Search for New Tumor Promoters Employing Chemical Calculation

本课题旨在通过有机合成和化学计算，发现具有不同骨架结构的tpa型肿瘤启动子（phorbol酯和telocidins）的共同结构信息，发现新的生物活性化合物。众所周知，在溶液中至少存在两种构象状态，扭曲和沙发形式之间的平衡。两种构象之间的低能垒使得很难确定这些启动子与共同靶标的相互作用模式。用苯环取代了远杀细胞毒素的吲哚环，合成了苯内酰胺- v，试图重现远杀细胞毒素的活性构象。8元内酰胺（BL-V8-310）在溶液中仅以扭转形式存在，而9元内酰胺（BL-V8-310）仅以沙发形式存在。BL-V8-310活性强，而BL-V9-310活性不强，说明远杀菌素促瘤活性的活性构象接近扭曲形态。我们还设计了几种含氧类固醇，其官能团包括类似于磷酯的官能团排列。其中一种含氧类固醇被发现是胞质核肿瘤启动子结合蛋白的特异性配体。

The purpose of this research project are discovery of common structural informations of TPA-type tumor promoters having different skeletal structures (phorbol esters and teleocidins) by organic synthesis and chemical calculation, and discovery of new biologically active compounds. Teleocidins are known to exist an equilibrium between at least two conformational states in solution, the twist and sofa forms. The low energy barrier between the two conformers makes it difficult to identify the mode of interaction of these promoters with common targets. Benzolactam-Vs, in which the indole ring of teleocidins was replaced with a benzene ring, were sesigned in attempt to reproduce the active conformation of teleocidins and synthsized. The 8-membered lactam (BL-V8-310) exist only in the twist form in solution and 9-membered lactam (BL-V9-310) exist only in the sofa form. The strong activities of BL-V8-310 and the lack of activity of BL-V9-310 clearly indicated that the active conformation for tumor-promoting activity of teleocidins is close to the twist form. We also designed several oxygenated steroids in which functional groups including are arranged analogously to those of phorbol esters. One of the oxygenated steroids was found to be a specific ligand for Cytosolic Nuclear Tumor Promoter Binding Protein.