Design and Synthesis of Insect Juvenile Hormone antagonists

制备了大量1,5-二取代咪唑和3-（1-烯基）吡啶，并对其诱导家蚕幼虫早熟变态的活性进行了评估，家蚕的早熟变态是由去除体或抗幼激素引起的。5-（2-烯丙氧基苯基）- 1 -辛基咪唑和5-（2-氯苯基）- 1 -辛基咪唑活性较高。甲基戊二烯（一种少年激素激动剂）和苯丙诺齐（一种表皮类固醇激动剂）都不能完全抵消高剂量化合物引起的早熟性变态，但这两种激素激动剂都是完全拯救所必需的。在3-（1-烯基）吡啶衍生物中，3-（2-甲基-1-苯基-1-丙烯基）吡啶和3-[(E)-7-（4-乙基苯氧基）-1-甲基-1-庚烯基]吡啶的活性最高。每一种化合物诱导的早熟性变态都可以通过饮食中添加20-羟基蜕皮激素而完全逆转，这表明这些化合物暂时降低了幼虫血淋巴中蜕皮激素的滴度，从而诱发了早熟性变态。合成了1-[3-(4-Phenoxyphenoxy) propyl]咪唑（KS-175），该化合物具有2种昆虫生长调节剂（IGRs）的特征基团、一个幼激素类似物的phenoxyphenoxyalkyl基团和一个咪唑环作为有效的细胞色素P450抑制剂，并对其在家蚕体内的生物活性进行了评价。对4龄幼虫局部施药20天以上，对2龄（4龄）幼虫既不蜕皮也不变态。这种活性不同于任何已报道的igr。治疗后，血淋巴外表皮激素水平未升高，前胸腺细胞萎缩。在人工饲料中添加20 ppm的20-羟基蜕皮激素后，4龄幼虫蜕皮至终龄（5龄），蜕皮时间与对照相似。这些结果表明，局部应用KS-175不可逆地破坏前胸腺蜕皮激素的生物合成。低浓度的甲基戊二烯可显著促进IPLB-Sf2l AE II昆虫细胞的生长，提示该细胞系可能具有识别JH的靶位样受体，进而促进细胞增殖。少

A large number of 1,5-disubstituted imidazoles and 3-(1-alkenyl)pyridines were prepared and evaluated for their activity to induce precocious metamorphosis in larvae of the silkworm, Bombyx mori, which is known to be caused by removal of the corpora allata or anti-juvenile hormone agents. 5-(2-Allyloxyphenyl)- 1 -octylimidazole and 5-(2-chlorophenyl)- 1 -octylimidazole showed relatively high activity. Neither methoprene, a juvenile hormone (JH) agonist, nor tebufenozide, an ecdysteroid agonist, could fully counteract precocious metamorphosis induced by high doses of each compound, but both hormone agonists were necessary for complete rescue. Among the 3-(1-alkenyl) pyridine derivatives tested, 3-(2-methyl-1-phenyl-1-propenyl) pyridine and 3-[(E)-7-(4-ethylphenoxy)-1-methyl-1-heptenyl] pyridine showed highest activity. Precocious metamorphosis induced by each compound was fully reversible by dietary administration of 20-hydroxyecdysone, indicating that these compounds temporarily depres … More s the ecdysteroid titer in the larval hemolymph to induce precocious metamorphosis. 1-[3-(4-Phenoxyphenoxy) propyl] imidazole (KS-175), which has two types of characteristic moieties of insect growth regulators (IGRs), a phenoxyphenoxyalkyl group of juvenile hormone analogs and an imidazole ring as a potent cytochrome P450 inhibitor, was synthesized and evaluated for its biological activity on the silkworm. KS-175 caused neither molting nor metamorphosis in the penultimate (4th) instar for more than 20 days when applied topically to the 4th instar larvae. This activity was different from any reported IGRs. After the treatment, ecdysteroid levels in hemolymph did not increase and the cells of the prothoracic gland had shrunk. When the treated 4th larvae were fed on artificial diet supplement with 20 ppm of 20-hydroxyecdysone, the larvae molted to the ultimate (5th) instar with a timing similar to that of control larvae. These results suggest that topical application of KS-175 irreversibly damages ecdysone biosynthesis in prothoracic glands. The growth of IPLB-Sf2l AE II insect cells was markedly promoted by a low concentration of methoprene, suggesting that this cell line may have a target site like receptor to recognize the JH followed by the promotion of cell proliferation. Less