Synthesis and Anti-Juvenile Hormone Activity of Ethyl 4-(2-Aryloxyhexyloxy)benzoates

Abstract

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...

Juvenile Hormone Activity of Ethyl 4-(2-Aryloxyhexyloxy)benzoates with Precocious Metamorphosis-Inducing Activity

“…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.…”

Synthesis and biological activity of novel anti-juvenile hormone agents

“…Among them, the phenyl analog 4 showed activity comparable to those of 2 and 3, suggesting that 6-methyl-3-pyridyl moiety is not significant for activity. 10) In this series of compounds, the introduction of a methyl or chloro substituent on the benzene ring did not increase activity. In the alkyl 4-(2-phenoxyhexyloxy)benzoate series, only methyl and ethyl esters showed precocious metamorphosis-inducing activity.…”

Synthesis and anti-juvenile hormone activity of ethyl 4-(2-benzylalkyloxy)benzoates and their enantiomers

“…The n-pentyl analog 7 had almost the same level of activity as 6 and was most effective at treatment of 1 mg. The n-hexyl (8) and benzyl (9) analogs showed lower activity at low doses in comparison with those of 6 and 7. Only compounds 6 and 7 showed some precocious metamorphosis-inducing activity at a very low dose of 0.1 mg.…”

“…By modifying the structure of ETB, we have recently found that ethyl 4-[4-methyl-2-(6-methyl-3-pyridyloxy)pentyloxy]-benzoate (1) 7) and ethyl 4-(2-phenoxyhexyloxy)benzoate (2) 8) showed stronger precocious metamorphosis-inducing activity than ETB against B. mori larvae (Fig. 1).…”