Synthesis and PKC binding of conformationally restricted indolactams by aza-Claisen rearrangement

通过氮杂克莱森重排合成构象限制的吲哚内酰胺并与 PKC 结合

• 批准号: 08660137
• 负责人: IRIE Kazuhiro
• 金额: $ 1.28万
• 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: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08660137/
• 关键词: aza-Claisen rearrangement; teleocidin; indolactam; tumor promoter; protein kinase C; conformation

Protein kinase C (PKC) is a key enzyme family involved in cellular signal transduction and tumor promotion. It consists of a catalytic domain for protein phosphorylation and a regulatory domain which binds tumor promoters like phorbol esters and teleocidins. The tumor promoter-binding site in PKC is a cysteine-rich domain (CRD) at the N-terminal regulatory region. With the discovery of eleven PKC isozymes, increasing importance is placed on isozyme specific analysis of function. Isozyme-selective activators or inhibitors represent powerful tools to analyze the role of PKC and become new medicinal leads for diseases related to PKC activation like the vascular complications by hyperglycemia.However, the development of such compounds has been hampered since pure PKC isozymes are not easily obtainable from natural sources. We have synthesized the CRD's of PKCgamma, delta, and eta consisting of ca.50 amino acids by solid phase strategy to establish the models of native PKCs. These peptides were efficiently folded upon zinc treatment to produce PKC regulatory domain surrogates that bind [^3H] phorbol 12,13-dibutyrate (PDBu) with high affinity comparable to native PKC itself, suggesting that these peptides serve as effective models for native PKCgamma, delta, and eta.Teleocidins and its core structure (-) -indolactam-V are most promising as lead compounds for isozyme selective activation or inhibition of PKC since they are chemically very stable and easily synthesized. Using the PKC surrogate peptides, we have identified two new indolactam derivatives with high PKCgamma CRD selectivity based on our strategy for the design of conformationally restricted indolactam derivatives by aza-Claisen rearrangement. Bridge formation between position 5 and 13 of (-) -indolactam-V was proved to be one of the most effective methods to fix the molecule to the active conformation and to develop new PKC activators with high isozyme selectivity.

蛋白激酶C（PKC）是参与细胞信号转导和肿瘤促进的关键酶家族。它由用于蛋白质磷酸化的催化结构域和结合凤凰酯等肿瘤启动子的调节结构域组成。 PKC中的肿瘤启动子结合位点是N末端调节区域中富含半胱氨酸的结构域（CRD）。随着11个PKC同工酶的发现，将越来越重要的重视放在同工酶特定的功能分析上。同工酶选择激活剂或抑制剂代表了分析PKC作用的强大工具，并成为与PKC激活相关的疾病（如高糖菌的血管并发症）的新药物铅。无论如何，此类化合物的发展自纯PKC同酶从自然源无法轻松获得，因此受到阻碍。我们通过固相策略合成了由CA.50氨基酸组成的PKCGAMMA，DELTA和ETA的CRD，以建立天然PKC的模型。在锌处理后将这些肽有效折叠，以产生与[^3H]佛波尔结合的PKC调节结构域的替代物12,13-二丁酸酯（PDBU），高亲和力与天然PKC本身相当，这表明这些肽是天然pkcgamma，delta，delta，eTa-eyelecids-assion-eyelecids和eRelecidins and-eyelecidins and-eyai assin-asci ins-necrind and-eypiens-and and-eypiens and-as and-asmin-assin-aScient and-assin-aScient and-necrind-ascin-） - ） - ） - ） - ）同工酶选择性激活或抑制PKC的化合物，因为它们在化学上非常稳定且易于合成。使用PKC替代肽，我们根据我们通过AZA-Claisen重排的构型限制了构型限制的indolactam衍生物的策略，确定了具有高PKCGAMMA CRD选择性的两个新的Indolactam衍生物。 （ - indolactam-v的位置5和13之间的桥梁形成被证明是将分子固定到活性构象并开发具有高同工酶选择性的新的PKC激活剂的最有效方法之一。

项目成果

Kazuhiro Irie et al.: "Comparison of chemical characteristics of the first and the second cysteine-rich domains of protein kinase Cgamma." Bioorg.Med.Chem.5(8). 1725-1737 (1997)

Kazuhiro Irie 等人：“蛋白激酶 Cgamma 的第一和第二富含半胱氨酸结构域的化学特征比较。”

Kazuhiro Irie: "Synthesis and biological activities of new conformationally restricted analogues of (-) -indolactam-V : elucidation of the biologically active conformation of the tumor-promoting teleocidins" J.Am.Chem.Soc.118・44. 10733-10743 (1996)

Kazuhiro Irie：“(-)-indolactam-V 的新构象限制类似物的合成和生物活性：促进肿瘤的 teleocidins 的生物活性构象的阐明”J.Am.Chem.Soc.118・44。 (1996)

Kazuhiro Irie: "Function and role of the two zinc-finger motifs of protein kinase C." Kagaku-to-Seibutsu. 35(7). 638-639 (1997)

Kazuhiro Irie：“蛋白激酶 C 的两个锌指基序的功能和作用。”

Kazuhiro Irie et al.: "Synthesis and biological activities new conformationally restricted analogues of (-) -indolactam -V : elucidation of the biologically active conformation of the tumor-promoting teleocidins." J.Am.Chem.Soc.118(44). 10733-10743 (1996)

Kazuhiro Irie 等人：“(-)-indolactam -V 的新构象限制类似物的合成和生物活性：阐明促进肿瘤的 teleocidins 的生物活性构象。”

Kazuhiro Irie: "Comparison of chemical characteristics of the first and the second cysteine-rich domains of protein kinase Cγ" Bioorg.Med.Chem.5・8. 1725-1737 (1997)

Kazuhiro Irie：“蛋白激酶 Cγ 的第一和第二富含半胱氨酸结构域的化学特性的比较”Bioorg.Med.Chem.5・8（1997）。