Toward the development of new medicinal leads with selectivity for protein kinase C isozymes
Toward the development of new medicinal leads with selectivity for protein kinase C isozymes
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DOI：
10.1002/tcr.20044
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发表时间：
2005-01-01
期刊：
影响因子：
6.6
通讯作者：
Ohigashi, H
中科院分区：
文献类型：
--
作者：
Irie, K;Nakagawa, Y;Ohigashi, H
佛波酯等肿瘤促进剂与蛋白激酶 C (PKC) 同工酶强烈结合，诱导其激活。由于每种 PKC 同工酶除了促进肿瘤外还参与多种生物事件，因此这些同工酶可作为有前景的治疗靶点。肿瘤启动子与常规（α、β I、β II 和 γ）和新型 PKC 同工酶（δ、ε、eta 和 theta）的 C1A 和/或 C1B 结构域结合。由于这些 C1 结构域在 PKC 激活及其在细胞中的易位中发挥着不同的作用，因此迫切需要开发对单个 C1 结构域具有结合选择性的药物。为此，我们建立了所有 PKC 同工酶的合成 C1 肽库。该库使我们能够确定吲哚内酰胺-V (1) 是一种有前途的先导化合物。我们对 1 的多种结构活性研究表明，吲哚环上疏水取代基的位置主导着 PKC 同工酶和 C1 结构域选择性结合，而不是九元内酰胺的构象。此外，我们认为 I 的吲哚环可能参与 CH/pi 与 PKC delta 的 C1B 结构域的 Pro-11 的相互作用。这些宝贵的信息将导致 PKC δ 配体的结构优化，例如萘内酰胺-V8 的设计和合成 (21)。 (c) 2005 年日本化学期刊论坛和 Wiley periodicals, Inc.
Tumor promoters such as phorbol esters bind strongly to protein kinase C (PKC) isozymes,to induce their activation. Since each PKC isozyme is involved in diverse biological events in addition to tumor promotion, the isozymes serve as promising therapeutic targets. Tumor promoters bind to the C1A and/or C1B domain of conventional (alpha, beta I, beta II, and gamma) and novel PKC isozymes (delta, epsilon, eta, and theta). As these C1 domains play differential roles in PKC activation and their translocation in cells, the development of agents with binding selectivity for individual C1 domains is a pressing need. For this purpose, we established a synthetic C1 peptide library of all PKC isozymes. The library enabled us to identify indolactam-V (1) as a promising lead compound. Our diverse structure-activity studies on 1 indicated that the position of the hydrophobic substituent on the indole ring dominates the PKC isozyme- and C1 domain-selective binding rather than conformation of the nine-membered lactam. Moreover, we suggested that the indole ring of I could be involved in the CH/pi interaction with Pro-11 of the C1B domain of PKC delta. This invaluable information will lead to the structural optimization of the PKC delta ligand as exemplified by the design and synthesis of naphtholactam-V8 (21). (c) 2005 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.