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

基本信息

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

项目摘要

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.

对二苯二酰氢化嗪具有各种取代基的类似物进行化学合成，并使用用米饭茎骨制备的培养基抑制作用，Chilo Sustressalis制备了培养的外皮系统。使用Hansch-Fujita方法对这些化合物的结构活性关系进行了定量分析，以表明分子疏水性越大，活性越大。此外，在苯甲酰基部分结合的to-n（t-bu）以及撤回正源性的电子的电子捐赠取代基有利于活动。笨重的群体的引入在任何职位上都是不利的。尽管Ecdysone和Dibenzoylhydrazine分子的二维（2D）结构截然不同，但通过比较它们的X射线结构，它们之间的3D结构看起来相似。使用3D定量结构 - 活性关系（QSAR）方法之一，对组合的ecdysone和Dibenzoylhydrazines及其烷基和苄基类似物组合的结构活性关系进行了定量分析，比较分子场分析（COMFA）。 COMFA的结果表明，Bezoyl部分结合了NH-NH-NH-NH-NH-NH-NH-NH-NH-NH链链的链链链，并且两个羰基氧的作用具有20-羟基甲虫的20和22-OH氧的作用。关于在COMFA分析中获得的活动的有利且不利的静电和空间场的信息对于预测Ecdysone受体的结合位点和设计化合物似乎非常重要。一些Dibenzoylhydrazine类似物显示了蟑螂神经系统以及昆虫全身的神经活性。因此，我们必须注意他们在哺乳动物系统中的毒理学问题。