Synthesis and protein kinase inhibitory activity of balanol analogues with modified benzophenone subunits
Synthesis and protein kinase inhibitory activity of balanol analogues with modified benzophenone subunits
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DOI：
10.1021/jm020018f
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发表时间：
2002-06-06
影响因子：
7.3
通讯作者：
Stamper, ML
中科院分区：
文献类型：
--
作者：
Lampe, JW;Biggers, CK;Stamper, ML
描述了蛋白激酶 C (PKC) 抑制性天然产物 balanol 的一系列类似物，其带有修饰的二苯甲酮亚基。设计这些类似物的目的是揭示结构-活性特征，这些特征可用于开发与 balanol 本身相比极性特征降低的 PKC 抑制剂。这些研究的结果表明，天然产物中发现的大多数二苯甲酮特征对于获得有效的 PKC 抑制化合物非常重要。然而，我们发现一些修饰可导致相关酶蛋白激酶 A (PKA) 的选择性抑制剂，并且发现对二苯甲酮极性结构元件的一些特定修饰可提供有效的 PKC 抑制剂。特别是，人们发现用生物电子电子等排物替代二苯甲酮羧酸盐可以产生有效的类似物。此外，还发现了末端二苯甲酮环上亲脂性取代基的耐受性。这些结果是根据最近可用的 PKA 结构信息进行讨论的。
A series of analogues of the protein kinase C (PKC) inhibitory natural product balanol which bear modified benzophenone subunits are described. The analogues were designed with the goal of uncovering structure - activity features that could be used in the development of PKC inhibitors with a reduced polar character compared to balanol itself. The results of these studies suggest that most of the benzophenone features found in the natural product are important for obtaining potent PKC inhibitory compounds. However, several modifications were found to lead to selective inhibitors of the related enzyme protein kinase A (PKA), and several specific modifications to the polar structural elements of the benzophenone were found to provide potent PKC inhibitors. In particular, it was found that replacement of the benzophenone carboxylate with bioisosteric equivalents could lead to potent analogues. Further, a tolerance for lipophilic substituents on the terminal benzophenone ring was uncovered. These results are discussed in light of recently available structural information for PKA.