Elucidation of the chemical structure necessary to the molting hormonal activity and the prediction of the hormone-receptor binding mode

阐明蜕皮激素活性所需的化学结构并预测激素-受体结合模式

• 批准号: 07660135
• 负责人: NAKAGAWA Yoshiaki
• 金额: $ 1.41万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07660135/
• 关键词: dibenzoylhydrazine; ecdysone; molting hormone; quantitative structure activity relationship; rice stem borer; steroid; CoMFA; coltured integument; エクダイソン; 培養表皮系; 殺虫活性; CoMFA法

Dibenzoylhydrazine analogs with various kinds of substituents were chemically synthesized, and their molting hormonal activity was measured using cultured integument system prepared from rice stem borer, Chilo suppressalis. The structure-activity relationship for these compounds was quantitatively analyzed using Hansch-Fujita method to show that the greater the molecular hydrophobicity, the greater the activity. In addition, the electron donating substituents at the benzoyl moiety bound to-N (t-Bu) -, as well as the electron withdrawing ortho-substituent, are favorable to the activity. Introduction of the bulky groups were unfavorable at any positions. Although the 2-dimensional (2D) structures of ecdysone and dibenzoylhydrazine molecules are extremely different, their 3D-structures look similar between them by comparing their X-ray structures. The structure activity relationship for the combined set of ecdysones and dibenzoylhydrazines, as well as their alkyl and benzyl analogs, was quantitatively analyzed using one of the 3D quantitative structure-activity relationship (QSAR) methods, comparative molecular field analysis (COMFA). CoMFA results showed that the bezoyl moiety bound to-NH-corresponds to the alkyl chain of ecdysones, and two carbonyl oxygens play a role of 20-and 22-OH oxygens of 20-hydroxyecdysones. The information regarding the favorable and unfavorable electrostatic-and steric-fields to the activity obtained in the CoMFA analysis seems to be very important to predict the binding site of ecdysone receptor and design the compounds. Some of the dibenzoylhydrazine analogs show the neuroactivity on the cockroach nerve system, and to the insect whole body as well. Therefore, we have to pay attention to their toxicological matter in the mammalian system.

化学合成了具有不同取代基的二苯甲酰肼类似物，并以水稻二化螟（Chilo suppressalis）为试材，测定了其蜕皮激素活性。采用Hansch-Fujita方法对化合物的构效关系进行了定量分析，发现分子疏水性越大，活性越高。此外，苯甲酰基上与-N（t-Bu）-键合的给电子取代基以及吸电子邻位取代基对活性有利。在任何位置引入庞大的组都是不利的。虽然蜕皮激素和二苯甲酰肼分子的二维（2D）结构非常不同，但通过比较它们的X射线结构，它们的3D结构看起来很相似。采用三维定量构效关系（QSAR）方法之一--比较分子场分析（COMFA），对蜕皮激素和二苯甲酰肼类化合物及其烷基和苄基类似物的构效关系进行了定量分析。CoMFA结果表明，结合到-NH-的苯甲酰基部分对应于蜕皮激素的烷基链，并且两个羰基氧起到20-羟基蜕皮激素的20-和22-OH氧的作用。CoMFA分析中获得的关于对活性有利和不利的静电场和空间场的信息对于预测蜕皮激素受体的结合位点和设计化合物是非常重要的。一些二苯甲酰肼类似物对蟑螂的神经系统和昆虫的全身均有神经活性。因此，我们必须关注它们在哺乳动物系统中的毒理学问题。

项目成果

Y.Nakagawa et al.: "Activity of ecdysone analogs in enhancing N-acetylglucosamine incorporation into the cultured integument of Chilo suppressalis." Steroids. 60. 401-405 (1995)

Y.Nakakawa 等人：“蜕皮激素类似物在增强 N-乙酰氨基葡萄糖掺入二化螟培养的珠被中的活性。”

Y.Nakagawa et al.: "Quantitative structure-activity studies of insect growth regulators. XI. Simulation and inhibition of N-acetylgucosamine incorporation in a cultured integument system by substituted N-tert-butyl-N, N'-dibenzoyl-hydrazines." Pestic. Sci

Y.Nakakawa 等人：“昆虫生长调节剂的定量结构活性研究。XI. 通过取代的 N-叔丁基-N, N-二苯甲酰肼模拟和抑制 N-乙酰氨基葡萄糖掺入培养的珠被系统中。

Y.Nakagawa et al.: "Three-dimensional quantitative structure-activity analysis of steroidal and dibenzoylhydrazine-type ecdysone agonists." ACS Symp.Ser.606. 288-301 (1995)

Y.Nakakawa 等人：“类固醇和二苯甲酰肼型蜕皮激素激动剂的三维定量结构活性分析。”

Y.Nakagawa et al.: "Three-dimensional quantitative structure-activity analysis of steroidal and dibenzoylhydrazine-type ecdysone agonists" ACS Symp. Ser.606. 288-301 (1995)

Y.Nakakawa 等人：“类固醇和二苯甲酰肼型蜕皮激素激动剂的三维定量结构活性分析” ACS Symp。

Y.Nakagawa et al.: "Quantitative structure-activity studies of insect growth regulators. XI.Stimulation and inhibition of N-acetylglucosamine incorporation in a cultured integument system by substituted N-tert-butyl-N,N'-dibenzoyl-hydrazines." Pestic.Sci.

Y.Nakakawa 等人：“昆虫生长调节剂的定量结构活性研究。XI.通过取代的 N-叔丁基-N,N-二苯甲酰肼刺激和抑制培养的珠被系统中 N-乙酰氨基葡萄糖的掺入。