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

化学合成了具有不同取代基的二苯甲酰肼类似物，并用二化螟的培养珠被系统测定了它们的蜕皮激素活性。用Hansch-Fujita方法定量分析了这些化合物的构效关系，结果表明分子疏水性越大，活性越强。此外，与-N(t-Bu)-结合的苯甲酰基上的供电子取代基以及拉电子的邻位取代基对活性有利。引入庞大的团队在任何位置都是不利的。虽然蜕皮酮和二苯甲酰肼分子的二维结构非常不同，但通过比较它们的X-射线结构，它们的三维结构看起来很相似。采用三维定量构效关系(QSAR)方法中的比较分子场分析(COMFA)方法，对蜕皮酮和二苯甲酰肼及其烷基和苯基类似物的构效关系进行了定量研究。CoMFA结果表明，与-NH-结合的苯甲酰基对应于蜕皮酮的烷基链，两个羰基起着20-羟基蜕皮酮的20-和22-OH氧基的作用。在CoMFA分析中获得的对活性有利和不利的静电场和立体电场的信息对于预测蜕皮激素受体的结合位置和设计化合物似乎非常重要。一些二苯甲酰肼类似物显示了对蟑螂神经系统和昆虫全身的神经活性。因此，我们必须关注它们在哺乳动物系统中的毒理物质。

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.