2-oxopiperazine-based γ-turn conformationally constrained peptides:: Synthesis of CCK-4 analogues
2-oxopiperazine-based γ-turn conformationally constrained peptides:: Synthesis of CCK-4 analogues
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DOI：
10.1021/jo0256336
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发表时间：
2002-05-31
影响因子：
3.6
通讯作者：
Herranz, R
中科院分区：
文献类型：
--
作者：
Herrero, S;García-López, MT;Herranz, R
2-氧代哌嗪衍生物 1 被设计为γ-转角构象受限三肽的模拟物。为制备 1 在 C-5 处的两种差向异构体而设计的合成途径涉及氰基亚甲基氨基伪肽与氨基酸衍生物的还原胺化，然后对所得 C-主链分支伪肽进行区域特异性内酰胺化。该方法的多功能性在四肽 Boc-[Nle(31)]-CCK-4 和 Boc-[Lys(o-tolylaminocarbonyl)(31)]-CCK-4 类似物的合成中得到了说明。在这些 Boc-CCK-4 类似物中引入新的构象限制导致 CCK 受体的亲和力损失 2 或 3 个数量级。这些结果表明 CCK-4 C 端三肽的生物活性构象中不存在 γ 转角。
2-Oxopiperazine derivatives 1 have been designed as mimetics of gamma-turn conformation ally constrained tripeptides. The synthetic pathway devised for the preparation of both epimers of 1 at C-5 involves a reductive amination of cyanomethyleneamino pseudopeptides with amino acid derivatives, followed by regiospecific lactamization of the resulting C-backbone branched pseudopeptides. The versatility of this methodology is illustrated in the synthesis of analogues of the tetrapeptides Boc-[Nle(31)]-CCK-4 and Boc-[Lys(o-tolylaminocarbonyl)(31)]-CCK-4. The introduction of the new conformational restriction into these Boc-CCK-4 analogues led to a loss of 2 or 3 orders of magnitude in the affinity at CCK receptors. These results suggest the absence of a gamma-turn in the bioactive conformation of the C-terminal tripeptide of CCK-4.