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

Abstract

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...

Synthesis and biological activity of novel anti-juvenile hormone agents

“…14) In the silkworm, JHE activity in the hemolymph is quite low in 4th-instar larvae and increases in 5th-instar larvae, thereby decreasing the JH titer and inducing metamorphosis. 15) We have found that compound 2 9) and KF-13 16) induce hemolymph JH esterase activity during the 4th instar when applied to 3rd-instar larvae of B. mori. This result supports the concept that the appearance of JHE activity in the hemolymph is indispensable for the initiation of pupation.…”

Physiological Activities of Anti-Juvenile Hormone Agents Against Insects and Their Role For Devising Fourth Generation Insecticides: A Comprehensive Review

“…Of these compounds, only the methyl and ethyl esters showed precocious metamorphosis-inducing activity. Fujita et al (2007) synthesized two ETB analogues: Ethyl 4-[2-(6-methyl-3-pyridyloxy)hexyloxy]benzoate and ethyl 4-(2phenoxyhexyloxy)benzoate which induced precocious metamorphosis in larvae of B. mori. Recently, Yamada et al (2016) synthesized a series of ethyl 4-[(7-substituted 1,4-benzodioxan-6-yl) methyl]benzoates and evaluated their anti-JH activities on B. mori.…”

“…In respect of ETB and its related compounds, ETB analogue ethyl 4-[4-methyl-2-(6-methyl-3-pyridyloxy)pentyloxy]benzoate induced precocious metamorphosis after topical application onto 1-day old 3 rd instar larvae of B. mori (Fujita et al, 2005). Fujita et al (2007) synthesized two ETB analogues which induced precocious metamorphosis in larvae of B. mori. KF compounds are structurally derived from ETB.…”