Preparation of insect juvenile hormone (JH) antagonists and identification of JH receptors

昆虫保幼激素（JH）拮抗剂的制备及JH受体的鉴定

基本信息

批准号：
14360031
负责人：
KUWANO Eiichi
金额：
$ 8.64万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

Ethyl 4-[2-(tert-butylcarbonyloxy)butyloxy]benzoate (ETB), an anti juvenile hormone (anti-JH) agent, has been reported to act as a partial JH antagonist at the target tissue of the larval epidermis. By modifying the structure of ETB, we have found that ethyl [2-(6-methyl-3-pyridyloxy)butyloxy]-benzoate (EMP) induced precocious metamorphosis in larvae of Bombyx mori, which is clearly recognized as a JH-deficiency symptom. In contrast to ETB, EMP induced precocious metamorphosis in a dose-dependent manner. The structure-activity relationship studies indicated that the 4-ethoxycarbonyl group on the benzene ring and the 6-methyl-3-pyridyl moiety were apparently essential for activity. The activity of EMP could be fully counteracted by methoprene, a JH agonist, but not by the dietary administration of 20-hydroxyecdysone, indicating that EMP causes a deficiency of JH titers in the larval hemolymph. In order to identify a target molecule of EMP, which might be related to a JH receptor, an EMP … More derivative coupled to horseradish peroxidase was prepared as an affinity ligand. However, high-affinity binding site for EMP was not found in the ovary follicular cell of the pupae and larval head capsules. To develop more potent anti-JH agent, the ethyl side chain of EMP was modified. Of the compounds tested, ethyl 4-[4-methyl-2-(6-methyl-3-pyridyloxy)pentyl-oxy]benzoate (1) was the most effective when applied to 24hr-old 3rd instar larvae. There was no significant different in precocious metamorphosis-inducing activity between 1R(+)- and 1S(-)-enantiomers. Since the benzoic acid analogs did not show any activity by both topical application and dietary administration, the ethoxycarbonyl group itself was responsible for activity. When 3rd instar larvae were treated with compound 1, hemolymph JH esterase, which is indispensable for the initiation of pupation in the last instar larvae, was induced during the 4th instar larvae. Compound 1 represents a structurally novel class of anti-JH agent. Less

据报道，乙二醇乙二醇（ETB）是抗幼年激素（抗JH）剂，乙二基乙二氧基（ETB）乙基4- [2-（TERT-叔丁基碳氧甲基氧基），据报道是幼虫表皮靶向组织的部分JH拮抗剂。通过修改ETB的结构，我们发现乙基[2-（6-甲基-3-吡啶氧基）丁氧基] - 苯甲酸酯（EMP）诱导的Bombyx Mori幼虫的早期变质，这清楚地被认为是JH缺乏症状的症状。与ETB相反，EMP以剂量依赖性方式诱导早熟的变形。结构活性关系研究表明，苯环和6-甲基-3-吡啶基部分的4-乙氧基殖民基团显然对于活性至关重要。 JH激动剂Methodprene可以完全抵消EMP的活性，但不能通过饮食给药20-羟基丁香酮的饮食给药，表明EMP会导致幼虫血淋巴中JH滴度的缺乏。为了鉴定可能与JH受体有关的EMP的靶分子，EMP…更具衍生物与辣根过氧化物酶的衍生物是作为亲和力配体制备的。然而，在p骨和幼虫头囊的卵泡细胞中未发现EMP的高亲和力结合位点。为了开发更多潜在的抗JH药物，对EMP的乙基侧链进行了修改。在测试的化合物中，乙基-2-（6-甲基-3-吡啶氧基）苯甲酸酯]苯甲酸酯（1）是最有效的，当应用于24小时的3龄幼虫。在1R（+） - 和1S（ - ） - 对映体之间，早熟变形诱导的活性没有显着差异。由于苯甲酸类似物没有表现出局部应用和饮食给药的任何活性，因此乙氧基辅助组本身是造成活性的。当第四级幼虫的血淋巴JH酯酶处理第三龄幼虫时，在第四龄幼虫期间诱导了化合物的血晶酯酶，这对于化合物是必不可少的。化合物1代表一种结构新颖的抗JH药物。较少的