Synthetic and structural studies on syringolin A and B reveal critical determinants of selectivity and potency of proteasome inhibition
Synthetic and structural studies on syringolin A and B reveal critical determinants of selectivity and potency of proteasome inhibition
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DOI：
10.1073/pnas.0901982106
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发表时间：
2009-04-21
影响因子：
11.1
通讯作者：
Kaiser, Markus
中科院分区：
文献类型：
--
作者：
Clerc, Jerome;Groll, Michael;Kaiser, Markus
Syrbactins是一种天然产物家族，属于阿姜黄素类或格列菌素类，是高效的蛋白酶体抑制剂。虽然它们具有相似的结构特征，但它们的大环内酰胺核心结构和环外侧链不同。这些结构变化严重影响抑制效力和蛋白酶体亚位点选择性。在这里，我们描述的总合成的姜辣素A和B，这与酶的动力学和结构的研究，使我们能够阐明潜在的蛋白酶体亚位点的选择性和结合亲和力的姜辣素的结构决定因素。这些发现被成功地用于合理的设计和合成的一个基于阿姜子素A的亲脂性衍生物，这被证明是迄今为止描述的最有效的基于阿姜子素的蛋白酶体抑制剂。胰凝乳蛋白酶活性的Ki '为8.65 +/- 1.13 nM，该姜酮苷A衍生物显示出比母体化合物姜酮苷A高100倍的效力。鉴于蛋白酶体抑制剂作为抗癌化合物的药用相关性，本研究结果可能有助于合理设计和开发基于阿曲库肽的化疗药物。
Syrbactins, a family of natural products belonging either to the syringolin or glidobactin class, are highly potent proteasome inhibitors. Although sharing similar structural features, they differ in their macrocyclic lactam core structure and exocyclic side chain. These structural variations critically influence inhibitory potency and proteasome subsite selectivity. Here, we describe the total synthesis of syringolin A and B, which together with enzyme kinetic and structural studies, allowed us to elucidate the structural determinants underlying the proteasomal subsite selectivity and binding affinity of syrbactins. These findings were used successfully in the rational design and synthesis of a syringolin A-based lipophilic derivative, which proved to be the most potent syrbactin-based proteasome inhibitor described so far. With a K-i' of 8.65 +/- 1.13 nM for the chymotryptic activity, this syringolin A derivative displays a 100-fold higher potency than the parent compound syringolin A. In light of the medicinal relevance of proteasome inhibitors as anticancer compounds, the present findings may assist in the rational design and development of syrbactin-based chemotherapeutics.