TMC-95A analogues with endocyclic biphenyl ether group as proteasome inhibitors
TMC-95A analogues with endocyclic biphenyl ether group as proteasome inhibitors
复制标题
DOI：
10.1002/cbdv.200490008
复制
发表时间：
2004-01-01
影响因子：
2.9
通讯作者：
Moroder, L
中科院分区：
文献类型：
--
作者：
Kaiser, M;Milbradt, AG;Moroder, L
TMC-95A是蒙古菌的环状三肽代谢产物，是一种强有力的蛋白酶体竞争性抑制物。基于其与酵母蛋白酶复合体的X射线结构，这一天然产物的合成挑战结构在第一代类似物中被简化，方法是用苯基-氧化吲哚取代高度氧化的侧链联芳基。在本研究中，TMC-95的联芳基被联苯醚取代，保留了显著的蛋白酶体抑制。由于新一代TMC-95类似物可方便地合成I，I+2位含异剂量酪氨酸型残基的三肽，因此有望成为进一步优化蛋白酶体抑制剂亲和力和选择性的先导结构。
TMC-95A, a cyclic tripeptide metabolite of Apiospora montagnei, is a potent competitive inhibitor of proteasome. Based on the X-ray structure of its complex with yeast proteasome, the synthetically challenging structure of this natural product was simplified in a first generation of analogues by replacing the highly oxidized side-chain biaryl system with a phenyl-oxindole group. In the present study, the TMC-95 biaryl group was substituted with a biphenyl ether with retainment of significant proteasome inhibition. Because of the facile synthetic access of tripeptides containing in i, i + 2 positions residues of the isodityrosine type, this new generation of TMC-95 analogues may represent promising lead structures for further optimization of affinity and selectivity of proteasome inhibitors.