Search for New Tumor Promoters Employing Chemical Calculation

利用化学计算寻找新的肿瘤促进剂

• 批准号: 04671288
• 负责人: ENDO Yasuyuki
• 金额: $ 1.34万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04671288/
• 关键词: Tumor promoter; Teleocidin; Phorbol ester; Synthetic Chemistry; Conformational Analysis; Nuclear Magnetic Resonance; Molecular Design; Steroids; 発癌プロモーター; 構造活性相関; 分子設計

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.

本研究项目的目的是通过有机合成和化学计算，发现具有不同骨架结构的TPA型肿瘤促进剂（佛波醇酯和teleocidin）的共同结构信息，并发现新的生物活性化合物。已知Teleocidin在溶液中存在至少两种构象状态之间的平衡，扭曲和沙发形式。两种构象异构体之间的低能垒使得难以确定这些启动子与共同靶标的相互作用模式。本文设计并合成了苯并内酰胺-Vs，其中的吲哚环被苯环取代，以重现teleocidin的活性构象。8元内酰胺（BL-V8-310）在溶液中仅以扭曲形式存在，9元内酰胺（BL-V9-310）仅以沙发形式存在。BL-V8-310的强活性和BL-V9-310的缺乏活性清楚地表明，teleocidin的促肿瘤活性的活性构象接近于扭曲形式。我们还设计了几种含氧类固醇，其中官能团包括类似于佛波酯的官能团。其中一种含氧类固醇被发现是胞质核肿瘤促进剂结合蛋白的特异性配体。

项目成果

Y.Endo: "Synthesis of Oxygenated Cholesterols as Structural Mimics of Phorbol Ester-type Tumor Promoters." Chemical and Pharmaceutical Bulltin. 42(in press). (1994)

Y.Endo：“合成含氧胆固醇作为佛波酯型肿瘤促进剂的结构模拟物。”

Endo, Y., Ohno, M., Hirano, M., Takeda, M.Itai, A., Shudo, K.: "Chiral Requirement for the Tumor Promoters. Conformation and Activity Study of Benzolactams." BioMed.Chem.Lett.4 (in press). (1994)

Endo, Y.、Ohno, M.、Hirano, M.、Takeda, M.Itai, A.、Shudo, K.：“肿瘤促进剂的手性要求。苯佐内酰胺的构象和活性研究。”

Endo, Y., Hashimoto, Y., Fukasawa, H., Shudo, K.: "Synthesis of Oxygenated Cholesterols as Structural Mimics of Phorbol Ester-type Tumor Promoters." Chem.Pharm.Bull.42 (in press). (1994)

Endo, Y.、Hashimoto, Y.、Fukasawa, H.、Shudo, K.：“合成含氧胆固醇作为佛波酯型肿瘤促进剂的结构模拟物。”

Kawai,T: "Active Conformation of Tumor Promoter,Teleocidin.A Molecular Dynamic Study" J.Med.Chem.35. 2248-2253 (1992)

Kawai,T：“肿瘤启动子的活性构象，Teleocidin。分子动力学研究”J.Med.Chem.35。

M.Ohno: "Designed Molecules Reproducing the Two Conformations of Teleocidin" Tetrahedron Letters. 34. 8119-8122 (1993)

M.Ohno：“设计分子再现 Teleocidin 的两种构象”四面体字母。