of compounds, the butyl side chain was fixed in the molecule, and a modification was made by replacing the 6-methyl-3-pyridyl moiety with other aromatic rings. In the present paper, we report the activity of a novel series of ethyl 4-(2-aryloxyhexyloxy)benzoates as anti-JH agents causing precocious metamorphosis in B. mori larvae.Ethyl 4-(2-aryloxyhexyloxy)benzoates were prepared in a similar manner to that reported previously. 7) All compounds showed a single spot by thin-layer chromatography and an appropriate 1 H-NMR spectrum. B. mori (Shunrei  Shougetsu strain) larvae were reared on an artificial diet as previously reported. 8) Test compounds in an acetone solution (1-4 ml/larva) were topically applied to the dorsal abdomen of 24-hr-old 3rd instar and n...

Ethyl 4-[2-(6-methyl-3-pyridyloxy)hexyloxy]benzoate (1) and ethyl 4-(2-phenoxyhexyloxy)benzoate (2), which induce precocious metamorphosis in larvae of Bombyx mori, a clear sign of juvenile hormone (JH) deficiency, showed JH activity when topically applied to allatectomized 4th instar larvae of B. mori. Compounds 1 and 2 induced precocious metamorphosis with doses at which they were effective as JH agonists.Key words: juvenile hormone; precocious metamorphosis; anti-juvenile hormone; silkwormSince the juvenile hormone (JH) is involved in a wide range of physiological processes in both developing and mature insects, 1) an anti-JH agent, which chemically blocks the functioning of the JH control system, could be an effective probe for studies on insect endocrinology as well as a potential insect growth regulator.2) We have recently reported ethyl 4-[2-(6-methyl-3-pyridyloxy)-hexyloxy]benzoate (1) 3) and ethyl 4-(2-phenoxyhexyloxy)benzoate (2) 4) as novel anti-JH agents (Fig. 1). These compounds induced precocious metamorphosis in larvae of the silkworm, Bombyx mori, a clear sign of JH deficiency, and their activity could be completely counteracted by the simultaneous application of methoprene, a JH agonist. Compounds 1 and 2 were found by modifying the structure of ethyl 4-[2-(tert-butylcarbonyloxy)butyloxy]benzoate (ETB). ETB is known to show anti-JH activity as well as JH activity toward the tobacco hornworm, Manduca sexta, 5) and B. mori,depending on the dose applied; low doses of ETB induced precocious metamorphosis, but at higher doses, this precocious metamorphosis-inducing activity disappeared and instead, JH activity was observed. Riddiford et al. have reported that ETB acted as a partial antagonist in the Manduca epidermis at the target-tissue level. 7) As previously reported, 3,4) in our bioassay using 24-hr-old 3rd instar larvae of B. mori, ETB at 1 mg induced precocious pupation in only 10% and no activity was observed at higher doses of 10 mg and 40 mg, while compounds 1 and 2 induced precocious metamorphosis even at high doses. ETB clearly acts as a JH agonist to counteract the effect of allatectomy, the induction of precocious metamorphosis, in a dose-dependent manner.6) To determine whether compounds 1 and 2 as well as ETB had JH activity, we tested these compounds on allatectomized 4th instar larvae of B. mori.B. mori (Shunrei x Shougetsu strain) larvae were reared on an artificial diet as previously described. 8)Twenty-four hours after the 3rd molt, the corpora allata were extirpated with fine forceps under a binocular microscope as described by Ohtaki et al.9) Test compounds in an acetone solution (14 ml/larva) were each applied topically to the dorsal abdomen of the larvae within 1 hour after the allatectomy. JH activity was evaluated by the molting into normal 5th instar larvae. Table 1 shows the effects of methoprene, ETB, 1 and 2 against the allatectomized 4th instar larvae. All of the allatectomized and acetone-treated control larvae underwent precocious metamorphosis. ETB as well as methopr...

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